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PTEN Mutation: Many Birds with One Stone in Tumorigenesis WEIJIN LIU 1, YONGGANG ZHOU 2, SVEN N

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PTEN Mutation: Many Birds with One Stone in Tumorigenesis WEIJIN LIU 1, YONGGANG ZHOU 2, SVEN N ANTICANCER RESEARCH 28 : 3613-3620 (2008) Review PTEN Mutation: Many Birds with One Stone in Tumorigenesis WEIJIN LIU 1, YONGGANG ZHOU 2, SVEN N. RESKE 3 and CHANGXIAN SHEN 4 1Department of Life Sciences, Huaihua University, Huaihua, P. R. of China; 2German Cancer Research Center, Heidelberg; 3Department of Nuclear Medicine, University of Ulm, Ulm, Germany; 4Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, TN, U.S.A. Abstract. The PTEN (phosphatase and tensin homolog combination with the loss of certain other tumor suppressor deleted on chromosome ten) tumor suppressor gene is genes or with genetically engineered reduction of PTEN mutated in a wide range of malignancies and recent studies expression just below heterozygosity (3-7). have demonstrated that PTEN prevents tumorigenesis PTEN is a multiple-domain polypeptide of 403 amino acids. through multiple mechanisms. PTEN functions as a plasma- It contains an amino-terminal phosphatase domain homologous membrane lipid phosphatase that antagonizes the PI3K to chicken tensin and a C2 domain, which mediates the (phosphoinositide 3 kinase)-AKT pathway. PTEN physically association of signal proteins to plasma membranes. The C- and genetically interacts with the central genome guardian terminal PDZ (PSD95, DlgA and Zo-1) domain-binding p53. PTEN also associates with the centromeric protein sequence and PEST (rich in proline, glutamate, serine, and CENP-C to maintain centromere integrity and suppresses threonine residues) domain regulate protein stability via the chromosomal instability from DNA double-strand breaks ubiquitin-proteasome pathway (2). PTEN has two canonical (DSBs) through transcriptional regulation of Rad51 PEST domains, which is a signature in many short-lived (radiosensitive yeast mutant 51). Moreover PTEN controls proteins degraded by the ubiquitin pathway. Given that the the growth and proliferation of haematopoietic stem cells protein level of PTEN is highly correlated with carcinogenesis (HSC) and restrains cells from leukemia in an mTOR in a wide range of cancer cases, it should be tightly controlled. (mammalian target of rapamycin) dependent manner. Thus, Indeed, PTEN is regulated by ubiquitin-mediated proteasomal restoring PTEN functions in cancer cells directly or degradation (8, 9). PTEN can be polyubiquitinated and indirectly holds great promise for cancer therapy. monoubiquitined by the same ubiquitin ligase NEDD4-1 (neural precursor cell expressed, developmentally down- PTEN (phosphatase and tensin homolog deleted on regulated gene 4-1), a potential proto-oncogene (10). However, chromosome ten) was first identified as a tumor suppressor only the polyubiquitinated PTEN is targeted to proteasomes for gene in 1997 (1). PTEN is mutated in a wide range of degradation in the cytoplasm through the C-terminal PEST malignancies, especially solid tumors and it is, second only domain, whereas monoubiquitinated PTEN is required for to p53, the most frequently affected tumor suppressor in nuclear import. Once in the nucleus, the ubiquitin moiety of human carcinomas. Somatic mutations of PTEN occur in PTEN is removed by an unidentified deubiquitinase (11). multiple sporadic malignancies while germline mutations of Another negative regulator of PTEN protein is DJ-1 (also PTEN lead to inherited hamartoma and Cowden syndrome called PARK7, Parkinson’s disease gene) but its role in (2). Importantly, PTEN is haploinsufficient because a single suppressing PTEN is unclear (12). Additionally, PTEN copy was unable to prevent prostate cancer either in enzymatic activity can be strictly regulated by protein phosphorylation (8, 13-15). PTEN Antagonizes PI3K-AKT Pathway in Correspondence to: Changxian Shen, Ph.D., Department of Carcinogenesis Molecular Pharmacology, St. Jude Children’s Research Hospital, 332 N Lauderdale St., Memphis, TN 38105, U.S.A. Tel: +1 9014952111, Fax: +1 9014954290, e-mail: [email protected] The current understanding of the molecular mechanisms of PTEN in carcinogenesis comes primarily from the study of Key Words: PTEN, mTOR, p53, AKT, genome stability, cell cycle, PTEN as a central negative regulatory factor of the PI3K review. (phosphoinositide 3 kinase)-AKT (AKT8 virus oncogene 0250-7005/2008 $2.00+.40 3613 ANTICANCER RESEARCH 28 : 3613-3620 (2008) cellular homolog) pathway (Figure 1). PI3K-AKT is one malignant transformation and its overexpression is found in of the major signal transduction pathways that promote cell a wide range of cancer cells (26, 27). Furthermore, AKT growth, survival and proliferation. It contributes to the phosphorylates and inactivates GSK3 kinase, which inhibits evasion