Pten Regulatory Functions in Tumor Suppression and Cell Bio

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Received: 2004.08.18 Accepted: 2004.08.19 Published: 2004.10.01
PTEN regulatory functions in tumor suppression and cell biology

Eric C. Chu, Andrzej S. Tarnawski
Department of Medicine, Division of Gastroenterology, VA Long Beach Healthcare System and University of California, Irvine
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Summary
PTEN tumor suppressor review http://www.MedSciMonit.com/pub/vol_10/no_10/6275.pdf 2624 2 101
Source of support: VA Merit Review and REAP to AST.
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PTEN is a dual-specicity phosphatase with both protein phosphatase and lipid phosphatase activity. PTEN is the rst phosphatase identied as a tumor suppressor. Not since the discovery of p53 has a tumor suppressor generated such interest. Initial studies performed on cancer cell lines suggested that PTEN may be responsible for almost all types of cancer, both solid tumors and hematological malignancies. Biallelic deletion of PTEN has been associated with advanced stage tumors or metastatic disease. PTEN has been shown to play a pivotal role in apoptosis, cell cycle arrest, and possibly cell migration. Emerging data suggest that this may be an oversimplication of PTENs role, and that PTEN may be haploinsufcient for tumor progression and may play important roles in other cellular functions such as angiogenesis and MAP kinase signaling.
Andrzej Tarnawski, Chief, Division of Gastroenterology, University of California, Irvine, Chief, Section of Gastroenterology, VA Medical Center, Long Beach, CA, 5901 East Seventh Street, 111-G, Long Beach, CA 90822, U.S.A., e-mail: atarnawski@yahoo.com
Indexed in: Current Contents/Clinical Medicine SCI Expanded ISI Alerting System Index Medicus/MEDLINE EMBASE/Excerpta Medica Chemical Abstracts Index Copernicus
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BACKGROUND
Phosphatase motif PDZ domain
ROLE OF PTEN AS TUMOR SUPPRESSOR

PTEN is one of the most common targets for mutation in sporadic human cancers, with a mutational frequency rivaling that of p53. PTEN mutations can be detected in at least 20% of primary glioblastomas, particularly those that were high-grade [1115]. PTEN is the most frequently mutated gene in prostate cancer. Loss of heterozygosity (LOH) at 10q23 can be detected in approximately 50% of human prostate cancers, whereas homozygous deletions of PTEN can be detected in approximately 10% of these cases [16 20]. PTEN is also the most frequently mutated gene in endometrial cancer, particularly the endometrioid type. The reported mutational inactivation of PTEN ranges from 33 83% in both low-grade as well as high-grade endometrioid endometrial cancers and 2055% in endometrial hyperplasia, suggesting that PTEN is involved in the initial stages of tumor development [2124]. Mutations of PTEN are seen in approximately 10% of primary melanomas [25 27]. Occasionally, PTEN mutations have been reported in sporadic breast cancer (5%), thyroid cancer (7%), head and neck cancer (12%), renal cell carcinoma (6%), lung
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Structurally, the PTEN protein is comprised of three parts: 1) an N-terminal phosphatase catalytic domain, 2) a C-terminal C2 domain, and 3) a 50 amino acid C-terminal tail that contains a PDZ binding motif and CK2 (formerly casein kinase II) phosphorylation sites (Figure 1). The C2 domain binds phospholipids in vitro and is believed to mediate binding of PTEN to cell membrane [6,7]. The PDZ motif permits PTEN to interact with the second PDZ domain of scaffolding proteins such as S-SCAM/MAGI-2 and MAGI-3. The interaction of the PTEN/MAGI complex has been shown to enhance the inhibitory effect of PTEN signaling [8,9]. The crystal structure of PTEN shows that its catalytic pocket is broader and deeper than most dual-specicity phosphatases, which accounts for the unique substrates of PTEN [10].
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PTEN (phosphatase and tensin homologue deleted on chromosome ten), also referred to as MMAC1 (mutated in multiple advanced cancers), is a dual-specicity phosphatase rst identied as a candidate tumor suppressor gene located at 10q23 by two separate groups of investigators in 1997 [1,2]. That same year, another group identied the same gene while searching for new dual-specicity phosphatases and named it TEP-1 (TGF-b-regulated and epithelial cellenriched phosphatase) [3]. The PTEN gene encodes for a 403-residue protein with a predicted molecular mass of approximately 47 kDa [1,3]. The cDNA sequence of PTEN suggests that it is a dual-specicity phosphatase within the protein-tyrosine phosphatase superfamily. PTEN also contains a sequence within its catalytic domain with extensive homology to cytoskeletal proteins tensin and auxilin, leading to speculation that PTEN may regulate tumor invasion and metastasis [1]. However, the biological signicance of this homology to tensin remains unclear, as many other protein-tyrosine phosphatases also contain a similar sequence in their catalytic domains [4]. This may simply represent convergent evolution of tensin-like proteins and protein-tyrosine phosphatases as opposed to the implication that PTEN has a specic role in cytoskeletal regulation [5].
