Cell Cycle Regulation in Plant Development

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Annu. Rev. Genet. 2006.40:77-105. Downloaded from www.annualreviews.org

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Cell Cycle Regulation

in Plant Development1
Dirk Inze and Lieven De Veylder
Department of Plant Systems Biology, Flanders Interuniversity Institute for
Biotechnology (VIB), Ghent University, Technologiepark 927, B-9052 Gent,
Belgium; email: dirk.inze@psb.ugent.be, lieven.deveylder@psb.ugent.be
Annu. Rev. Genet. 2006. 40:77105
Key Words
First published online as a Review in

Advance on September 1, 2006
Arabidopsis, cell cycle, cyclin, cyclin-dependent kinase,

endoreduplication, plant development
The Annual Review of Genetics is online at

http://genet.annualreviews.org
This articles doi:
10.1146/annurev.genet.40.110405.090431
c 2006 by Annual Reviews.
Copyright
All rights reserved
0066-4197/06/1215-0077$20.00
1
NOMENCLATURE
By convention all names for plant genes

are in uppercase italics, proteins in
uppercase roman, and mutant genes or
alleles in lowercase italics. Much of the
work described has been generated with
Arabidopsis thaliana as experimental
system. When no species reference is
given for any gene, protein, or mutant, it
should be understood that it refers to
Arabidopsis research. In all other cases, the
species name is mentioned.
Abstract
Cell cycle regulation is of pivotal importance for plant growth and
development. Although plant cell division shares basic mechanisms
with all eukaryotes, plants have evolved novel molecules orchestrating the cell cycle. Some regulatory proteins, such as cyclins and
inhibitors of cyclin-dependent kinases, are particularly numerous in
plants, possibly reecting the remarkable ability of plants to modulate their postembryonic development. Many plant cells also can continue DNA replication in the absence of mitosis, a process known as
endoreduplication, causing polyploidy. Here, we review the molecular mechanisms that regulate cell division and endoreduplication
and we discuss our understanding, albeit very limited, on how the
cell cycle is integrated with plant development.
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UNIQUE FEATURES OF PLANT

CELL DIVISION

Contents
INTRODUCTION . . . . . . . . . . . . . . . . .
UNIQUE FEATURES OF PLANT
CELL DIVISION . . . . . . . . . . . . . . .
THE BASIC CELL CYCLE
MACHINERY . . . . . . . . . . . . . . . . . . .
Cyclin-Dependent Kinases . . . . . . . .
Cyclins . . . . . . . . . . . . . . . . . . . . . . . . . .
Proteolysis . . . . . . . . . . . . . . . . . . . . . . .
CDK Phosphorylation . . . . . . . . . . . .
CDK Inhibitors . . . . . . . . . . . . . . . . . .
The RBR/E2F/DP Pathway . . . . . .
CELLULAR VERSUS
ORGANISMAL THEORY . . . . . . .
ENDOREDUPLICATION . . . . . . . . .
CONCLUDING REMARKS . . . . . . .
78
78
79
79
81
84
85
86
87
89
90
93
INTRODUCTION
Meristem: tissue
undergoing mitosis,
giving rise to new
cells and tissues
Pluripotent:
property of
differentiated cell to
reinitiate cell
division to generate
new plant organs
SAM: shoot apical
meristem
78
The cell cycle is one of the most comprehensively studied biological processes, particularly given its importance for growth and
development and deregulation in many human disorders. No other eld has beneted
as much as the cell cycle from an extensive interplay between research performed on a diversity of model organisms. Studies on yeast,
worms, ies, frogs, mammals, and plants have
contributed to a universal picture on how the
basic cell cycle machinery is regulated, and
research on these many divergent organisms
is also elucidating how evolution modied
the basic cell cycle machinery to cope with
the specic developmental and environmental challenges of each organism. However, this
picture is mainly based on experiments performed on single cells. Indeed, the role of the
cell cycle machinery during development has
received relatively little attention. To understand how, in different organisms, the basic
cell cycle machinery integrates with development remains an important scientic challenge. With this review, we hope to convince
the reader that plants offer exceptional opportunities to contribute signicantly to such
a challenge.
Inze
De Veylder
In contrast to animals, plant development is

largely post-embryonic. New organs, such as
roots, stems, leaves, and owers, originate
from life-long iterative cell divisions followed
by cell growth and differentiation. Such cell
divisions occur at specialized zones known as
meristems. Leaves and owers are formed at
the shoot and oral meristems, respectively,
whereas the root meristems continuously add
new cells to the growing root. The cells at
the meristem are pluripotent so that their
progeny can become committed to a spectrum
of developmental fates. Initially, the shoot apical meristem (SAM) produces leaves, but under the right developmental or environmental
conditions, the SAM will be converted into a
oral meristem that produces owers.
Another interesting aspect of many differentiated plant cells is their ability to dedifferentiate and acquire pluripotentiality, a
feature that allows an even larger developmental plasticity (70, 172, 173). For example,
quiescent root pericycle cells can be stimulated to undergo cell divisions and to form
lateral roots de novo (22). On the other hand,
root cortical cells of Fabaceae can initiate cell
division to produce large nitrogen-xing nodules upon infection with symbiotic bacteria,
the Rhizobia (65). In another well-known example, protoplasts of leaf mesophyll cells can
construct a new cell wall, divide, and regenerate roots or shoots upon treatment with appropriate plant growth factors (67).
Development of plants is also unique because rigid cell walls surrounding plant cells
prevent any cell migration. Consequently, local cell-division parameters, such as the number of cells produced at the meristems and
the cell division plane, are important in determining the organization of plant tissues,
as illustrated by the scarecrow mutant, in
which the deciency of a specic asymmetric
division event in one of the descendants of
the root stem cells results in lack of a complete root cell layer (44). Furthermore, the
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rigid cell wall prevents cytokinesis by means

of constriction (as is the case for animal cells).
Therefore, plants have developed an elaborate mechanism to generate two daughter
cells that involves two unique cytoskeletal arrays, termed the preprophase band (PPB) and
the phragmoplast (4, 163, 164). Another interesting feature of plant cells is that, unlike
mammalian cells, they do not develop tumors,
except as specialized responses to certain
pathogens (48).
THE BASIC CELL CYCLE

MACHINERY
Any discussion on the role of cell division
in plant development and growth requires a
thorough understanding of the basic machinery that controls the cell cycle. As in other eukaryotic organisms, cyclin-dependent kinases
(CDKs) govern the plant cell cycle. Different CDK-cyclin complexes phosphorylate a
plethora of substrates at the key G1-to-S and
G2-to-M transition points, triggering the onset of DNA replication and mitosis, respectively. The catalytic CDK subunit is responsible for recognizing the target motif (a serine
or threonine followed by a proline) present in
substrate proteins, whereas the exchangeable
regulatory cyclins play a role in discriminating
distinct protein substrates.
Cyclin-Dependent Kinases
All eukaryotic organisms studied to date possess at least one CDK with the PSTAIRE hallmark in their cyclin-binding domain. In plants
too, a bona de PSTAIRE CDK, designated
CDKA, plays a pivotal role at both the G1-toS and G2-to-M transition points (Figures 1
and 2). The universal nature of PSTAIRE
CDKs is best illustrated by their ability to
complement functionally CDK-decient mutants of yeasts (58, 80). CDKA protein levels remain constant throughout the cell cycle
(116, 137, 168). Overproduction of a dominant negative CDKA of Arabidopsis thaliana in
tobacco (Nicotiana tabacum) plants results in an
overall reduction of the cell division rate, thus