of apoptosis, loss of cell cycle control and genomic Myc (myelocytomatosis oncogene cellular homolog) and instability during tumorigenesis through numerous cyclin D1 as well (16). Myc is a proto-oncogene and is mechanisms (16, 17). In response to ligand binding to mutated in numerous carcinomas. It is an important receptor tyrosine kinase (RTK) or G-protein coupled transcription factor for cell cycle progression, particular receptor (GPCR), PI3K is activated and converts the during S-phase. Thus PTEN suppresses malignant phosphatidylinositol 4,5 phosphate (PIP2) to transformation by controlling proper cell cycle progression phosphatidylinositol 3,4,5 trisphosphate (PIP3), a major and DNA damage checkpoint responses through regulating second messenger in cellular signaling. PIP3 then recruits the key checkpoint proteins Chk1, p27 kip1 , p130 Rb2 , cyclin and binds to proteins with pleckstrin homology domain D1 and Myc (Figure s 1 and 2). (PH) such as phosphatidylinositide-dependent kinase 1 Taken together, PTEN suppresses tumorigenesis at least in (PDK1) and AKT (also called protein kinase B, PKB) (18). part by antagonizing PI3K-AKT signaling events that After membrane enrichment, PDK1, together with contribute to the resistance to the growth inhibitory signal, mTORC2 (mammalian target of rapamycin complex 2) the evasion of apoptosis and cell cycle progression during phosphorylates and activates AKT (19). Activated AKT the multistep process of tumorigenesis. then promotes proliferation and survival through the inhibition of numerous tumor suppressor-like signal PTEN and p53 molecules such as Bad (Bcl-XL/Bcl-2-associated death promoter), FOXO3 (forkhead box O3), GSK3 (glycogen Mutations of PTEN and p53 tumor suppressor genes are the synthase kinase 3) and TSC2 (tuberous sclerosis complex most common mutations found in carcinomas and 2), and activation of many oncogenes such as MDM2 interestingly these mutations are often mutually exclusive (murine double minute 2), PDK1 and IKK (I κB kinase) by suggesting a functional connection underlying these two phosphorylation. Finally activated AKT inhibits apoptosis tumor suppressors. Indeed, PTEN null mice that die during by decreasing proapoptotic proteins Bad, Fas L (Fas embryonic development can be rescued by simultaneous p53 ligand), Bim (bcl-2-interacting mediator of cell death) and mutation and PTEN null cells show p53-dependent cellular p53 while increasing anti-apoptotic nuclear factor- κB (NF- senescence (28). The molecular mechanistic investigation κB) signaling (16-18). Therefore PTEN functions as the reveals that PTEN regulates p53 stability in a phosphatase- central negative regulator of the PI3K/AKT pathway in dependent manner by counteracting the PI3K-AKT-MDM2 controlling apoptosis during tumorigenesis. signaling pathway, which targets p53 to the proteasome for It has been established that the deregulation of cell cycle degradation (29, 30). Furthermore, PTEN interacts with and control results in tumorigenesis (20). Activated AKT also maintains the highly acetylated p53 in a phosphatase- phosphorylates and sequesters Chk1 (checkpoint kinase 1), independent way that enhances p53 DNA binding ability. On an essential factor for DNA replication and cell cycle the other hand, p53 positively controls the transcription of checkpoints in G 1, S and G 2-phase (21), in the cytoplasm. PTEN (31-33) (Figure 2). This functional interdependence This mechanism prevents Chk1 from entering the nucleus as may be the reason why mutations in PTEN and p53 are so a guardian for genome integrity (22) (Figure 2). Moreover frequent and gives an explanation for the role of PTEN in AKT inactivates FOXO3, which activates the transcription of carcinogenesis through p53. p27 kip1 and p130 Rb2 , and represses the expression of cyclin D1 (16-18). p27 kip1 is one of the most important inhibitors PTEN and Chromosomal Integrity of the cyclin-dependent kinases Cdk2 and Cdk1, masters of the propeller of cell cycle progression (23, 24). p130 Rb2 is a PTEN is found not only in the plasma membrane, but also member of the Rb (retinoblastoma) family, which is a in the nucleus of different normal and cancer cells, indicating negative regulator of G 1/S-phase transition through inhibition a functional role in the nucleus (33-35). Nuclear PTEN has of the E2F (transcription factor family including E2F and been found to be required for the maintenance of genome DP-like subunits) that mediate gene transcription essential stability. In PTEN null mouse embryonic fibroblast (MEF) for G 1/S-phase transition and S-phase progression. Both cells there is a high frequency of centromere breakage. p27 kip1 and p130 Rb2 are tumor suppressors, mutated in many Further data have shown that PTEN localizes at the carcinomas (25). Cyclin D1 plays a vital role in the activity centromere via physical interaction with an essential
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