1 Phosphatase domain C2 domain
403 Tail
N-terminal region
C-terminal region
Figure 1. Diagrammatic representation of PTEN protein structure. PTEN contains a phosphatase domain (residues 1185) in the N-terminal region with the phosphatase motif (HCSSGSSR, residues 123130) implicated in its tumor suppressor activity. The C2 domain (residues 186351) allows for the binding of PTEN to phospholipids, possibly for eective positioning of PTEN at the membrane. Proline-, glutamate-, serine-, and threonine-rich (PEST) sequences (degradation motif) are located in the tail, between residues 350375 and 379396 (indicated by hatched stripes). The tail region also contains protein kinase CK2 phosphorylation sites important for the stability and activity of PTEN. Also within the tail region is a PDZ domain, which allows PTEN to bind membrane-associated guanylate kinase inverted (MAGI) proteins, which enhance eciency of PTEN signaling. PDZ derives from three proteins that contain repeats of this domain: 1) mammalian postsynaptic density protein, PSD-95, 2) Drosophila disc large tumor suppressor, Dlg, and 3) mammalian tight junction protein, Zo-1.
cancer (9%), lymphoma (5%), hepatocellular carcinoma (6%), and ovarian cancer (9%) [25,2849]. Germline PTEN mutations result in autosomal dominant harmatoma tumor syndromes. Approximately 80% of patients with Cowden syndrome and 60% of patients with BannayanRiley-Ruvalcaba syndrome harbor germline PTEN mutations [50]. Cowden syndrome is characterized by multiple harmatomas occurring in the skin, breast, thyroid, endometrium, gastrointestinal tract, and brain. These patients have an increased risk of malignancies, particularly of the breast, thyroid, and endometrium. Macrocephaly, subcutaneous lipomas, vascular malformations, intestinal harmatomatous polyps, and penile lentigines characterize Bannayan-RileyRuvalcaba syndrome. Additionally, up to 20% of Proteus syndrome and approximately 50% of Proteus-like syndrome contain germline PTEN mutations [51]. Proteus syndrome is characterized by a mosaic distribution of harmatomas in multiple tissues, connective tissue nevi, epidermal nevi, hyperostoses, and asymmetric hypertrophy of organ, body, or bones. Proteus-like syndrome is still ill dened, but minimal criteria have included lipomas, any single harmatoma, overgrowth, and failure to meet diagnostic criteria of the other harmatoma tumor syndromes. Dual-specicity phosphatases are capable of efcient hydrolysis of phosphotyrosine and phosphoserine/threonine. Unexpectedly, PTEN displayed low activity towards the classic substrates of dual-specicity phosphatases despite its homology to other phosphatases [52]. Further investigation revealed that phosphatidylinositol 3,4,5-triphosphate (PIP3), rather than phosphoproteins, is the main biologically rele-
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Chu EC et al. PTEN regulatory functions in tumor suppression and cell biology
PtdIns-4,5-P2
PtdIns-3,4,5-P3 (PIP3)
PtdIns-4,5-P2
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P P BAD Casp 9 Apoptosis
Receptor Tyr Kinase
SH2
PI3K
PTEN
P Akt
PDK1
p53
Cell-cycle arrest Apoptosis DNA repair
vant substrate of PTEN [53]. Indeed, mutant Pten/ cells have elevated levels of PIP3 [54,55]. Phosphoinositides (PtdIns) are rare lipids, yet they play an important role as second messengers in signal transduction pathways regulating cell growth, apoptosis, differentiation, metabolism, migration, and membrane trafcking. PtdIns are phosphorylated to PIP3 and diacylglycerol by PI3K (phosphatidylinositol 3kinase). PIP3 is absent or undetectable in quiescent cells, but rapidly increases in response to growth factors or extracellular matrix-dependent signaling, which recruit PI3K. PIP3 is the major activator of the cell survival kinase Akt. PTEN negatively regulates the AKT/PI3K pathway, one of the most important pathways for cell growth, proliferation, and survival (Figure 2). PTEN indirectly inactivates Akt kinase, the downstream effector of PI3K by dephosphorylation of PIP3 at the D3 position. By keeping levels of PIP3 low by dephosphorylation at the D3 position, PTEN prevents activation of phosphoinositide-dependent kinase-1 (PDK-1), thereby preventing phosphorylation and thus activation of AKT [56]. The biological consequences of AKT inhibition