yielding smaller plants. However, the G1/G2
ratio remains unaltered, corresponding with
the observation that CDKA activity can be
detected at both checkpoints (78, 92, 138).
Thus, CDKA is essential at both the G1-toS and G2-to-M transitions of the cell cycle.
The requirement of CDKA at least for entry
into mitosis has been demonstrated by null
mutants, whose primary defect appears to be
a failure to progress through the second mitosis during male gametophytic development
(86, 132).
No orthologs of the mammalian G1/Sspecic CDK4 and CDK6 genes are present in
plants. As such, CDKA is seemingly the only
CDK active at the G1 and S phases in plant
cells, whereas the entry into mitosis is probably controlled by multiple CDKs (Figure 2).
Plants possess a unique class of CDKs, the socalled B-type CDKs that have not been described for any other organism (16, 80, 91).
The PSTAIRE hallmark present in CDKAs is
replaced by either PPTALRE or PPTTLRE,
reecting the existence of two subgroups,
CDKB1 and CDKB2 (186). Arabidopsis harbors two CDKB1 (CDKB1;1 and CDKB1;2)
and CDKB2 (CDKB2;1 and CDKB2;2) family members. The two CDKB subgroups are
found in both monocotyledonous and dicotyledonous species, suggesting a conserved
unique role for each of the CDKB subgroups
in cell cycle regulation, but have a slightly different timing in cell cycle phasedependent
transcription. CDKB1 transcripts accumulate
during S, G2, and M phases, whereas CDKB2
expression is specic to the G2 and M phases
(18, 31, 60, 116, 123, 125, 138, 159, 168, 185).
The accumulation of CDKB proteins follows
their transcription pattern, and their associated kinase activity reaches a maximum during
mitosis. The requirement for CDKB1 activity
to progress through mitosis has been demonstrated with a dominant negative approach,
illustrating that a reduction in CDKB1 activity results in an increased 4C/2C ratio because of a block at the G2-to-M transition
(15, 138).
www.annualreviews.org Cell Cycle in Plants
Preprophase band
(PPB): cytoskeletal
array encircling the
cell plate inside the
plasma membrane at
the site where the
future cell wall will
join the parent wall
Phragmoplast:
cytokinetic organelle
consisting of parallel
aligned microtubules
and actin laments
that participate in the
building of a new cell
wall by targeting cell
wall material to the
growing cell plate
CDKs:
cyclin-dependent
kinases
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Sucrose
CYCD2/4
Cytokinin
BR
CYCD3
CDKA
CYCD
Inactive
CDK/cyclin
complex
CDKD
CDKF
T160
CYCH
P
CDKA
KRP
CYCD
Active
CDK/cyclin
complex
G1
ABA
Cold

Auxin
CDKA
Auxin
E2Fa/b
P
E2Fc
DP
Inactive
DP E2F/DP
RBR
complex
SCF
P P P
Targeted for
destruction
E2Fa/b
E2Fc
DP
RBR
Active
DP E2F/DP
RBR
complex
DEL
Expression of S phase genes
G1-S transition
S
Figure 1
Schematic representation of the regulation of the G1-to-S transition in plants. In the presence of growth
factors [such as sucrose, auxin, cytokinin, and brassinosteroids (BR)] D-type cyclins (CYCD) associate
with the A-type CDK (CDKA), forming an inactive CDKA/CYCD complex. This complex is probably
activated through phosphorylation by the CDK-activating kinase pathway, which involves CDKF and
CDKD associated with an H-type cyclin (CYCH). Full activation of the CDKA/CYCD complex
requires as well the phosphorylation of the CYCD subunit by an as-yet unknown kinase (not shown). In
response to antimitogenic stimuli, such as abscisic acid (ABA) and cold, KRPs can inhibit the activated
CDK/CYCD complexes. CDKA/CYCD complexes trigger the G1-to-S transition via two parallel
pathways. On the one hand, CDKA/CYCD phosphorylation will initiate the destruction of the
E2Fc/DP/RBR transcriptional repressor complex by the SCF E3-ubiquitin-protein ligase; on the other
hand, RBR phosphorylation will release the transcriptional activity of the E2Fa-b/DP/RBR complexes.
As a result, the expression of S-phase genes is activated. The atypical E2F-like DEL transcription factors
might ne-tune the expression of a subset of E2F target genes.
Remarkably, both Chlamydomonas reinhardtii and Ostreococcus tauri contain only one
CDKB gene that resembles the CDKB1 genes
of higher plants (11, 149). The O. tauri CDKB
contains a novel cyclin-binding motif that is
80
Inze
De Veylder
midway between the PSTAIRE CDKA and

the P[S/P]T[A/T]LRE CDKB motifs. Just as
observed for CDKBs of higher plants, the
CDKB protein levels and activity in O. tauri
appear to be regulated by the cell cycle (31).

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Surprisingly, O. tauri CDKB complements a

CDK mutant of budding yeast (Saccharomyces
cerevisiae), whereas the higher plant orthologs
are unable to do so (31, 80, 137).
Plants that overexpress a dominant negative allele of CDKB1;1 have abnormal stomata and a decreased number of stomatal complexes. This feature indicates a specic role
for CDKB1 in the series of sequential divisions required to form a stomatal complex,
as substantiated by the strong expression of
CDKB1;1 observed in all progenitor cells of
stomatal complexes (15). In addition, CDKB1
has also been demonstrated to control the onset of cell cycle exit (17) (see below).
CDK activity is regulated by phosphorylation. Phosphorylation of Thr160 (or the
equivalent residue) of CDKs induces a conformational change allowing proper recognition of substrates and is performed by
CDK-activating kinases (CAKs). Arabidopsis contains four CAK-encoding genes, divided into two functional classes (CDKD and
CDKF; Figures 1 and 2) (182, 183, 186,
207). CDKD is functionally related to vertebrate CAKs, whereas CDKF is a plantspecic CAK displaying unique enzyme characteristics. The functional diversity between
the two CAK classes is exemplied by their
substrate specicity and cyclin dependence.
Only CDKDs phosphorylate the C-terminal
domain (CTD) of the largest subunit of RNA
polymerase II. Moreover, in contrast to the
CDKDs, activation of CDKF requires no association with H-type cyclin (CYCH) (206).
Recently, CDKF has been shown to phosphorylate and activate CDKDs in Arabidopsis
(161) (Figures 1 and 2).
Through their regulation of CDK activity,
CAKs have been shown to be potentially important regulators of the cell cycle in response
to endogenous hormone gradients. Whereas
normally undifferentiated callus cells can be
induced only from leaf tissue by applying both
auxin and cytokinin, calli derived from plants
overproducing a rice (Oryza sativa) CDKD
grew independently of cytokinin. This effect
relied on the activation of CDK activity and
could even be enhanced by the co-production

of CYCH (206). Likewise, inducible downregulation of CDKF activity resulted in a
gradual reduction in CDK activity and a premature differentiation of root meristem cells
(184), whereas increased expression of the
rice CDKD;1 (also known as R2) accelerated
S-phase progression and the overall growth
rate of suspension cells (56). These data indicate that CAKs play an important role in
determining the growth rate and the differentiation status of cells by controlling the overall
level of CDK activity.
Plants also contain C-type and E-type
CDK-related genes, designated CDKC and
CDKE, with no clear role in cell cycle control. CDKCs contain PITAIRE or SPTAIRE
hallmarks, interact with CYCT, and play a
presumed role in transcription elongation
by phosphorylating the CTD of RNA polymerase II (6, 63, 94). A CDKC/CYCT complex of Medicago truncatula phosphorylates the
retinoblastoma-related (RBR) protein as well,
suggesting that, like their mammalian counterparts, plant CDKCs might control cellular differentiation through RBR inactivation
(63). In agreement with this postmitotic role
for CDKC, transcripts were found mainly in
differentiated tissues (6, 93).
CDKE contains a SPTAIRE motif and is
identical to HUA ENHANCER3 (HEN3)
(197). Phenotypic characterization of hen3
mutants demonstrated that CDKE acts in cell
expansion in leaves and cell-fate specication
in oral organs. Like CDKCs, CDKE phosphorylates CTD of RNA polymerase II, but in
contrast, is produced in dividing tissues (197).
Ostreococcus tauri:
unicellular green alga
that was discovered
in the Mediterranean
Thau lagoon
CAKs:
CDK-activating
kinases
CTD: C-terminal
domain
CYC: cyclin
RBR:
retinoblastomarelated
protein
HEN3: HUA
ENHANCER3
Cyclins
Little is known to date on the interaction
of cyclins with CDKs. This lack of information stems in part from the observation that
plants contain many more cyclins than previously described in other organisms (186).
For example, despite its small genome size,
A. thaliana has at least 32 cyclins with a putative role in cell cycle progression. The plant
81
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CYCD
CDKA
CYCA
CDKB
CYCB
E2Fa/b
DP
CDKA/B CDK/cyclin
CYC

