Académique Documents
Professionnel Documents
Culture Documents
Mutagenesis &
Carcinogenesis
Jamil Momand, Ph.D.
California State University at Los
Angeles
Maintenance of
homeostasis
Adult human maintains ~1015 cells
Stem cells undergo ~1012 divisions
per day
There is a balance between cell
birth and cell death
Random mutations disrupt
homeostasis
List of carcinogens
Chemical
Physical
Asbestos
Gamma radiation
Arsenic
UV light
Chromium
Radon
Polyaromatic
X-rays
hydocarbons
Viruses*
dichlorodiphenyltrichloroethane (DDT)
http://www.eur.nl/fgg/ch1/gen_research/dbr-man.html
http://www.hhmi.org/communic/annrep/research/regulate
Epstein-Barr virus
Human papilloma virus
Hepatitis B virus
RNA viruses
HIV-1
HTLV-1
HTLV-2
Protection
DNA Damage
Progression
Normal
Cell
Repair
Mutation
Proliferation
Initiatied
Cell
Apoptosis
Immortality
Chemotherapy
Radiation therapy
Mutator phenotype
Cancer
Cell
Angiogenesis
Mutations
Proliferation
Necrosis
Metastasis
Definitions of terms
Amplification
Immortal
Oncogene
Point mutation
Proto-oncogene
Transformation
Translocation
DNA Amplification
c-myc translocation
Oncoprotein pathways
http://www.biocarta.com/pathfiles/pdgfPathway.asp
Her2/neu/erbB-2
This gene was discovered by three
different groups. That is why it has three
different names.
Its oncogene counterpart is v-erbB-2
Dr. Slamon (UCLA) described the role of
Her2/neu in breast cancer and ovarian
cancer.
Overexpression, amplification, rare
translocations
No ligand is known
http://www.kent.k12.wa.us/staff/vhoward/apbio/oncogenes/brc-ablcartoon.gif
STI-571--an inhibitor of
BCR-ABL function
http://www.blc.arizona.edu/courses/181gh/Lectures_WJG.01/cell_signaling.01/Applications.html
http://www.blc.arizona.edu/courses/181gh/Lectures_WJG.01/cell_signaling.01/Applications.html
Point mutation
Overexpression
Transformed
Cell fusion
Normal
Normal
Genetics of
Retinoblastoma
Pedigree of Rb-prone
family
Alfred Knudson
Knudsons hypothesis
Mechanisms of tumor
suppressor gene
inactivation
Deletion
Point mutation
Mutation followed by duplication
Loss of heterozygosity
DNA methylation
Post-translational mechanismbinding to DNA viral oncoproteins
Genetic mapping of Rb
susceptibility gene
RB function
http://p53.curie.fr/p53%20site%20version%202.0/p53%20in%20cancer/p53_databaseANAL.htm
p53 structure
p53 signal
transduction pathway
[MDM2/p53] complex
(transient)
degradation
p53 Latent
p53
Stabilization
Transcription
DNA damage
Other p53 functions
1. MDM2
2. GADD45
3. WAF1/CIP1
4.
5.
synthesis
n
DNA Repair
Cell cycle
arrest
Cell Death
Functional domains of
BRCA1
Transcriptional
activation
Dimerization
Ring finger
NLS
BRCA1
Mapped to chromosome 17q by Mary Clair King in
1990
Linkage was also found in ovarian cancer families.
More than 90% of women with germline BRCA1
mutations lose the wild-type allele in breast tumor.
The gene encodes a nuclear phosphoprotein of 220
kD (1863 aas)
The mRNA is 5711 bases long
24 exons, 22 of which is coding
BRCA1 (cont. 1)
BRCA1-deficient ES cells are hypersensitive to
oxidative reagents
BRCA1-deficient ES cells are defective in
transcription-coupled repair
Expression of BRCA1 leads to p21CIP1/WAF1
upregulation and G1-S cell cycle arrest (is this
through p53?)
BRCA1del11 maintain G1-S cell cycle arrest but
not G2-M arrest.
http://www.biocarta.com/pathfiles/atmPathway.asp
Apoptosis-programmed
cell death
Future studies-profiling
cancers with DNA arrays
http://cmgm.stanford.edu/pbrown/
http://www.pnas.org/cgi/content/full/241500798
References
Bertram, J.S. (2001) The molecular biology of cancer.
Molecular Aspects of Medicine 21, 167-223.
Gelehrter et al. Principles of Medical Genetics, 2nd ed.
pp 245-272, Williams & Wilkins, Baltimore, 1998.
Levine and Lane, (2000) Surfing the p53 network.
Nature 408, 307-310
Angier, N., Natural Obsessions: Striving to Unlock the
Deepest Secrets of the Cancer Cell, Mariner
Books/Houghton Mifflin Co, 1999.
Bazell,R., Her-2: The Making of Herceptin, a
Revolutionary Treatment for Breast Cancer, Crown
Publishing Group, 1998.