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Figure 2. The AKT/PI3K pathway. Growth and survival factors stimulate receptor tyrosine kinases to recruit receptor-PI3K complexes to the plasma membrane where PI3K generates PIP3 as a second messenger. PIP3 recruits Akt and PDK1 to the membrane where PDK1 phosphorylates Akt at Thr-308. Phosphorylation of Akt at Ser-473 by yet molecularly unidentied kinase, often termed PDK2, causes further activation. Through phosphorylation, activated AKT mediates the activation and inhibition of a variety targets that ultimately result in cell growth, proliferation, and survival. Akt phosphorylates and inactivates several components of the cell-death machinery: Bad, caspase 9, and Forkhead transcription factors. Akt phosphorylates and activates IKK, which degrades Ikb, thereby releasing NF-kb. Phosphorylation of GSK3b blocks its kinase activity, thereby saving cyclin D1 from degradation and allowing it to accumulate. Both Akt and PTEN can negatively regulate the CDK inhibitor, p27 (not shown). Phosphorylated MDM2 translocates to the nucleus where it can bind p53, resulting in enhanced p53 proteolysis. PTEN turns o the AKT/PI3K pathway.
include stimulation of apoptosis and inhibition of cell cycle entry by halting G1 to S phase progression. Activated (phosphorylated) AKT is a well-known survival factor. Activated AKT phosphorylates, thereby inactivating, the Forkhead transcription factors, which induce expression of apoptotic genes, and the pro-apoptotic proteins Bad and caspase 9 [57]. Akt also prevents release of cytochrome c from mitochondria and blocks Fas-dependent apoptosis through still unknown pathways [58]. Indirectly, AKT inuences cell survival by its effects on NF-kb and p53. AKT can release NF-kb by phosphorylation and activation of Ikb kinase (IKK), with resulting degradation of the NF-kb inhibitor [59]. AKT is capable of phosphorylating MDM2, a p53-binding protein that targets p53 for degradation by the proteasome. Phosphorylated MDM2 translocates more efciently to the nucleus where it binds to p53, promoting in enhanced degradation of p53 [60]. In addition to promoting survival, AKT phosphorylates and inactivates GSK3b (glycogen synthase kinase-3b), resulting in stabilization of
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P MDM2 P P P P mTOR IKK GSK3 FKHR NF- Growth Translation Cell Cycle
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Gene transfer and knockout studies have established the role of PTEN as a tumor suppressor. Restoration of PTEN expression in PTEN-decient mutant glioblastoma multiforme cell lines cause growth suppression; increasing PTEN expression in those glioblastoma multiforme lines that retain normal PTEN expression does not suppress growth [64]. Reconstitution of PTEN into PTEN- prostate, melanoma, or breast cancer cell lines inhibits their growth [6567]. Homozygous Pten gene inactivation results in early embryonic lethality in mice, suggesting that PTEN is crucial for embryonic development. Heterozygous Pten+/ mice develop gonadostromal, germ-line, and hematopoietic tumors, and cancers of the endometrium, thyroid, prostate, breast, liver, and intestine [6871].
PTEN HAPLOINSUFFICIENCY
Most studies to date that examined human tumors for PTEN mutations rst prescreened samples for loss of heterozygosity (LOH) at 10q23, and then analyzed for mutations in the remaining allele. The results indicate that the rate of LOH at 10q23 greatly exceeds the apparent rate of inactivation of the remaining PTEN allele. With the exception of endometrial carcinoma, biallelic inactivation of PTEN appears to occur in advanced cancers or metastasis. In light of these ndings and since complete loss of PTEN is extremely common in tumor cell lines, loss of PTEN has been regarded as a late event in the neoplastic process. However, recent studies have suggested that inactivation of just only one PTEN allele may have important biological consequences on cell proliferation and survival. Haploinsufciency is a condition that arises when normal phenotype requires protein product of both alleles, and reduction of 50% of gene function due to loss of one allele results in abnormal phenotype. In murine models, PTEN haploinsufciency accelerated the progression of prostate cancer [72]. In a hypomorphic Pten mouse mutant series with decreasing Pten activity, the extent of Pten inactivation correlates in a dose-dependent fashion prostate caner progression [73]. Hence, haploinsufciency of PTEN may be sufcient to promote tumorigenesis.