Stress
complex
formation
WEE1
T14
Y15
P P
CDKA/B Inactive
CYC
CDK/cyclin
complex
G2
CDKD
CDKF
CYCH
T14
Y15
T160
CDKA/B Inactive
CYC
CDC25
CDK/cyclin
complex
T160
P
CDKA/B Active
CYC
CDK/cyclin
complex
Entry into mitosis
G2-M transition
T160
P
CDKA/B Active
CDK/cyclin
complex
CYC
CCS52
APC
Cyclin
degradation
Exit of mitosis
M-G1 transition
G1
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cyclin nomenclature is based on the functional

similarity with the mammalian counterparts.
Arabidopsis gene annotation identied 10 Atype, 11 B-type, 10 D-type, and 1 H-type cyclins (186, 193). In addition, at least 17 other
cyclin-related genes have been found in the
Arabidopsis genome and are classied in types
C, P, L, and T (179, 193). Although some of
these cyclin members have been found to associate with CDKs, a function in the cell cycle
has not been demonstrated for any of them.
In a broad sense, D-type cyclins are
thought to regulate the G1-to-S transition,
A-type cyclins, the S-to-M phase control,
and B-type cyclins both the G2-to-M transition and intra-M-phase control (19, 126, 140)
(Figures 1 and 2). A number of deviations
of this general functional assignment have
been reported. For Medicago sativa, CYCA2
has been shown to contribute to cell cycle
specic kinase activity, not only at the entry
to the S phase, but also during the G2-to-M
transition (151). In contrast to animals, some
preliminary evidence points to an additional
function of D-type cyclins at the G2-to-M
transition. For example, CYCD4;1 has been
found to associate and activate the G2/Mspecic CDKB2;1 in vitro (100). In addition,
ectopic expression of CYCD3;1 in trichomes
not only promotes S-phase entry but also induces mitosis (155). Likewise, induced overexpression of the tobacco CYCD3;3 and the
snapdragon (Anthirrhinum majus) CYCD1;1
in tobacco Bright Yellow-2 (BY-2) cell suspensions stimulated both S phase and mitotic
entry (101, 129). These data should, however, be interpreted with caution because a
mechanism might exist by which the activation of DNA replication stimulates mitotic
entry, as demonstrated by the observation that
transcription of the CDKB1;1 gene is at least
in part controlled by the G1/S-specic E2F
transcription factors (17, 115). In such a scenario, any positive effect on the G1-to-S transition would result in the activation of later
cell cycle phases as well. In addition, it remains possible that by ectopic expression of
the cyclin subunit, CDK/CYCD complexes
are formed that do not exist during normal
development. On the other hand, in favor of a
direct involvement of D-type cyclins in controlling the G2-to-M transition, some D-type
cyclins show a transcriptional peak at the G2to-M transition (124, 125, 166). Furthermore,
CYCD3;3-associated kinases were found to
be active at both the G1/S and G2/M boundaries (129).
D-type cyclins have a large sequence divergence and were originally identied by
functional complementation of a yeast strain
decient for G1 cyclins (34, 165). In Arabidopsis, the 10 CYCDs are classied into
seven groups, designated CYCD1 to CYCD7,
with the CYCD3 and CYCD4 groups consisting of three and two members, respectively
(186). Although the complexity of plant cyclins can be attributed partly to extensive duplications of the Arabidopsis genome (162), the
large number of cyclins might reect the high
developmental plasticity of sessile plants to
BY-2: fast-growing
tobacco cell culture,
comparable to Hela
cells for human
research
E2F: E2
promoter-binding
factor
Figure 2
Schematic representation of the regulation of the G2-to-M transition in plants. During the G2 phase of
the cell cycle, cyclins of the A, B, and probably D types (CYCA, CYCB, and CYCD) associate with both
CDKs of the A and B types (CDKA and CDKB). Some B-type CDKs are under transcriptional control
of the E2F pathway, probably providing a mechanism by which the G1-to-S and G2-to-M transitions
communicate. The CDK-activating kinase pathway, involving CDKF and CDKD associated with an
H-type cyclin (CYCH), controls the activity of the distinct CDK/CYC complexes. CDK activity can be
negatively regulated by phosphorylation by the WEE1 kinase, which is triggered upon loss of DNA
integrity. The CDC25-related kinase, if existing, which removes the inhibitory phosphate groups, still
needs to be identied. Once the CDK/CYC complexes are active, they trigger the G2-to-M transition
through the phosphorylation of a plethora of different substrates. Exit from mitosis requires the
proteolytic destruction of the cyclin subunits. This destruction is initiated by the activation of the
anaphase-promoting complex (APC) through its association with the CCS52 protein.
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respond to both intrinsic developmental signals and extrinsic environmental cues. Possibly, the complex cell cycle machinery is the
trade-off for the tremendous plasticity and robustness of plant growth, which require the
presence of exible regulatory networks. The
different cyclins might possess a wide range of
expression patterns and confer different substrate specicities.
The expression of D-type cyclin genes is
modulated by plant growth factors, such as
cytokinins, auxins, brassinosteroids, sucrose,
and gibberellins (62, 68, 81, 121, 133, 146
148, 154, 165). Some D-type cyclins probably act as key switches in triggering hormonal
effects. For example, expression of CYCD3;1
appears to be rate-limiting for cell division
in calli deprived of cytokinin. Correspondingly, overexpression of CYCD3;1 is sufcient
to compensate for the lack of cytokinins in the
culture medium (147). Similarly, CYCD2;1
seems to stimulate the progression through
G1 in roots and shoots, leading to a faster
growth rate of transgenic tobacco plants overexpressing CYCD2;1 (29). There is probably
an extensive functional redundancy among Dtype cyclins, because the genome-wide insertional mutagenesis surveys have yet to report
severe phenotypes for D-cyclin knockouts
(21, 177). To date, some specic D-type cyclin knockouts displayed only a slightly delayed cell cycle reactivation in the root meristem during seed germination, supporting the
anticipated important role for D-type cyclins
in the regulation of cell cycle entry upon
meristem activation (119). Analogously, a cycD
knockout in the moss Physcomitrella patens has
a surprisingly limited phenotype. While wildtype plants react to exogenous glucose sources
with prolonged growth of juvenile stages and
retarded differentiation, cycD knockouts exhibited developmental progression independently of the sugar supply. However, growth
rate, cell size, or plant size were not affected.
These data suggest that the Physcomitrella
CYCD is not essential for cell cycle progression but seems important for coupling the development to nutrient availability (111).

