PTEN is a tumor suppressor for gliomas and many other tumor types. PTEN encodes a phosphatase specific for phosphatidylinositol phosphate (PIP) and reverses the action phosphatidylinositol 3-kinase (P13K). Although P13K is a well studied regulator of neuronal survival, our recent publication (Lachyankar et al., Appendix) was the first to propose a role for PTEN in the nervous system. We found that PTEN is expressed by neurons in adult brain. In cell culture models, PTEN is expressed during neurotrophin-induced differentiation and is detected in both cytoplasm and nucleus. Suppression of PTEN levels with antisense oligonucleotides leads to death of immature neurons during neurite extension. These results provide the basis for this application. In Sp.
Aim 1, we will determine the mechanism by which nerve growth factor (NOF) regulates PTEN levels. We do not observe significant changes in PTEN mRNA levels during NGF-induced differentiation. We will test the hypothesis that NGF induces PTEN protein by altering the rate of translation or the rate of degradation of PTEN. The latter is a particularly appealing possibility because PTEN has two PEST sequences and turns over rapidly. For Sp.
Aim 2, we will analyze the nature and function of PTEN in the nucleus. We will identify nuclear localization signals associated with PTEN, any secondary modifications of nuclear PTEN, and the relation of PTEN with nuclear PIPs and other nuclear domains. In Sp.
Aim 3, we will test whether P13K and PTEN are the controlling enzymes for PIP levels. We also will examine the role of two other PIP phosphatases, SHIP and synaptojanin. We will determine whether PIPs provide feedback regulation of PTEN, and whether PTEN action is associated with subcellular compartments of the neuron. These experiments address how PTEN and, in turn, PIPs regulate development, neuronal survival, neurodegeneration, and development of brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021716-20
Application #
6777600
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Leblanc, Gabrielle G
Project Start
1988-03-01
Project End
2005-12-31
Budget Start
2004-06-01
Budget End
2005-12-31
Support Year
20
Fiscal Year
2004
Total Cost
$413,723
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pharmacology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Weatherbee, Jessica L; Kraus, Jean-Louis; Ross, Alonzo H (2016) ER stress in temozolomide-treated glioblastomas interferes with DNA repair and induces apoptosis. Oncotarget 7:43820-43834
Heinrich, Frank; Chakravarthy, Srinivas; Nanda, Hirsh et al. (2015) The PTEN Tumor Suppressor Forms Homodimers in Solution. Structure 23:1952-1957
Harishchandra, Rakesh K; Neumann, Brittany M; Gericke, Arne et al. (2015) Biophysical methods for the characterization of PTEN/lipid bilayer interactions. Methods 77-78:125-35
Ramirez, Yulian P; Mladek, Ann C; Phillips, Roger M et al. (2015) Evaluation of novel imidazotetrazine analogues designed to overcome temozolomide resistance and glioblastoma regrowth. Mol Cancer Ther 14:111-9
Karpel-Massler, Georg; Shu, Chang; Chau, Lily et al. (2015) Combined inhibition of Bcl-2/Bcl-xL and Usp9X/Bag3 overcomes apoptotic resistance in glioblastoma in vitro and in vivo. Oncotarget 6:14507-21
Pareja, Fresia; Macleod, David; Shu, Chang et al. (2014) PI3K and Bcl-2 inhibition primes glioblastoma cells to apoptosis through downregulation of Mcl-1 and Phospho-BAD. Mol Cancer Res 12:987-1001
Jiang, Zhiping; Redfern, Roberta E; Isler, Yasmin et al. (2014) Cholesterol stabilizes fluid phosphoinositide domains. Chem Phys Lipids 182:52-61
Ramirez, Yulian P; Weatherbee, Jessica L; Wheelhouse, Richard T et al. (2013) Glioblastoma multiforme therapy and mechanisms of resistance. Pharmaceuticals (Basel) 6:1475-506
Gericke, Arne; Leslie, Nicholas R; Lösche, Mathias et al. (2013) PtdIns(4,5)P2-mediated cell signaling: emerging principles and PTEN as a paradigm for regulatory mechanism. Adv Exp Med Biol 991:85-104
Shenoy, Siddharth; Shekhar, Prabhanshu; Heinrich, Frank et al. (2012) Membrane association of the PTEN tumor suppressor: molecular details of the protein-membrane complex from SPR binding studies and neutron reflection. PLoS One 7:e32591

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