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OTHER ROLES OF PTEN REGULATION OF PTEN

Accumulated evidence suggests that the tumor suppressive effect of PTEN is mediated largely by its lipid phosphatase activity. Transfection of wild-type PTEN causes growth arUnlike many signaling proteins, which require phosphorylation for activation, phosphorylation of PTEN at its C-termi-
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cyclin D1 and down-regulation of p27, a negative regulator of cyclin dependent kinases (CDKs), thus resulting in cell cycle progression and cellular proliferation [61]. Indeed, PTEN has been demonstrated to coordinate G1 arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity [62]. The mammalian target of rapamycin, mTOR, has been shown to be a direct target of AKT. mTOR enhances biogenesis by activating p70 S6 kinase (RSK), which enhances translation of mRNA that have 5 polypyrimidine tracts, and by inhibiting 4E-BP1, a translational repressor of mRNAs that have a 5 CAP structure. However, it is still unclear if phosphorylation of mTOR by AKT is a mechanism for activation [63]. Loss of PTEN function results in Akt hyperactivation due to increased concentrations of PIP3, and thus, protection from various apoptotic stimuli, creating an environment conducive to tumorigenesis.
rest in many cancer cell lines, but Cowden syndrome-type PTEN mutations that retain protein phosphatase activity but lack lipid phosphatase activity were unable to suppress the growth of glioma cell lines [74,75]. Although the negative regulatory role of PTEN in the AKT/PI3K pathway is well established, PTEN may inuence other cellular functions. Recently, PTEN has been found to inactivate plateletderived growth factor receptor upstream of the AKT/PI3K pathway [76]. PTEN has been shown to associate with and to dephosphorylate focal adhesion kinase (FAK), and thus, proposed to regulate focal adhesion structure, cell migration, and cell invasion by controlling FAK activity [77,78]. However, extremely high stoichiometric amounts of PTEN were required in these experiments to dephosphorylate FAK. Moreover, a Cowden syndrome (lipid phosphatase-inactive) derived cell line (G129E) was able to dephosphorylate FAK, implying that this function depends on the tyrosine phosphatase activity of PTEN and that FAK may not be a major biologically relevant target of PTEN [5]. Others have not been able to replicate the interaction between PTEN and FAK or the dephosphorylation of FAK [79]. PTEN has also been proposed to modulate the mitogen-activated kinase (MAPK) pathway in several ways. PTEN has been shown to dephosphorylate adaptor protein Shc, resulting in down-regulation of Grb2 and ultimately, MAPK [80]. Independent of Shc, PTEN may decrease activation of MAPK by preventing the translocation of Gab1 to the membrane by dephosphorylating PIP3 [81]. Gab1 contains a pleckstrin-homology domain, which interacts with PIP3-rich membranes [82]. In addition, PTEN has been shown to negatively regulate insulin stimulation of MAPK by dephosphorylating insulin-receptor substrate-1 (IRS-1). This prevents the assembly of the IRS1/Grb2/Sos complex, a requisite complex for MAPK activation [83]. PTEN may be involved in angiogenesis. Studies have shown that PTEN down-regulates both hypoxia-inducible factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF) in tumor cells, thereby inhibiting angiogenesis [84,85]. In an ex vivo rat aortic ring model of angiogenesis, PTEN inhibited vascular sprouting [86]. PTEN decreased vascularity of human glioma xenografts in both an orthotopic and an ectopic model [87]. Cellular senescence, the loss of proliferative potential as a result of accumulated cell doublings, is integral to lifespan and longevity. The AKT/PI3K pathway is evolutionarily conserved in the nematode C. elegans, and an insulin-like pathway modulates its metabolism similar to control of mammalian glucose homeostasis by insulin. Mutations in the C. elegans insulin/IGF-I receptor-like gene (daf-2) or PI3K catalytic subunit homolog (age-1) can nearly double the lifespan of mutant animals, and mutations in the PTEN homolog (daf-18) can suppress this increased longevity [88]. In human broblast cells, inhibition of PI3K accelerates the onset of senescence and the CDK inhibitor p27 accumulates in senescent murine and human broblasts [89]. PTEN plays a key role in inhibiting PI3K and increasing levels of p27 to inhibit the cell cycle. Although clearly an area of future research, the tantalizing prospect exists that PTEN and the AKT/PI3K pathway may be intimately involved in the aging process itself.