Physcomitrella
patens: moss
enabling direct
loss-of-function
studies by gene
targeting
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Just as for D-type cyclins, only marginal

phenotypes have been reported for CYCA
mutants. In tardy asynchronous meiosis (tam),
the substitution of a conserved amino acid
residue probably results in an incorrect folding of CYCA1;2, causing a slower cell cycle
progression during male meiosis (113, 198).
Knockouts for CYCA2;3 display a slight increase in their DNA ploidy level (85). In
both cases, the occurrence of only relatively
mild phenotypes can be explained by the fact
that these particular A-type cyclins are part
of a family of closely related genes; as such,
multiple knockouts will presumably have to
be combined before any severe phenotype
is revealed. It is even likely that combining multiple knockouts will result in embryo
lethality, as suggested by the observed defects on embryo formation upon antisense
expression of the tobacco CYCA3;2 cyclin
(208).
In contrast to their knockdown, overexpression of the A-type cyclin genes triggers an
acute phenotype: Arabidopsis plants that overproduce the tobacco CYCA3;2 cyclin show
ectopic cell division and delayed differentiation, correlated with an increase in expression
of S phasespecic genes and CYCA3;2associated CDK activity. In addition, overproduction of CYCA3;2 impairs shoot and root
regeneration in tissue culture (208). These
data indicate that for cell differentiation the
CDK activity must be down-regulated.
The potential of B-type cyclins to trigger the G2-to-M transition was originally
shown by microarray injection experiments
in oocytes of Xenopus laevis (77) and later by
illustrating that ectopic CYCB1;1 expression
promotes root growth (47). CYCB1;1 was
demonstrated in vitro to interact with and activate both A- and B-type CDKs (199).
Proteolysis
Proteolysis ensures that the cell cycle moves
unidirectionally by triggering the rapid proteolysis of target proteins, thus providing an
irreversible mechanism that drives the cycle

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forward. In all cases, the route to destruction

runs via the ubiquitin-proteasome system,
which uses the highly conserved polypeptide
ubiquitin as a tag to mark target proteins for
degradation by the 26S proteasome. Ubiquitination requires the generation of polyubiquitin chains on target proteins through the combined action of ubiquitin-carrying enzymes
(or E2s) and ubiquitin-protein ligases (or E3s)
that bring targets and E2s together (135).
Two related E3 complexes are most intimately
dedicated to basic cell cycle control, namely
the anaphase-promoting complex (APC)
and the Skp1/Cullin/F-box (SCF)-related
complex (192).
Plant cyclins are, as in other organisms,
subject to extensive regulation by proteolysis. A- and B-type cyclins contain destruction
box (D-box) sequences that mediate protein
degradation (69, 145). B1 cyclins, a subclass
of B-type cyclins, are the substrate for the
ubiquitin-dependent protein ligase complex
that strongly resembles APC (32). The illustration for the functional signicance of this
cyclin destruction is that constitutive overexpression of a non-degradable B1 cyclin, lacking the destruction box, causes severe growth
retardation and abnormal development with
a higher percentage of cells exhibiting duplicated ploidy levels than the controls (199).
Ectopic expression of CYCA2;3 that lacks a
functional destruction box stabilizes protein
levels in plants and results in dwarsm (85).
On the other hand, proteolysis of B2 cyclins
at prometaphase appears to be proteasome independent (200).
Recently, CYCD3;1, but not CYCD2;1,
has been shown to be a highly unstable
protein whose proteolysis is mediated by
a proteasome-dependent pathway (136). In
concert, the CYCD3;1 protein is stabilized in
mutant plants, defective in a ring-box (RBX1)
protein part of the plant SCF complexes
(108). Many D cyclins isolated to date contain
PEST sequences, regions rich in Pro, Glu,
Ser, and Thr, suggesting that they are labile
proteins degraded through a pathway similar
to that of animal D-type cyclins (133, 165).
CYCD1 instability also depends on the proteasome, whereas CDKA amounts are unaffected by the proteasome inhibitor MG132
(101). Other cell cycle regulators, such as
CDC6 (24), CDT1a (23), E2Fc (42), and
the CDK inhibitor ICK2/KRP2 (188), are
destroyed via the ubiquitin/26S proteasome
pathway as well. It is not yet known which of
the 694 F-box proteins of Arabidopsis (189) are
involved in the specic recognition of the cell
cycle regulatory proteins.
Proteins that are degraded through the
proteasome frequently require prior phosphorylation. The Arabidopsis CDT1a contains
multiple CDK phosphorylation sites, suggesting that they might affect CDT1a regulation (23). In concert, treatment of Arabidopsis seedlings with roscovitine, a well-known
CDK inhibitor, causes CDT1a to accumulate (23). Also ICK2/KRP2 proteolysis
seems to be preceded by CDK-dependent
phosphorylation (188).
The activation and substrate specicity of
the APC complex is in part determined by
two adaptor proteins, CDC20 and CDH1.
The Arabidopsis genome encodes ve CDC20
genes, as well as three CDH1-related proteins, designated CCS52A1, CCS52A2, and
CCS52B (178). In Schizosaccharomyces pombe,
expression of the three Arabidopsis CCS52
genes elicits distinct phenotypes, supporting
a nonredundant function of the CCS52 proteins. Consistent with these different functions, CCS52B is expressed from G2/M to M,
whereas CCS52A1 and CCS52A2 are from late
M until early G1, suggesting consecutive actions of these APC activators in the plant cell
cycle. In addition, the CCS52 proteins interact with different subsets of mitotic cyclins,
either in free or CDK-bound forms (64).
Proteasome:
multisubunit
complex involved in
protein breakdown
E2s:
ubiquitin-carrying
enzymes
E3s:
ubiquitin-protein
ligases
APC:
anaphase-promoting
complex
SCF:
Skp1/Cullin/F-box
protein
CDK Phosphorylation
Similarly to that in yeasts and animals, the activity of plant CDK/cyclin complexes is regulated by phosphorylation/dephosphorylation
and the interaction with regulatory proteins.
Yeast CDK/cyclin complexes are subject to an
85
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inhibitory phosphorylation of an N-terminal

Tyr residue in the CDK partner, whereas
in vertebrates CDKs are phosphorylated on
both an N-terminal Tyr and Thr residue. Tyr
phosphorylation is catalyzed by the WEE1 kinase, and both Tyr and Thr phosphorylation
is counteracted by the dual-specicity phosphatase CDC25.
Tyr phosphorylation of A-type CDK has
been detected unambiguously and shown
to down-regulate CDKA activity under cytokinin deprivation, osmotic stress, or DNA
damage (158, 210; D.I. & L.D.V., unpublished
data). The inhibitory phosphorylation sites
are also conserved in B-type CDKs, but biochemical evidence for CDKB phosphorylation is still lacking, the only known exception
being the picoeukaryote O. tauri, in which
CDKB, but not CDKA, is phosphorylated
on Tyr upon activation of the DNA integrity
checkpoint (31, 57).
Plants possess a WEE1 kinase that is putatively involved in the inhibitory phosphorylation of CDKs (167, 176, 186; D.I. & L.D.V.,
unpublished results). Overexpression of the
maize (Zea mays) or Arabidopsis WEE1 genes
in S. pombe causes cell cycle arrest (167, 176),
although its in planta inhibitory effect on the
cell cycle remains to be proven.
Recently, in the primitive unicellular algae, O. tauri, a bona de CDC25 has been
found (97) that presumably controls the activity of the B-type CDK (57). However, in Arabidopsis, rice, and Chlamydomonas, whose entire
genome sequences are available, no CDC25
gene encoding a CDK-activating phosphatase
could be identied (11, 186). Nevertheless,
biochemical and genetic evidence suggest that
higher plants also have a phosphatase that
can activate CDK/cyclin complexes; for instance, inactive CDK/cyclin complexes puried from cytokinin-starved and G2-arrested
tobacco cells can be activated in vitro by the
yeast CDC25 (210). Furthermore, overexpression of the S. pombe cdc25 gene in transgenic tobacco and Arabidopsis plants promotes
mitosis (10, 120, 134, 204, 209). In general,
overexpression of the S. pombe cdc25 mimics

