PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein

Paramio, Jesús M.; Navarro, Manuel; Segrelles, Carmen; Gómez‐Casero, Elena; Jorcano, José L.

doi:10.1038/sj.onc.1203151

Cited by 110 publications

(89 citation statements)

References 42 publications

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“…Similarly, the literature has suggested that PTEN down-regulates cyclin D1. 68 If this were true, then we should have observed a trend of increased cyclin D1 expression with decreased PTEN expression. In our series, cyclin D1 expression levels and subcellular location were random irrespective of PTEN or P-Akt status.…”

Section: Discussionmentioning

confidence: 99%

Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas

Kurose

Zhou

Araki

et al. 2001

The American Journal of Pathology

219

145

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PTEN (MMAC1/TEP1), a tumor suppressor gene on chromosome subband 10q23.3, is variably mutated and/or deleted in a variety of human cancers. Germline mutations in PTEN, which encode a dual-specificity phosphatase, have been implicated in at least two hamartoma tumor syndromes that exhibit some clinical overlap, Cowden syndrome and BannayanRiley-Ruvalcaba syndrome. Among several series of ovarian cancers, the frequency of loss of heterozygosity (LOH) of markers flanking and within PTEN, is ϳ30 to 50%, and the somatic intragenic PTEN mutation frequency is <10%. In this study, we screened primary adenocarcinomas of the ovary for LOH of polymorphic markers within and flanking the PTEN gene and for intragenic mutations of the PTEN gene and compared them to PTEN expression using immunohistochemistry. Furthermore, we sought to detect the expression of the presumed downstream targets of PTEN, such as P-Akt, p27, and cyclin D1 by immunohistochemistry. LOH at 10q23 was observed in 29 of 64 (45%) cases. Of the 117 samples, 6 somatic intragenic PTEN mutations, 1 germline mutation, and 1 novel polymorphism were found in 7 (6%) patients. Immunostaining of 49 ovarian cancer samples revealed that 13 (27%) were PTEN immunostain-negative, 25 (51%) had reduced staining, and the rest (22%) were PTEN expression-positive. Among the 44 informative tumors assessed for 10q23 LOH and PTEN immunostaining, there was an association between 10q23 LOH and decreased or absent staining (P ‫؍‬ 0.0317). Of note, there were five (11%) tumors with neither mutation nor deletion that exhibited no PTEN expression and 10 (25%) others without mutation or deletion but had decreased PTEN expression. Among the 49 tumors available for immunohistochemistry, 28 (57%) showed P-Akt-positive staining, 24 (49%) had decreased p27 staining, and cyclin D1 was overexpressed in 35 (79%) cases. In general, P-Akt expression was inversely correlated with PTEN expression (P ‫؍‬ 0.0083). These data suggest that disruption of PTEN by several mechanisms, allelic loss, intragenic mutation, or epigenetic silencing, all contribute to epithelial ovarian carcinogenesis, and that epigenetic silencing is a significant mechanism. The Akt pathway is prominently involved, but clearly not in all cases. Surprisingly, despite in vitro demonstration that p27 and cyclin D1 lies downstream of PTEN and Akt, there was no correlation between p27 and cyclin D1 expression and PTEN or P-Akt status. Thus, in vivo, although PTEN and Akt play a prominent role in ovarian carcinogenesis, p27 and cyclin D1 might not be the primary downstream targets. Alternatively, these observations could also suggest that pathways involving other than Akt, p27 and cyclin D1 that lie downstream of PTEN play roles in ovarian carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas

Kurose

Zhou

Araki

et al. 2001

The American Journal of Pathology

219

145

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“…PTEN is primarily expressed, in parallel to Akt, in the mid to late G 1 phase during cell-cycle progression before pRb hyperphosphorylation (33). However, coexpression of PTEN with activated PI3-K or Akt, as reported in our study, efficiently antagonizes PTEN-mediated growth suppression (33). Therefore, PTEN induction may suggest the existence of a negative feedback loop that occurs after Rho-dependent PI3-K activation.…”

Section: Discussionmentioning

confidence: 60%

“…Indeed, PTEN overexpression inhibits cell growth in a variety of normal and transformed cells. PTEN is primarily expressed, in parallel to Akt, in the mid to late G 1 phase during cell-cycle progression before pRb hyperphosphorylation (33). However, coexpression of PTEN with activated PI3-K or Akt, as reported in our study, efficiently antagonizes PTEN-mediated growth suppression (33).…”

Section: Discussionmentioning

confidence: 70%

RhoA Activation Mediates Phosphatidylinositol 3-Kinase–Dependent Proliferation of Human Vascular Endothelial Cells