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PTEN appears to be constitutively active. Factors that up-regulate transcription are beginning to be identied. Activation of peroxisome proliferator-activated receptor gamma (PPARg) by rosiglitazone has been shown to up-regulate PTEN, with a corresponding decrease in PI3K activity as measured by decreased phosphorylation of Akt [94]. The PTEN locus has a p53 binding element upstream of the PTEN gene, which is necessary for the inducible transactivation of PTEN by p53 [95]. Early growth response-1 (Egr-1) transcription factor has also been shown to up-regulate PTEN transcription [96]. Insulin-like growth factor 2 (IGF-II) induced PTEN transcription and increased protein levels via Egr-1 [97]. Recently, NSAIDs, both non-selective and selective COX-2 inhibitors, have been shown to induce PTEN gene expression as well as active (unphosphorylated) PTEN protein [98]. This may explain the inhibitory action of NSAIDs on angiogenesis as well as on cancer cell growth. PTEN expression is variable in human endometrium throughout the menstrual cycle, with estradiol down-regulating PTEN activity by phosphorylation and progesterone increasing protein levels by decreasing phosphorylation [99]. Less is known about factors that down-regulate PTEN, but transforming growth factor beta (TGF-b), NF-kb, and tumor necrosis factor-alpha (TNF-a) have been reported to suppress PTEN expression [3,100,101].
CONCLUSIONS
Numerous studies have established the role of PTEN as a tumor suppressor, the rst phosphatase to be identied as a tumor suppressor. Germline mutations of PTEN are associated with autosomal dominant hamartomatous and often, cancerprone syndromes. PTEN has been found to be homozygously inactivated in a wide spectrum of sporadic human cancers. The lipid phosphatase activity of PTEN mediates its tumor suppressor effect by negatively regulating the AKT/PI3K pathway. Specically, PTEN indirectly inactivates Akt kinase, the downstream effector of PI3K, by dephosphorylating phosphatidylinositols in the D3 position. Growing evidence suggests that one copy of PTEN may be haploinsufcient, that the protein phosphatase activity plays a physiological role, and that PTEN is intimately involved in other essential cellular processes such as angiogenesis and MAP kinase signaling. PTEN is crucial for developmental processes and may very well be involved in aging and senescence. Elucidating novel substrates of PTEN and the regulators that control PTEN expression will have important clinical implications.
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nal tail inhibits its activity [90]. Phosphorylated PTEN exists in a monomeric closed conformation, which masks the PDZ binding domain, with reduced ability to bind to other PDZ domain-containing proteins. Unphosphorylated PTEN exists as an open conguration and participates in formation of a high molecular weight complex (PTEN-associated complex) via interactions with PDZ-containing proteins such as MAGI-2 [91]. The protein kinase CK2 has been shown to phosphorylate Pten on serine residues 370, 380, and 385, and on threonine residue 383 [92]. This phosphorylation maintains PTEN protein stability by protecting PTEN from caspase-3 cleavage and proteasome-mediated degradation [93]. Unphosphorylated PTEN is less stable but more active; this loss of protein stability is offset by a gain of PTEN activity [89]. This suggests that the corresponding protein instability following protein activation provides a mechanism for rapid protein degradation and termination of PTEN signaling.
