PTEN is a tumor suppressor and the first phosphatase identified to be frequently mutated/deleted somatically in a variety of human cancers. Substantial evidence supports that loss of PTEN promotes the development of human cancer. PTEN normally serves to repress the activation of the PIS kinase signaling pathway. However, little is yet known regarding PTEN-mediated changes in gene expression that are lost in cells that lack PTEN. Our studies will examine the novel idea that PTEN, and PIS kinase/Akt signaling, regulates RNA polymerase (pol)Ill-dependent gene expression and that this regulatory event is lost in human carcinoma cells that exhibit reduced PTEN expression. As RNA pol III products, tRNAs and 5S rRNAs, determine the translational capacity of cells, repression of RNA pol III transcription by PTEN is likely to be fundamental to its tumor suppressing function. Our studies will identify new targets of PTEN, and elucidate in detail, the mechanism for how loss of PTEN leads to deregulation of RNA pol III transcription in several different human cell lines. By comparing cells that contain alterations in the levels of functional PTEN, we will: (1) Determine whether PTEN represses transcription of the three major classes of RNA pol III promoters;(2) Determine the PTEN/Akt-regulated signaling pathways involved in this response;and determine whether PTEN may also function in the nucleus to directly repress the transcription process. (3) Identify quantitative and/or qualitative changes in factor(s) of the RNA pol III transcription machinery that is/are specifically targeted by PTEN;and (4) Determine how these changes in the transcription components alters their function and the formation of transcription initiation complexes in vivo. From these studies, we will identify novel downstream targets of PTEN that are important for its function as a tumor suppressor and provide the first evidence that the deregulation of RNA pol III genes is a consequence of the loss of PTEN. Defining the PTEN-mediated signaling pathways and targets that are aberrantly regulated in cells that have lost PTEN function, giving rise to these specific consequences gene expression, will provide a valuable nexus for investigation of therapeutic agents that mimic PTEN function.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108614-05
Application #
7749054
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2006-02-06
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$224,748
Indirect Cost
Name
University of Southern California
Department
Biochemistry
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Johnson, Deborah L; Stiles, Bangyan L (2016) Maf1, A New PTEN Target Linking RNA and Lipid Metabolism. Trends Endocrinol Metab 27:742-50
Khanna, Akshat; Johnson, Deborah L; Curran, Sean P (2014) Physiological roles for mafr-1 in reproduction and lipid homeostasis. Cell Rep 9:2180-91
Palian, Beth M; Rohira, Aarti D; Johnson, Sandra A S et al. (2014) Maf1 is a novel target of PTEN and PI3K signaling that negatively regulates oncogenesis and lipid metabolism. PLoS Genet 10:e1004789
Zeng, Ni; Yang, Kai-Ting; Bayan, Jennifer-Ann et al. (2013) PTEN controls β-cell regeneration in aged mice by regulating cell cycle inhibitor p16ink4a. Aging Cell 12:1000-11
Rohira, Aarti D; Chen, Chun-Yuan; Allen, Justin R et al. (2013) Covalent small ubiquitin-like modifier (SUMO) modification of Maf1 protein controls RNA polymerase III-dependent transcription repression. J Biol Chem 288:19288-95
Lin, H Helen; Li, Xu; Chen, Jo-Lin et al. (2012) Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia. Mol Cell Biol 32:1124-38
Zhong, Shuping; Machida, Keigo; Tsukamoto, Hide et al. (2011) Alcohol induces RNA polymerase III-dependent transcription through c-Jun by co-regulating TATA-binding protein (TBP) and Brf1 expression. J Biol Chem 286:2393-401
Zhong, Shuping; Johnson, Deborah L (2009) The JNKs differentially regulate RNA polymerase III transcription by coordinately modulating the expression of all TFIIIB subunits. Proc Natl Acad Sci U S A 106:12682-7
Woiwode, Annette; Johnson, Sandra A S; Zhong, Shuping et al. (2008) PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex. Mol Cell Biol 28:4204-14
Johnson, Sandra A S; Dubeau, Louis; Johnson, Deborah L (2008) Enhanced RNA polymerase III-dependent transcription is required for oncogenic transformation. J Biol Chem 283:19184-91

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