In the previous grant period, we made the unexpected discovery that members of the epidermal growth factor receptor family differentially regulate expression of the central transcription initiation factor, TBP, and defined new signaling pathways and transcription factors that regulate TBP expression. In addition to identifying positive regulators of TBP, we discovered a novel human protein, Maf1, which represses TBP transcription. Maf1 is an important transcriptional repressor that uniquely targets both RNA pol II- and pol III-transcribed genes that promote oncogenic transformation. Our new results support the idea that Maf1 is a key target of PTEN that is critical for its tumor suppressor function. Loss of PTEN results in a marked decrease in Maf1 expression;increased Maf1 expression suppresses cellular transformation in PTEN- deficient cells;and nuclear Maf1 expression is diminished in both mouse and human prostate cancers that are PTEN-deficient. Our overall goal is to understand the molecular and biological function of Maf1, and to use mouse models to determine whether the resultant decrease in Maf1 expression, by loss of PTEN, contributes to the development of prostate cancer.
Aim 1 will identify Maf1 occupied regions genome- wide in primary human prostate epithelial cells. Given our newly identified interaction between Maf1 and the transcription factor Mediator CDK8 subcomplex, we will further test the novel hypothesis that Maf1 blocks the ability of this subcomplex to induce both RNA pol II- and III-dependent gene expression. These studies will define new paradigms by which transcription from different RNA polymerases are co-repressed, thus elucidating important gene repression pathways. Given that CDK8 is a potent oncoprotein, Aim 2 will further assess whether Maf1 abrogates CDK8-mediated oncogenic transformation. A transgenic mouse model will be established to test the idea that restoring Maf1 expression in PTEN-deficient mouse prostate will block or delay prostate intraepithelial neoplasia and tumorigenesis. Characterization of Maf1 will provide a new paradigm for how cells suppress a transformed phenotype and define a novel PTEN target whose loss is critical to the development of prostate cancer.

Public Health Relevance

This proposal will characterize a novel protein, Maf1, which selectively represses the expression of genes that drive oncogenesis. Importantly, Maf1 acts to repress transcription from all three nuclear RNA polymerases. Key to this function is the ability of Maf1 to regulate the expression of the central transcription initiation factor, TBP. Furthermore, Maf1 expression is deregulated in cancer through the inactivation of the tumor suppressor, PTEN. Elucidating the function of Maf1 will greatly enhance our understanding of how cells maintain a non-transformed state and provide a new paradigm for how distinct RNA polymerase systems are coordinately regulated.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-OBT-Z (02))
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Mietz, Judy
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University of Southern California
Schools of Medicine
Los Angeles
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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; 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
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
Fromm, Jody A; Johnson, Sandra A S; Johnson, Deborah L (2008) Epidermal growth factor receptor 1 (EGFR1) and its variant EGFRvIII regulate TATA-binding protein expression through distinct pathways. Mol Cell Biol 28:6483-95
Johnson, Sandra S; Zhang, Cheng; Fromm, Jody et al. (2007) Mammalian Maf1 is a negative regulator of transcription by all three nuclear RNA polymerases. Mol Cell 26:367-79
Zhong, Shuping; Fromm, Jody; Johnson, Deborah L (2007) TBP is differentially regulated by c-Jun N-terminal kinase 1 (JNK1) and JNK2 through Elk-1, controlling c-Jun expression and cell proliferation. Mol Cell Biol 27:54-64
Zhang, Cheng; Comai, Lucio; Johnson, Deborah L (2005) PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex. Mol Cell Biol 25:6899-911
Zhong, Shuping; Zhang, Cheng; Johnson, Deborah L (2004) Epidermal growth factor enhances cellular TATA binding protein levels and induces RNA polymerase I- and III-dependent gene activity. Mol Cell Biol 24:5119-29
Johnson, Sandra A S; Dubeau, Louis; Kawalek, Michael et al. (2003) Increased expression of TATA-binding protein, the central transcription factor, can contribute to oncogenesis. Mol Cell Biol 23:3043-51

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