REFERENCES:
1. Li J, Yen C, Liaw D, Podsypanina K et al: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 1997; 275: 194347 2. Steck PA, Pershouse MA, Jasser SA et al: Identication of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet, 1997; 15: 35662 3. Li DM, Sun H: TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res, 1997; 57: 212429
5. Cantley LC, Neel BG: New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA, 1999; 96: 424045 6. Lee JO, Yang H, Georgescu MM et al: Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell, 1999; 99: 32334 7. Tsugawa K, Jones MK, Sugimachi K et al: Biological role of phosphatase PTEN in cancer and tissue injury healing. Front Biosci, 2002; 7: e24551
SE
4. Haynie DT, Ponting CP: The N-terminal domains of tensin and auxilin are phosphatase homologues. Protein Sci, 1996; 5: 264346
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8. Wu X, Hepner K, Castelino-Prabhu S et al: Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multiPDZ domain containing scaffold protein MAGI-2. Proc Natl Acad Sci USA, 2000; 97: 423338 9. Wu Y, Dowbenko D, Spencer S et al: Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase. J Biol Chem, 2000; 275: 2147785
10. Lee JO, Yang H, Georgescu MM et al: Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell, 1999; 99: 32334
11. Wang SI, Puc J, Li J et al: Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res, 1997; 57: 418386 12. Rasheed BK, Stenzel TT, McLendon RE et al: PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res, 1997; 57: 418790 13. Liu W, James CD, Frederick L et al: PTEN/MMAC1 mutations and EGFR amplication in glioblastomas. Cancer Res, 1997; 57: 525457
14. Bostrom J, Cobbers JM, Wolter M et al: Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res, 1998; 58: 2933
15. Duerr EM, Rollbrocker B, Hayashi Y et al: PTEN mutations in gliomas and glioneuronal tumors. Oncogene, 1998; 16: 225964 16. Cairns P, Okami K, Halachmi S et al: Frequent inactivation of PTEN/ MMAC1 in primary prostate cancer. Cancer Res, 1997; 57: 49975000
17. Wang SI, Parsons R, Ittmann M: Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. Clin Cancer Res, 1998; 4: 81115 18. Feilotter HE, Nagai MA, Boag AH et al: Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene, 1998; 16: 174348 19. Pesche S, Latil A, Muzeau F et al: PTEN/MMAC1/TEP1 involvement in primary prostate cancers. Oncogene, 1998; 16: 287983 20. Ali IU, Schriml LM, Dean M: Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst, 1999; 91: 192232 21. Tashiro H, Blazes MS, Wu R et al: Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res, 1997; 57: 393540 22. Kong D, Suzuki A, Zou TT et al: PTEN1 is frequently mutated in primary endometrial carcinomas. Nat Genet, 1997; 17: 14344 23. Risinger JI, Hayes AK, Berchuck A, Barrett JC: PTEN/MMAC1 mutations in endometrial cancers. Cancer Res, 1997; 57: 473638 24. Mutter GL, Lin MC, Fitzgerald JT et al: Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst, 2000; 92: 92430 25. Teng DH, Hu R, Lin H et al: MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res, 1997; 57: 522125 26. Reifenberger J, Wolter M, Bostrom J et al: Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas. Virchows Arch, 2000; 436: 48793
RA239
Review Article
27. Pollock PM, Walker GJ, Glendening JM et al: PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines. Melanoma Res, 2002; 12: 56575 28. Rhei E, Kang L, Bogomolniy F et al: Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res, 1997; 57: 365759 29. Chen ST, Yu SY, Tsai M et al: Mutation analysis of the putative tumor suppression gene PTEN/MMAC1 in sporadic breast cancer. Breast Cancer Res Treat, 1999; 55: 8589 30. Ueda K, Nishijima M, Inui H et al: Infrequent mutations in the PTEN/ MMAC1 gene among primary breast cancers. Jpn J Cancer Res, 1998; 89: 1721 31. Dahia PL, Marsh DJ, Zheng Z et al: Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res, 1997; 57: 471013 32. Halachmi N, Halachmi S, Evron E et al: Somatic mutations of the PTEN tumor suppressor gene in sporadic follicular thyroid tumors. Genes Chromosomes Cancer, 1998; 23: 23943 33. Hsieh MC, Lin SF, Shin SJ et al: Mutation analysis of PTEN/MMAC 1 in sporadic thyroid tumors. Kaohsiung J Med Sci, 2000; 16: 912 34. Frisk T, Foukakis T, Dwight T et al: Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer. Genes Chromosomes Cancer, 2002; 35: 7480 35. Okami K, Wu L, Riggins G et al: Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors. Cancer Res, 1998; 58: 50911
Med Sci Monit, 2004; 10(10): RA235-241