CKIs:
cyclin-dependent
kinase inhibitors
86
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the developmental effect caused by cytokinins

(174), in agreement with the pivotal role of
cytokinins for the G2-to-M transition in tobacco cells (107, 210).
Recently, an Arabidopsis gene has been
identied that encodes a CDC25-like protein, capable of binding a phosphothreonine 14/phosphotyrosine 15 peptide and of
activating Arabidopsis CDK activity in vitro
(105). However, unlike the classical CDC25s,
this CDC25 lacks the important N-terminal
regulatory domain. Additionally, Arabidopsis
CDC25 cannot complement yeast cdc25 mutants and does not affect the cell cycle when
overexpressed or knocked-down in plants
(D.I. & L.D.V., unpublished data). The plant
CDC25 protein also displays similarity with
the yeast Arsenate [As(V)] reductase and, correspondingly, has recently been demonstrated
to possess reductase As(V) activity. Moreover,
its overexpression improves the tolerance of
transgenic Arabidopsis plants to mildly toxic
levels of As(V), whereas its knockout increased
As(V) sensitivity (13). As such, it is unlikely
that the Arabidopsis CDC25-like gene encodes
a true otholog of the classical CDC25, but
rather has a function totally unrelated to cell
division.
Cyclins are also subject to phosphorylation. The tobacco D cyclin CYCD3;3 is phosphorylated on Thr191, and this phosphorylation is required for nuclear localization and
maximum kinase activity (129). In vivo phosphorylation of the Arabidopsis CYCD3;1 occurs when cells are sucrose starved (136).
CDK Inhibitors
Cyclin-dependent kinase inhibitors (CKIs)
regulate cell cycle progression by binding and
inhibiting CDKs (127). Budding yeast has
three CKIs: Far1p inhibits G1 CDK activity; Sic1p controls S-phase entry by regulating G1/S CDK complexes; and Pho81p inactivates a CDK/cyclin complex that plays
a role in regulating gene expression under low-phosphate conditions. The situation
in ssion yeast (Schizosaccharomyces pombe) is

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considerably simpler because only one CKI,

designated Rum1, is known to control mitotic
CDK complexes. Mammals have seven CKIs,
which are subdivided into two very different
classes. The INK4 family proteins contain an
ankyrin repeat and selectively inhibit the G1
CDKs, CDK4 and CDK6. The Cip/Kip family of CKIs comprises p21Cip1 (also called Sdi1,
Waf1, or CAP20), p27Kip1 , and p57Kip2 , all
of which have a conserved domain at the N
terminus. The Cip/Kip CKIs inhibit a broad
range of CDK/cyclin complexes involved in
the control of both G1-to-S and G2-to-M
(131).
The rst plant CKIs have been characterized in a yeast two-hybrid screen for CDKAinteracting proteins (40, 89, 112, 194, 211).
Additional plant CKIs have been identied
in silico through genome data mining (30,
40). The specic interaction of ICK2/KRP2
with CDKA has also been conrmed in vivo
(188). Plant CKIs have a peculiar structure: They all share a C-terminally located
31-amino-acid domain. This conserved domain is involved in binding CDKs and cyclins and is essential for the inhibitory activity of the proteins (30, 40, 88, 89, 112,
157, 194, 212). Because of its similarity with
the N-terminally located CKI domain of the
mammalian Cip/Kip proteins, plant CKIs
are most commonly known as Kip-Related
Proteins or KRPs, although the two founding members are also known as Interactors
of Cdc2 Kinase or ICK (40, 112, 194). Arabidopsis encodes seven ICKs/KRPs, denominated ICK1/KRP1, ICK2/KRP2, KRP3,
KRP4, KRP5, KRP6, and KRP7. All seven
ICKs/KRPs also interact with D cyclins
(CYCD1, CYCD2, and CYCD3) (40, 112,
195, 211). Proof of in vivo binding specicity between plant ICKs/KRPs and D-type
cyclins is that the cell division inhibitory
activity caused by ICK/KRP overexpression
(see below) can be complemented by cooverexpression of D-type cyclins (89, 157,
212). Monocotyledonous ICKs/KRPs might
differ slightly in their biochemistry from their
dicotyledonous counterparts, because maize
ICKs/KRPs inhibit both A- and D-type cyclin/CDK complexes (30).

Length and primary structure of the
N-terminal part are highly variable within
ICKs/KRPs of a single plant species (40). A
functional analysis of ICK1/KRP1 indicates
that the N-terminal domain contains a sequence that decreases the protein stability in
vivo. Possibly, such a sequence could drive the
temporal selective degradation of ICK/KRP
proteins at different time points in the cell cycle (157, 195, 212). In accordance with a role
for proteolysis as an important mechanism to
control ICK/KRP activity, the ICK2/KRP2
levels have been shown to be controlled by
the proteasome (188). So far, no INK-type
inhibitors have been found in plants, in agreement with the absence of the known INK substrates (at least in mammals) being CDK4and CDK6-related CDKs.
ICKs/KRPs:
inhibitors of plant
CDKs
The RBR/E2F/DP Pathway

Despite the billion years of evolution that separate animals from plants, both types of organisms use the same Rb/E2F/dimerization
partner (DP) pathway to control the G1to-S transition. In the two cases, Rb proteins interact with the E2F/DP complex to
repress transcription of E2F-regulated genes
(50, 144, 160). Even the canonical DNA sequence (TTTCCCGC) recognized by the
E2F/DP transcription factors of animals and
plants is identical (2, 102). This identity argues
in favor of the hypothesis that the Rb/E2F/DP
pathway had already evolved in primitive organisms, before the branching between animal and plant taxa. However, whereas Arabidopsis encodes multiple CDKs, cyclins, and
KRPs, its genome contains only one Rbrelated gene (RBR). All known plant RBR proteins have, like their animal counterpart, two
blocks of conserved sequences that form the
so-called A/B pocket domain (1, 49, 72, 205),
which is the docking place for the E2F transcription factors.
In animals, Rb is phosphorylated by
CDK4/CYCD, CDK6/CYCD, CDK2/
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Megagametophyte:
the female
gametophyte, which
develops from a
megaspore
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15:33
CYCE, and CDK2/CYCA complexes at

