PTEN and p53 #1@<Johns Hopkins work>#2NYU work
Abstract Number: 4230
Presentation Title: PTEN has tumor promoting properties in the setting of gain-of-function p53 mutations
Presentation Start/End Time: Tuesday, Apr 04, 2006, 1:00 PM - 5:00 PM
Location: Exhibit Hall, Washington Convention Center
Poster Section: 7
Poster Board Number: 16
Author Block: Yunqing Li, Sherwin Kwon, Manish Kumar, Amandeep Salhotra, Bachchu Lal, Yasmine Assadipour, John Laterra, David Schiff, Roger Abounader. University of Virginia, Charlottesville, VA, Kennedy Krieger Institute, Baltimore, MD, Johns Hopkins University, Baltimore, MD
PTEN is a tumor suppressor and dual specificity phosphatase that is frequently mutated in various human cancers. PTEN inhibits multiple malignancy parameters including cell proliferation and cell survival. Here we show, for the first time, that PTEN can also act as a tumor promoter in cancer cells that possess gain-of-function p53 mutations. We found that PTEN restoration to PTEN-null glioblastoma cells unexpectedly and consistently induces cell cycle progression and cell proliferation and inhibits tumor cell death and apoptosis in two glioblastoma cell lines (U373 and SNB19) while generating the opposite and expected effects in two other glioblastoma cell lines (U87 and A172). We examined the genetic background of the four cell lines and noticed that U373 and SNB19 cells were mutated for p53 at 273 and 248 sites respectively, while U87 and A172 cells were wild-type for p53. Based on published work that shows that PTEN can stabilize and increase the levels of wild-type p53, we hypothesized that PTEN might also stabilize p53 gain-of-function mutants (to which 273 and 248 belong) and thereby act as a tumor promoter. To test this hypothesis, we first studied the effects of PTEN restoration on the levels of mutant and wild-type p53 protein in all four cell lines and found that PTEN restoration leads to an increase in wild-type p53 levels in U87 and A172 as well as to an increase in mutant p53 levels in U373MG and SNB19. We showed that PTEN increases mutant p53 levels via direct binding and stabilization of mutant p53 protein as well as via inhibition of Mdm-2, leading to decreased degradation of mutant p53 protein. We then used two approaches to demonstrate the dependency of the tumor promoting effects of PTEN on the expression of p53 mutants. We first showed that expression of the 273 mutant in p53-null LNZ-308 glioma cells induces cell cycle progression and inhibits apoptosis while expression of wild-type p53 inhibits cell cycle progression and induces apoptosis. Importantly, co-expression of PTEN in these PTEN-null cells amplified the effects of both mutant p53 and wild-type p53 on cell cycle and apoptosis. We then showed that inhibition of mutant p53 expression in U373 and SNB19 cells with siRNA leads to the inhibition of the tumor promoting effects of PTEN restoration in these cells. We therefore demonstrated that PTEN can have tumor promoting properties via activation of gain-of-function mutants of p53. This novel finding provides a potential explanation to why PTEN and p53 mutations are frequently mutually exclusive in human cancers and could have important implications on therapeutic strategies that aim at restoring PTEN expression to PTEN deficient human tumors. Supported by NIH grant RO1 NS045209 (RA).
Abstract Number: 2643
Presentation Title: Loss of the tumor suppressor p53 decreases PTEN expression and enhances signaling pathways leading to activation of AP-1 and NF?B induced by UV radiation
Presentation Start/End Time: Monday, Apr 03, 2006, 1:00 PM - 5:00 PM
Location: Exhibit Hall, Washington Convention Center
Poster Section: 8
Poster Board Number: 1
Author Block: Weiming Ouyang Sr., Jingxia Li, Qian Ma, Zhuo Zhang, Qiangsong Tong, Chuanshu Huang. Medical School of New York University, Tuxedo Park, NY
Transcription factor p53 and phosphatase PTEN are two tumor suppressors that play essential roles in suppression of carcinogenesis. However, the mechanisms by which p53 mediates anti-cancer activity and relationship between p53 and PTEN are not well understood. In the present study, we found that pretreatment of mouse epidermal Cl 41 cells with pitithrin-a (PTF-a), an inhibitor for p53-dependent transcriptional activation, resulted in a marked increase in UV-induced activation of AP-1 and NF?B. Consistent with activation of AP-1 and NF?B, PTF-a was also able to enhance the UV-induced phosphorylation of JNKs and p38 kinase (p38K), whereas it did not show any effect on phosphorylation of ERKs. Furthermore, the UV-induced signal activation, including phosphorylation of JNKs, p38K, Akt and p70S6K, was significantly enhanced in p53 deficient cells (p53-/-), which can be reversed by p53 reconstitution. In addition, knockdown of p53 expression by its siRNA also caused the elevation of AP-1 activation and Akt phosphorylation induced by UV radiation. These results demonstrate that p53 has a suppressive activity on the cell signaling pathways leading to activation of AP-1 and NF?B in cell response to UV radiation. More importantly, deficiency of p53 expression resulted in a decrease in PTEN protein expression, suggesting that p53 plays a critical role in the regulation of PTEN expression. Since PTEN is a well known phosphatase involved in the regulation of PI-3K/Akt signaling pathway, taken together with the evidence that PI-3K/Akt plays an important role in the activation of AP-1 and NF?B during tumor development, we anticipate that inhibition of AP-1 and NF?B by tumor suppressor p53 appears to be mediated via PTEN, which may be an novel mechanism involved in anti-cancer activity of p53 protein.
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