54. Stambolic V, Suzuki A, de la Pompa JL et al: Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 1998; 95: 2939 55. Sun H, Lesche R, Li DM et al: PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci USA, 1999; 96: 6199204 56. Wu X, Senechal K, Neshat MS et al: The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA, 1998; 95: 1558791 57. Datta SR, Brunet A, Greenberg ME: Cellular survival: a play in three Akts. Genes Dev, 1999; 13: 290527
59. Romashkova JA, Makarov SS: NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature, 1999; 401: 8690 60. Mayo LD, Donner DB: A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA, 2001; 98: 11598603 61. Cross DA, Alessi DR, Cohen P et al: Inhibition of glycogen synthase kinase3 by insulin mediated by protein kinase B. Nature, 1995; 378: 78589
36. Shao X, Tandon R, Samara G et al: Mutational analysis of the PTEN gene in head and neck squamous cell carcinoma. Int J Cancer, 1998; 77: 68488
37. Alimov A, Li C, Gizatullin R et al: Somatic mutation and homozygous deletion of PTEN/MMAC1 gene of 10q23 in renal cell carcinoma. Anticancer Res, 1999; 19: 384146
38. Kohno T, Takahashi M, Manda R, Yokota J: Inactivation of the PTEN/ MMAC1/TEP1 gene in human lung cancers. Genes Chromosomes Cancer, 1998; 22: 15256
39. Petersen S, Rudolf J, Bockmuhl U et al: Distinct regions of allelic imbalance on chromosome 10q22-q26 in squamous cell carcinomas of the lung. Oncogene, 1998; 17: 44954
40. Yokomizo A, Tindall DJ, Drabkin H et al: PTEN/MMAC1 mutations identied in small cell, but not in non-small cell lung cancers. Oncogene, 1998; 17: 47579 41. Forgacs E, Biesterveld EJ, Sekido Y et al: Mutation analysis of the PTEN/ MMAC1 gene in lung cancer. Oncogene, 1998; 17: 155765 42. Nakahara Y, Nagai H, Kinoshita T et al: Mutational analysis of the PTEN/ MMAC1 gene in non-Hodgkins lymphoma. Leukemia, 1998; 12: 127780
43. Gronbaek K, Zeuthen J, Guldberg P et al: Alterations of the MMAC1/ PTEN gene in lymphoid malignancies. Blood, 1998; 91: 438890
45. Butler MP, Wang SI, Chaganti RS et al: Analysis of PTEN mutations and deletions in B-cell non-Hodgkins lymphomas. Genes Chromosomes Cancer, 1999; 24: 32227 46. Kawamura N, Nagai H, Bando K et al: PTEN/MMAC1 mutations in hepatocellular carcinomas: somatic inactivation of both alleles in tumors. Jpn J Cancer Res, 1999; 90: 41318 47. Obata K, Morland SJ, Watson RH et al: Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res, 1998; 58: 209597 48. Yokomizo A, Tindall DJ, Hartmann L et al: Mutation analysis of the putative tumor suppressor PTEN/MMAC1 in human ovarian cancer. Int J Oncol, 1998; 13: 10115 49. Saito M, Okamoto A, Kohno T et al: Allelic imbalance and mutations of the PTEN gene in ovarian cancer. Int J Cancer, 2000; 85: 16065 50. Marsh DJ, Coulon V, Lunetta KL et al: Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet, 1998; 7: 50715 51. Zhou X, Hampel H, Thiele H et al: Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet, 2001; 358: 21011 52. Myers MP, Stolarov JP, Eng C et al: P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specicity phosphatase. Proc Natl Acad Sci USA, 1997; 94: 905257 53. Maehama T, Dixon JE: The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem, 1998; 273: 1337578
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44. Sakai A, Thieblemont C, Wellmann A et al: PTEN gene alterations in lymphoid neoplasms. Blood, 1998; 92: 341015
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62. Weng LP, Brown JL, Eng C: PTEN coordinates G(1) arrest by downregulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum Mol Genet, 2001; 10: 599604 63. Vivanco I, Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer, 2002; 2: 489501 64. Furnari FB, Lin H, Huang HS, Cavenee WK: Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci USA, 1997; 94: 1247984
65. Myers MP, Pass I, Batty IH et al: The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA, 1998; 95: 1351318
66. Robertson GP, Furnari FB, Miele ME et al: In vitro loss of heterozygosity targets the PTEN/MMAC1 gene in melanoma. Proc Natl Acad Sci USA, 1998; 95: 941823 67. Li DM, Sun H: PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci USA, 1998; 95: 1540611 68. Di Cristofano A, Pesce B, Cordon-Cardo C, Pandol PP: Pten is essential for embryonic development and tumour suppression. Nat Genet, 1998; 19: 34855
69. Suzuki A, de la Pompa JL, Stambolic V et al: High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol, 1998; 8: 116978 70. Podsypanina K, Ellenson LH, Nemes A et al: Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA, 1999; 96: 156368