the G1-to-S transition. A PP1 phosphatase
dephosphorylates Rb at G2/M. Much less is
known about the kinases and phosphatases
that govern the plants RBR phosphorylation
state. Plant RBR proteins interact with D
cyclins through a conserved LxCxE motif at
the N terminus of the latter (1, 34, 84, 129,
130, 165). The plant RBR-associated kinase
complex contains CDKA and a D cyclin (14,
101, 129) (Figure 1). Phosphorylation of
plant RBR proteins by CDKs depends on the
cell cycle phase (55, 129).
Arabidopsis RBR knock-outs are sterile, because they fail to arrest the mitotic divisions
in the mature female megagametophyte before fertilization, resulting in excessive nuclear divisions in the embryo sac. In addition, the central cell nucleus, which gives rise
to the endosperm after fertilization, initiates
autonomous endosperm development. These
data indicate that RBR controls the arrest
of the mature unfertilized megagametophyte
(51). Analogously, RBR regulates the differentiation of root stem cells (202).
Whereas in dicots the cell cycle and postcell cycle-related functions of RBR appear to
be performed by a single RBR gene, monocotyledonous species possess two types of
RBR genes. In maize, two RBR proteins
have a complementary accumulation pattern:
RBR3 is exclusively present during the mitotic
phase of endosperm development, whereas
RBR1 is mainly observed post-mitotically
in endoreduplicating and differentiating cells
(152). These data suggest a division of labor,
whereby RBR3 participates in cell cycle control and RBR1 in cell differentiation.
Rb proteins control the activity of the adenovirus E2 promoter-binding factor (E2F)
family of transcription factors that, in turn,
control the expression of many genes required
for entry into and execution of S phase and
cell cycle progression (3, 12, 46, 170). Arabidopsis contains six E2Fs (E2Fa, E2Fb, E2Fc,
E2Fd/DEL2, E2Fe/DEL1, and E2Ff/DEL3)
and two DPs (DPa and DPb). E2Fa and E2Fb
act as transcriptional activators as illustrated
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by their ability to induce reporter genes harboring the E2F consensus cis-activating element (102, 118, 171). Moreover, transient
overexpression of E2Fa and DPa induces quiescent mesophyll cells to re-enter S phase
(150), whereas ectopic co-expression of E2Fa
and DPa induces sustained cell proliferation in
differentiated cotyledon and hypocotyl cells
(39, 103, 150). Also co-expression of E2Fb
with DPa stimulates cell division, resulting
in shortening of the cell cycle (115). By contrast, E2Fc, which lacks a strong activation
domain, operates as a negative regulator of
the E2F-responsive genes (42, 102, 118, 150)
(Figure 1) and, consequently, its overexpression inhibits cell division (42).
In mammals, numerous E2F target genes
are well characterized. These genes encode
proteins active during DNA replication, mitosis, DNA checkpoint control, apoptosis, and
differentiation (46). By contrast, only a few
plant E2F targets have been validated experimentally, including MCM3, CDC6, CDT1a,
PCNA, RBR, and RNR (26, 27, 37, 39, 53,
54, 102, 142, 152, 171). In silico analysis of
the Arabidopsis genome for the presence of
the TTTCCCGCC canonical motif identied 183 putative E2F target genes, including genes involved in DNA replication and
cell cycle regulation (142). A more profound
analysis using microarray data and bioinformatics tools allowed the identication of 70
putative E2F target genes conserved over Arabidopsis and rice. These genes encode proteins
involved in cell cycle regulation, DNA replication, and chromatin dynamics. In addition,
several genes have been identied with potentially novel roles in the regulation of the S
phase (187).
E2Fs and DPs contain only one DNAbinding domain and, therefore, require
dimerization to interact with the canonical
E2F motif (2, 102, 114, 141). By contrast,
E2Fd/DEL2, E2Fe/DEL1, and E2Ff/DEL3
proteins are atypical E2F factors because
they contain two DNA-binding domains
that allow them to bind as a monomer
in a DP-independent manner to the E2F

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DNA-binding sequence. Additionally, these

proteins do not contain a transactivation domain and, as such, might play a role in a negative feedback loop to repress E2F-activated
promoters (118, 186) (Figure 1). The atypical E2F/DEL proteins lack an Rb-binding
motif. Only very recently have two mammalian homologs, designated E2F7 and E2F8,
been discovered (28, 36, 45, 110, 117), highlighting that cell cycle research in plants can
yield novel insights into cell cycle research in
animals.
The biphasic expression pattern of
E2Fe/DEL1 during the cell cycle, with transcripts peaking at the G1-to-S and G2-to-M
transition points, while absent during S
phase (118), suggests that E2Fe/DEL1 might
control the temporal expression of E2F
target genes. E2Ff/DEL3 overexpression in
Arabidopsis reduces the size of differentiated
cells in roots and hypocotyls, whereas cells
with reduced E2Ff/DEL3 levels are larger,
especially in the hypocotyls. These effects
of E2Ff/DEL3 are not associated with
changes in the nuclear ploidy levels or in
the expression of cell cycle genes. However,
expression of a subset of cell wall biogenesis
genes is misregulated in an E2Ff/DEL3dependent manner and, based on chromatin
immunoprecipitation experiments, these
seem to be direct E2Ff/DEL3 targets (143).
In contrast to E2Ff/DEL3, E2Fe/DEL1
plays an important role in the control of
endoreduplication (see below).
CELLULAR VERSUS
ORGANISMAL THEORY
The role of the cell cycle machinery in plant
development has been subject to debate. Obviously, cell division is essential in generating
the cells that constitute tissues and organs.
However, whether cell division is the driver
of growth and development (the cellular theory) or, alternatively, cell division merely follows a developmental plan (the organismal
theory) is more difcult to answer. Basically,
to what extent do oriented cell divisions con-
tribute to the determination of form? Experiments in the late 1950s and early 1960s suggested that cell division has little function in
growth and morphogenesis. Seedlings from
heavily -irradiated wheat (Triticum aestivum)
grains grow to some extent without negligible
cell division and resemble untreated seedlings
in many aspects of metabolism (74), growth
(73, 75), and maturation of cells present in the
embryo (59). A 10-day-old -irradiated wheat
seedling is as large as a 3-day-old unirradiated
seedling, but contains threefold and 8.5-fold
fewer, albeit much larger, epidermal and mesophyll cells, respectively (73). Habers work
provided the rst experimental evidence that
genetic information species leaf form independently of the extents and orientations of
cell divisions.
Thanks to the ability to alter cell cycle parameters in transgenic plants the longstanding
question on the importance of cell division in
determining organ size and shape has been readdressed recently. In agreement with Habers
work (59, 7375), at least for leaves, development seems to follow the concept laid down in
the organismal theory. Transgenic Arabidopsis plants constitutively overproducing any of
the ICKs/KRPs have smaller leaves that consist of tenfold fewer cells with sixfold greater
average size than control cells. The reduction in cell number is thus compensated for
by an increased cell size (40, 89, 196). Also in
rice, OsKRP1 overexpression causes a reduction in cell number that is compensated for
by an increased cell size (D.I. & L.D.V., unpublished data). Similarly, overexpression of a
dominant negative CDKA or a nondegradable
CYCB1;1 in tobacco retards the cell cycle and
causes the formation of larger cells (78, 199).
On the other hand, constitutive overexpression of positive regulators of the cell cycle,
such as E2Fa, CYCA3;2, or CYCD3;1, results
in more cells (39, 43, 208). Here, the increase
in cell number is compensated for by a decrease in cell size. All these observations support the organismal theory of plant development in which the size and shape of an organ
or organism is set to some extent by a certain
89
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endogenous mechanism independently of cell

division processes (96). The phenomenon by
which cell numbers is inversely correlated to
cell size is called compensated cell enlargement (181). Also in animals, cell division
and cell expansion can compensate each other
to achieve an optimal species-specic organ
size (35, 139). In Drosophila melanogaster, this
phenomenon is also known as the total mass
checkpoint (139).
It is not known what determines the
blueprint for leaf shape and size, but hormonal gradients probably play an important
role. However, not all experimental data t
the organismal theory. For example, overexpression of a dominant negative CDKA under the control of a seed-storage promoter
deregulates embryo development (79). Furthermore, overexpression of CYCB1;1 under
the control of the CDKA;1 promoter accelerates growth of roots, as would be expected under the cellular theory (47). Previously, we had
proposed that these two theoriesthe cellular and the organismalare too polarized (9).
Rather, cell division, cell differentiation, and
morphogenesis can be considered as integral
parts of a higher-level ontogenetic program
dened by both short-range and long-range
signaling between growth zones (9). The future challenge is to elucidate how the developmental signaling components interact with
the cell cycle machinery in animals and plants.