Coupel

Leboeuf

Boulday

et al. 2004

Journal of the American Society of Nephrology

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Abstract. HLA class I ligation on graft endothelial cells (EC) has been shown to promote graft arteriosclerosis and chronic allograft nephropathy. This study investigated transcriptional and functional changes mediated by anti-HLA antibodies (Ab), developed by transplant recipient, on vascular renal EC. For mimicking interactions that occur between alloantibodies and graft endothelium, HLA-typed primary cultures of human EC were incubated in vitro in the presence of monomorphic or polymorphic anti-HLA class I Ab. Gene expression analysis identified the upregulation of several molecules involved in cell signaling and proliferation, including the GTP-binding protein RhoA. It was demonstrated further that HLA class I ligation on EC induced a rapid translocation of RhoA to the cell membrane associated with F-actin stress fiber formation and cytoskeleton reorganization. Western blot analysis showed that anti-HLA class I Ab induced, in addition to RhoA, the activation of phosphatidylinositol 3-kinase, reflected by the phosphorylation of Akt (Ser473) and GSK3␤ (Ser9), in EC. C3 exoenzyme, an inhibitor of RhoA, inhibited RhoA translocation in response to HLA class I ligation and reduced phosphatidylinositol 3-kinase activation. EC proliferation and cell cycle progression, examined by 5,6-carboxyfluorescein diacetate succinimidyl ester staining, demonstrated that anti-HLA-induced EC proliferation was efficiently prevented by the 3-hydroxy-3-methylglutaryl CoA reductase inhibitor simvastatin (0.1 mol/L) through inhibition of RhoA geranylgeranylation. Taken together, these findings support the conclusion that RhoA is a key mediator of signaling pathways that lead to cytoskeletal reorganization and EC proliferation in response to alloantibodies that bind to HLA class I and demonstrate the specific and potent inhibitory effect of simvastatin on allostimulated EC growth.Chronic allograft nephropathy is the major factor limiting long-term survival of renal allografts (1,2). The hallmark of chronic allograft nephropathy is transplant arteriosclerosis, which is characterized by the intimal proliferation of endothelial cells (EC), smooth muscle cells (SMC), and fibroblasts, leading to vessel obstruction and ischemia that causes late graft failure (3). Several risk factors have been identified, including both immune injury to transplant vessels and nonimmunological factors (e.g., ischemia/reperfusion, hypertension, hyperlipidemia). The immunologic mechanisms that induce chronic allograft nephropathy are poorly understood, but it is suspected that the associated vascular changes are a result of early injury to the endothelium of the graft mediated by allogeneic T cells and anti-HLA alloantibodies (2). The incidence of transplant arteriosclerosis is increased in transplant recipients who produce anti-donor HLA antibodies (Ab) after transplantation, suggesting that anti-HLA Ab play a role in the pathogenesis of the disease (4,5). In previous studies, it has been shown that anti-HLA Ab, developed by transplant recipients after trans...

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“…In fact, it has been shown that PTEN over-expression inhibits cell growth in a variety of normal and transformed, human and murine cells (Paramio et al 1999). This study is in line with previous reports, compared to the control group, that over-expression PTEN cells led to a decrease in cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Over-expression of PTEN on proliferation and apoptosis in canine mammary tumors cells

Tong

Zhang

Sun

et al. 2016

Animal Cells and Systems

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Phosphatase and tensin homolog (PTEN) is an important tumor-suppressor gene which constitutes an important PI3K/Akt pathway by regulating the signaling of multiple biological processes, including apoptosis, metabolism, cell proliferation, and cell growth has been gaining increasing attention. However, the role of PTEN in regulating apoptosis of canine mammary tumors cells still needs further investigation. In this experiment, the effect of PTEN on proliferation and apoptosis in canine mammary tumors (CMT) cells was analyzed. As a result, gene and protein expression levels of apoptosis-related genes were detected. Eukaryotic expression vector pcDNA3.1+-PTEN were successfully constructed and stably transferred into canine CMT cells after geneticin (G418) selection. After pcDNA3.1+-PTEN transfection, compared with control group, the cells proliferation was inhibited and the cell apoptosis was increased in CMT cells. The expression of p-Akt was decreased and the apoptosis-related genes, such as caspase-3, caspase-9, and Bax, were increased. These data serve to demonstrate the function of PTEN on apoptosis and gene regulatory in PI3K/Akt pathway in CMT cells. Collectively, our data link the tumorsuppressor activities of PTEN to the machinery controlling cell cycle through the modulation of signaling molecules whose signal target is the functional inactivation of the apoptosis gene product. ARTICLE HISTORY

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PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein

Cited by 110 publications

References 42 publications

Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas

Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas

RhoA Activation Mediates Phosphatidylinositol 3-Kinase–Dependent Proliferation of Human Vascular Endothelial Cells

Over-expression of PTEN on proliferation and apoptosis in canine mammary tumors cells

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