The tumor suppressor gene PTEN is notable for two characteristics, first, being a direct inhibitor of the PI3-kinase (PI3K) growth stimulatory pathway via dephosphorylation of pathway products, phosphatidylinositol 3' phosphates. Second, in the majority of cancers including gliomas, PTEN appears to be preferentially altered in the high-grade form, suggesting its involvement in the malignant aspects of oncogenesis. A number of studies have shown that PTEN regulates the PI3K pathway, known to influence the growth, metabolism, migration and survival of cells. Our data suggest that while regulation of the PI3K pathway is essential for suppression of tumorigenicity, it is not sufficient, implying additional functions for PTEN. This is highlighted by two mutant forms of PTEN, Y315A and Y240A, which are tumorigenic when expressed in PTEN-deficient glioma cells, yet still able to mediate the activity of the PI3K pathway. Furthermore, we have recently made two highly interesting observations: 1) we have identified two proteins that specifically bind to a phosphorylated form of Y315, but not to the non-phosphorylated sequence; 2) subcellular localization of PTEN is cell cycle dependent. The major focus of this proposal is to define the additional signaling networks involving PTEN by characterizing their members, and to define the mechanisms that regulate PTEN's localization, activities and functions. Our data also suggest that PTEN activities are under strict regulation. We propose these activities are mediated, in part, by post-translational modifications (serine/threonine and tyrosine phosphorylations), associations with other proteins, and subcellular localization. The overall hypothesis of this study is that PTEN is a component of a multifunctional signaling complex whose function mediates biological and biochemical activities that are involved in the malignancy of tumor cells.
The specific aims of this proposal are: 1) to delineate the molecular mechanisms involved in the regulation of PTEN's cell cycle-dependent subcellular localization. 2) to characterize the biological functions of PTEN in the nucleus and identify the downstream target genes specifically involved in nuclear PTEN-mediated growth suppression. 3) to identify and characterize proteins, which interact with PTEN to form a putative signaling complex, particularly proteins that interact with PTEN at phosphorylated tyrosine 315.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA056041-11A1
Application #
6679590
Study Section
Special Emphasis Panel (ZRG1-ONC (05))
Program Officer
Mietz, Judy
Project Start
1992-04-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
11
Fiscal Year
2003
Total Cost
$302,000
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Saito, Norihiko; Fu, Jun; Zheng, Siyuan et al. (2014) A high Notch pathway activation predicts response to ? secretase inhibitors in proneural subtype of glioma tumor-initiating cells. Stem Cells 32:301-12
Fu, Jun; Koul, Dimpy; Yao, Jun et al. (2013) Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells. Cancer Res 73:3062-74
Koul, Dimpy; Fu, Jun; Shen, Ruijun et al. (2012) Antitumor activity of NVP-BKM120--a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin Cancer Res 18:184-95
Liu, Juinn-Lin; Mao, Zhenyu; Gallick, Gary E et al. (2011) AMPK/TSC2/mTOR-signaling intermediates are not necessary for LKB1-mediated nuclear retention of PTEN tumor suppressor. Neuro Oncol 13:184-94
Koul, Dimpy; Shen, Ruijun; Kim, Yong-Wan et al. (2010) Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol 12:559-69
Liu, Ta-Jen; Koul, Dimpy; LaFortune, Tiffany et al. (2009) NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 8:2204-10
Freire, Pablo; Vilela, Marco; Deus, Helena et al. (2008) Exploratory analysis of the copy number alterations in glioblastoma multiforme. PLoS One 3:e4076
Liu, Juinn-Lin; Mao, Zhenyu; LaFortune, Tiffany A et al. (2007) Cell cycle-dependent nuclear export of phosphatase and tensin homologue tumor suppressor is regulated by the phosphoinositide-3-kinase signaling cascade. Cancer Res 67:11054-63
Koul, Dimpy; Shen, Ruijun; Shishodia, Shishir et al. (2007) PTEN down regulates AP-1 and targets c-fos in human glioma cells via PI3-kinase/Akt pathway. Mol Cell Biochem 300:77-87
Koul, Dimpy; Takada, Yasunari; Shen, Ruijun et al. (2006) PTEN enhances TNF-induced apoptosis through modulation of nuclear factor-kappaB signaling pathway in human glioma cells. Biochem Biophys Res Commun 350:463-71

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