ANRV293-GE40-04
ENDOREDUPLICATION
The normal cell cycle mode is characterized
by a round of DNA replication (S phase) followed by mitosis and cytokinesis (M phase).
Two gap phases (G1 and G2) usually separate
the S and M phases. However, many plant cells
have a different cell cycle mode with cells undergoing iterative DNA replications without
any subsequent cytokinesis. This endoreduplication is frequently observed in some, but
not all, plants (20, 33, 38, 66, 128, 175, 180).
The level of ploidy varies between species
and tissues. In Arabidopsis, nuclei with up to
32C are detected (66), but some maize en90
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De Veylder
dosperm cells attain a DNA content as high

as 96C or 192C (104, 109). The physiological role of endoreduplication is subject to debate, and several hypotheses have been proposed. Endoreduplication probably plays an
important role in the differentiation process
of postmitotic cells because the onset of the
endocycle often characterizes the switch between cell proliferation and differentiation,
as observed during hypocotyl elongation, trichome growth, and fruit and leaf development
(7, 17, 95, 99, 106). In addition, plant species
that endoreduplicate are often characterized
by a rapid life cycle and improved yield stability, implying that endoreduplication might
support fast development (5). Endoreduplication was long believed to be essential to
support cell growth and to maintain an optimal balance between cell volume and nuclear
DNA (61, 82, 83, 122, 180). However, this
concept is currently being challenged (175).
For example, cell size and overall ploidy level
are not correlated in root cells of different
Arabidopsis ecotypes (8). Similarly, recent experiments in which the level of endoreduplication is modied do not support this hypothesis. For example, high overexpression of
ICK/KRP genes causes a remarkable overall
decrease in the ploidy level but, at the same
time, greatly increases cell size (40, 89, 211).
Also, cell size of the starchy endosperm did
not change dramatically when the endoreduplication process in the maize endosperm was
specically inhibited by overexpression of a
dominant negative allele of the CDKA gene
(109). An alternative hypothesis is that mutations, which plants accumulate during their
sessile life, are buffered by endoreduplication. Indeed, many plants are exposed during their life cycle to less favorable conditions, and the various copies, such as 8, 16,
32, 64, etc., of the genome would safeguard
that the genome retains functional copies.
Another hypothesis is that endoreduplication
is important to maintain an optimal balance
between organellar and nuclear DNA. Additionally, endoreduplication might enhance
the metabolic capacity of plant cells. This

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hypothesis is based on the high polyploidy of

the endosperm cells of cereal seeds. An increase in the gene copy numbers of metabolic
genes might allow the endosperm cells to synthesize very large amounts of storage products, such as starch and storage proteins (90,
99, 106, 180). In favor of this hypothesis,
genome amplication of maize endosperm
cells coincides with cell enlargement and the
onset of starch and protein accumulation.
However, recent experiments argue against
a role of endoreduplication in enhancing
metabolic activity, because by overexpression
of the dominant negative CDKA in the maize
endosperm, starch and protein accumulation
were only slightly reduced as a consequence
of the decrease in the endoreduplication level
(109).
How are cells triggered to undergo endoreduplication? In Arabidopsis, the exit of the
mitotic cycle correlates with the onset of endoreduplication, suggesting that this process
can be perceived as a continuum of the mitotic cell cycle in which mitosis, but not DNA
replication, is inhibited (87). In the maize endosperm, the tomato (Lycopersicon esculentum)
fruit, and the Arabidopsis leaf, the onset of endoreduplication coincides with a decrease in
M phasespecic CDK activity (7, 17, 71, 95,
106). In S. pombe and in D. melanogaster inhibition of the M phaseassociated CDK activity
is sufcient to drive cells into the endoreduplication cycle (52, 76, 153). As such, it is reasonable to believe that in plants too an active process controls the decrease in M-phase CDK
activity. Over the past few years, considerable
progress has been made in understanding the
molecular basis of endoreduplication in plants
(Figure 3). The mitotic cycle and endocycle
have DNA replication in common, and both
cell cycle modes probably make use of the
same machinery. In agreement, constitutive
overexpression of genes that stimulate DNA
replication has been shown to promote both
the mitotic cell cycle and the endocycle (23,
39, 103, 155). Thus, the difference between
the mitotic cycle and the endocycle must be
looked for in the mechanism regulating the
G2-to-M transition. The decision of a cell to

either undergo endoreduplication or continue
mitosis might depend on a cellular factor, designated Mitosis-Inducing Factor (MIF) (39), a
hypothesis based on extensive ectopic cell divisions in some tissues (such as root cap) and
extensive endoreduplication in other tissues
(such as root cortex) caused by the overexpression of both E2Fa and DPa. The ectopic cell
division phenotype has mostly been observed
in the proximity of stomata that are known to
be able to divide. Possibly, the cells in which
E2Fa-DPa overexpression triggers additional
cell division might possess a MIF that is inactive or absent in the endoreduplicating cells.
Sorting cell types in which E2Fa-DPa has different effects and comparing their transcriptome should help in unraveling the nature of
MIF. A likely candidate to be part of MIF is the
CDKB1;1 kinase whose role in the mitosisto-endocycle switch has been hinted by its
temporal expression pattern during leaf development. CDKB1;1 is highly expressed in dividing cells and is down-regulated at the onset
of endoreduplication. In concert, transgenic
plants overproducing a dominant negative
CDKB1;1 undergo increased endoreduplication. When the dominant negative CDKB1;1
is co-expressed with the heterodimeric transcription factor E2Fa-DPa, the endoreduplication phenotype is enhanced, whereas the
extra mitotic cell divisions normally induced
by ectopic E2Fa-DPa expression are repressed
(17). Thus, CDKB1;1 activity seemingly controls the balance between mitotic cell division and endoreduplication. Candidate cyclin genes that act together with CDKB1;1
are CYCA3;2, CYCA2;3, and CYCD3;1, as
they inhibit the endoreduplication process
upon their overproduction (43, 85, 208). Also
the cyclin CYCB1;2 is a possible candidate,
as illustrated by its ectopic expression that
changes the developmental fate of trichome
cells from endocycling into mitotically dividing cells (156).
Recently, the ICKs/KRPs have been
demonstrated to contribute to the control of
the mitosis-to-endocycle transition. Whereas
MIF:
mitosis-inducing
factor
91
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b
CDKA
CDKA
High CDKA
activity
CYC
CYC
Low CDKA
activity
P
WEE1
KRP
E2Fa/b
DP
CDKB

Destruction
E2Fa/b
CYCA/B
?
DEL1
P
WEE1
KRP
CDKB
DP
DEL1
CCS52
Destruction
Mitotic cell cycle
Destruction
CYCA/B
KRP
KRP
?
?
CCS52
Destruction
Endoreduplication cycle
Figure 3
Schematic overview of the mitosis-to-endocycle transition. (a) Mitotic cell cycle. (b) Endoreduplication
cycle. Colored and gray-shaded symbols correspond to active and inactive molecules, respectively.
Mitotically dividing cells are characterized by high CDKA/CYC and CDKB/CYC activities. B-type
CDKs, of which some family members are under transcriptional control of the E2F pathway, prevent the
inhibition of the CDKA/CYC complexes through phosphorylation of the CDK inhibitory ICK/KRP
proteins, triggering their destruction. Exit from the mitotic cell cycle is also negatively regulated by the
atypical E2F-like E2Fe/DEL1 transcription factor, in a manner yet to be determined, and is
accompanied with the activation of the CCS52 protein that probably targets B-type CDK-associated
cyclins for destruction. The decrease in B-type CDK activity will result in a stabilization of the
ICK/KRP proteins, which, in turn, will down-regulate the activity of the CDKA/CYC complexes. The
WEE1 kinase might also be partly responsible for the decrease in CDKA/CYC activity. The decrease in
CDKA/CYC activity results in inhibition of mitosis, but still allows DNA replication to occur with
endoreduplication as a consequence.
high ICK2/KRP2 levels repress both cell division and endoreduplication, weak overexpression inhibits the mitotic cell cyclespecic
CDKA complexes only, resulting in a premature onset of the endoreduplication program (188). A similar dose-dependent effect on the cell cycle has been observed for
ICK1/KRP1 (201). The difference in sensitivity of CDK complexes toward ICK2/KRP2
inhibition might be caused by the nature of the
cyclins in complex with CDKA at either the
G1-to-S or the G2 phases (188).
The abundance of the ICK2/KRP2 protein is developmentally regulated and controlled through CDK phosphorylation and
proteasome-dependent degradation. Its accumulation in plants overexpressing a dom92
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inant negative allele of CDKB1;1 strongly

suggests that this particular CDK targets
ICK2/KRP2 for degradation by phosphorylation. In this model, the CDKB1;1 kinase
inhibits ICK2/KRP2 activity, resulting in a
higher CDKA activity at the G2-to-M transition and consequently less endoreduplication
(188) (Figure 3).
At this stage, the possibility that the
CDKB1;1 kinase suppresses the endocycle
also via other mechanisms cannot be excluded.
In ssion yeast, the mitotic CDK complex has
been demonstrated to prevent the relicensing of replicated DNA by its association with
the replication complex during chromosome
duplication, preventing reinitiation of DNA
synthesis (203). Similarly, CDKB1;1 might