71. Stambolic V, Tsao MS, Macpherson D et al: High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/ mice. Cancer Res, 2000; 60: 360511 72. Kwabi-Addo B, Giri D, Schmidt K et al: Haploinsufciency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci USA, 2001; 98: 1156368 73. Trotman LC, Niki M, Dotan ZA et al: Pten dose dictates cancer progression in the prostate. PLoS Biol, 2003; 1: E59 (38596) 74. Furnari FB, Huang HJ, Cavenee WK: The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res, 1998; 58: 50028 75. Myers MP, Pass I, Batty IH, Van der Kaay J et al: The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci USA, 1998; 95: 1351318 76. Mahimainathan L, Choudhury GG: Inactivation of platelet-derived growth factor receptor by the tumor suppressor PTEN provides a novel mechanism of action of the phosphatase. J Biol Chem, 2004; 279: 1525868 77. Tamura M, Gu J, Matsumoto K et al: Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science, 1998; 280: 161417 78. Tamura M, Gu J, Danen EH et al: PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem, 1999; 274: 20693703
SE
58. Di Cristofano A, Pandol PP: The multiple roles of PTEN in tumor suppression. Cell, 2000; 100: 38790
Med Sci Monit, 2004; 10(10): RA235-241

79. Maier D, Jones G, Li X et al: The PTEN lipid phosphatase domain is not required to inhibit invasion of glioma cells. Cancer Res, 1999; 59: 547982 80. Gu J, Tamura M, Pankov R et al: Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J Cell Biol, 1999; 146: 389403 81. Yart A, Laffargue M, Mayeux P et al: A critical role for phosphoinositide 3-kinase upstream of Gab1 and SHP2 in the activation of ras and mitogen-activated protein kinases by epidermal growth factor. J Biol Chem, 2001; 276: 885664 82. Ong SH, Hadari YR, Gotoh N et al: Stimulation of phosphatidylinositol 3-kinase by broblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc Natl Acad Sci USA, 2001; 98: 607479 83. Weng LP, Smith WM, Brown JL, Eng C: PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. Hum Mol Genet, 2001; 10: 60516 84. Zundel W, Schindler C, Haas-Kogan D et al: Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev, 2000; 14: 39196 85. Gomez-Manzano C, Fueyo J, Jiang H et al: Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann Neurol, 2003; 53: 10917 86. Huang J, Kontos CD: PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects. J Biol Chem, 2002; 277: 1076066 87. Abe T, Terada K, Wakimoto H et al: PTEN decreases in vivo vascularization of experimental gliomas in spite of proangiogenic stimuli. Cancer Res, 2003; 63: 23005 88. Gil EB, Malone Link E et al: Regulation of the insulin-like developmental pathway of Caenorhabditis elegans by a homolog of the PTEN tumor suppressor gene. Proc Natl Acad Sci USA, 1999; 96: 292530 89. Bringold F, Serrano M: Tumor suppressors and oncogenes in cellular senescence. Exp Gerontol, 2000; 35: 31729 90. Vazquez F, Ramaswamy S, Nakamura N, Sellers WR: Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol, 2000; 20: 501018
91. Vazquez F, Grossman SR, Takahashi Y et al: Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem, 2001; 276: 4862730 92. Torres J, Pulido R: The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem, 2001; 276: 99398 93. Torres J, Rodriguez J, Myers MP et al: Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase-3: implications for the control of protein stability and PTEN-protein interactions. J Biol Chem, 2003; 278: 3065260 94. Patel L, Pass I, Coxon P et al: Tumor suppressor and anti-inammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol, 2001; 11: 76468
96. Virolle T, Adamson ED, Baron V et al: The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol, 2001; 3: 112428 97. Moorehead RA, Hojilla CV, De Belle I et al: Insulin-like growth factor-II regulates PTEN expression in the mammary gland. J Biol Chem, 2003; 278: 5042227
SE
95. Stambolic V, MacPherson D, Sas D et al: Regulation of PTEN transcription by p53. Mol Cell, 2001; 8: 31725
PE
R SO O N N A LY L U
RA
98. Chu EC, Chai J, Tarnawski AS: NSAIDs activate PTEN and other phosphatases in human colon cancer cells: novel mechanism for chemopreventive action of NSAIDs. Biochem Biophys Res Commun, 2004; 320: 87579
99. Guzeloglu-Kayisli O, Kayisli UA, Al-Rejjal R et al: Regulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression by estradiol and progesterone in human endometrium. J Clin Endocrinol Metab, 2003; 88: 501726
100. Vasudevan KM, Gurumurthy S, Rangnekar VM: Suppression of PTEN expression by NF-kappa B prevents apoptosis. Mol Cell Biol, 2004; 24: 100721 101. Kim S, Domon-Dell C, Kang J et al: Down-regulation of the tumor suppressor PTEN by the tumor necrosis factor-alpha/nuclear factor-kappaB (NF-kappaB)-inducing kinase/NF-kappaB pathway is linked to a default IkappaB-alpha autoregulatory loop. J Biol Chem, 2004; 279: 428591
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Received: 2004.08.18 Accepted: 2004.08.19 Published: 2004.10.01