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negatively regulate pre-replication complex

assembly and thereby inuence the progression of endocycles as well as the mitosis-toendocycle progression. In concert with this
hypothesis, and despite its anticipated role
during mitosis, CDKB1;1 transcripts and associated protein activity can already be detected during S-phase progression (18, 124,
138, 168). Actually, the kinetics of CDKB1;1
transcription during S phase are identical to
those of genes that encode the pre-replication
complex itself (such as MCMs and CDC6).
The reason could be that CDKB1;1 promoter activity is controlled by E2F activity,
as shown by its up-regulation in E2Fa/DPaoverexpressing plants and mutational analysis
of the E2F-binding site in the CDKB1;1 promoter (17, 115) (Figures 2 and 3).
Another well-documented molecular
switch for the mitotic cycle to the endocycle
is the CCS52A protein. In M. sativa, expression of CCS52 correlates with the onset of
endoreduplication, and down-regulation of
CCS52A expression signicantly reduces the
ploidy level (25, 178, 190). Mitotic cyclins
are likely candidates of CCS52A-mediated
proteolysis (64, 98). We hypothesize that the
cyclin partner of CDKB1;1 is the target for
CCS52A-mediated proteolysis (Figure 3).
Mitotic CDK activity could also be negatively
regulated by WEE1, because in the maize endosperm the WEE1 transcript levels increase
when cells undergo endoreduplication (176).
Through a still unspecied molecular

mechanism, E2Fe/DP-E2F-like protein 1
(DEL1) also regulates the onset to endoreduplication (191). Loss of function of
E2Fe/DEL1 results in increased ploidy levels,
whereas ectopic expression of E2Fe/DEL1 reduces endoreduplication. The observed DNA
ploidy changes are correlated with altered expression of a subset of E2F target genes that
encode proteins necessary for DNA replication. Because E2Fe/DEL1 transcripts are detected exclusively in mitotically dividing cells,
the E2Fe/DEL1 operates as an important inhibitor of the endocycle onset by preserving
the mitotic state of proliferating cells and by
suppressing transcription of genes that are required for cells to enter the DNA endoreduplication cycle (191) (Figure 3).
CONCLUDING REMARKS
Considerable progress has been made in recent years in our knowledge of the basic
mechanisms that regulate cell division and endoreduplication in higher plants. In contrast,
very little is known on how the cell cycle machinery communicates with both intrinsic development signals and external cues. Understanding this process might help to explain
growth rates and architecture of plants. Furthermore, it might open new perspectives in
the breeding or engineering of plants with improved yield.
SUMMARY POINTS
1. The cell cycle machinery of plants is regulated by components that are conserved in
other eukaryotes as well as by molecules that are plant specic.
2. Plants contain many more cyclins than animals, possibly reecting their role in rendering plant development very plastic.
3. Plants are particularly well suited to study how the cell cycle machinery is regulated
by intrinsic developmental signals and environmental cues.
4. An increase in cell number in leaves is compensated for by a decrease in cell size and
vice versa.
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5. Endoreduplication results from a controlled down-regulation of cyclin-dependent

kinase activity at the G2-to-M transition. Various mechanisms can account for this
down-regulation.
ACKNOWLEDGMENTS

The authors thank Aurine Verkest for critical reading of the manuscript, Martine De Cock for
help preparing it, and Karel Spruyt for artwork. This work was supported by a grant from the
Interuniversity Poles of Attraction Program-Belgian Science Policy (P5/13) and the Research
Foundation-Flanders (grant no. G008306). L.D.V. is a Postdoctoral Fellow of the Research
Foundation-Flanders.
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This study reports

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CDKA deficiency is
shown to block
mitosis during male
gametogenesis,
illustrating the
need for the
universal A-type
CDKs to progress
through mitosis.
101

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This report
demonstrates that
CYCD3;1
overexpression
results in
cytokininindependent callus
growth, suggesting
that plant
hormones drive the
cell cycle though
the induction of
D-type cyclins.
102
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A study
demonstrating that
the level of CDK
activity controls
the differentiation
status of cells.
Article
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the CDK inhibitory
proteins ICK/KRP
control the onset of
endoreduplication
and providing
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phosphorylationdependent
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105
Contents
ARI
10 October 2006
14:59
Contents
Annual Review of
Genetics
Volume 40, 2006

Frontispiece
David A. Hopwood p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p xii
Soil to Genomics: The Streptomyces Chromosome
David A. Hopwood p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Discovering DNA Encodes Heredity and Prions are Infectious
Proteins
Stanley B. Prusiner and Maclyn McCarty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p24
Origin and Evolution of Spliceosomal Introns
Francisco Rodrguez-Trelles, Rosa Tarro, and Francisco J. Ayala p p p p p p p p p p p p p p p p p p p p p p p p p p47
Cell Cycle Regulation in Plant Development
Dirk Inze and Lieven De Veylder p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p77
Chromatin Insulators
Lourdes Valenzuela and Rohinton Kamakaka p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 107
Intersection of Signal Transduction Pathways and Development
Pavithra Vivekanand and Ilaria Rebay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 139
Mitochondrial Retrograde Signaling
Zhengchang Liu and Ronald A. Butow p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 159
Cellular Responses to DNA Damage: One Signal, Multiple Choices
Tin Tin Su p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 187
Surviving the Breakup: The DNA Damage Checkpoint
Jacob C. Harrison and James E. Haber p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 209
The Role of the Nonhomologous End-Joining DNA Double-Strand
Break Repair Pathway in Telomere Biology
Karel Riha, Michelle L. Heacock, and Dorothy E. Shippen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 237
DNA Helicases Required for Homologous Recombination and Repair
of Damaged Replication Forks
Leonard Wu and Ian D. Hickson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279
Bacterial Contingency Loci: The Role of Simple Sequence DNA
Repeats in Bacterial Adaptation
Richard Moxon, Chris Bayliss, and Derek Hood p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 307
v
Contents
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14:59
Regulation of Imaginal Disc Growth by Tumor-Suppressor Genes in

Drosophila
Iswar K. Hariharan and David Bilder p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 335
DNA Double-Strand Break Repair: Alls Well That Ends Well
Claire Wyman and Roland Kanaar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 363
Mechanisms of Cyclic-di-GMP Signaling in Bacteria
Urs Jenal and Jacob Malone p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 385
Interplay of Circadian Clocks and Metabolic Rhythms
Herman Wijnen and Michael W. Young p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 409
Genetic Analysis of Brain Circuits Underlying Pheromone Signaling

C. Dulac and S. Wagner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 449
Aspects of Genetic Susceptibility to Human Infectious Diseases
Adrian V. S. Hill p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 469
Genetics of Egg-Laying in Worms
William F. Schafer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 487
ERRATA
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ANRV293-GE40-04

Annu. Rev. Genet. 2006.40:77-105. Downloaded from www.annualreviews.org