This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Disruption of regulated gene expression pathways leading to the loss of cell proliferation control is a hallmark of human cancer cells. Accordingly, diverse signaling pathways have evolved to carefully orchestrate the timely proliferation of multiple cell types in multi-cellular organisms. In the mammalian ovary, somatic folli-cle granulosa cells surround and nurture the developing oocyte during normal oognesis. TAF4b is a gonadal-specific component of the multi-protein TFIID complex that is a general RNA polymerase II transcription fac-tor. The production of TAF4b-null mice has uncovered a specific role for TAF4b in the timely regulation of gene expression required for normal granulosa cell proliferation. Based on these data, we hypothesize that over-expression of TAF4b in the ovary will cause aberrant gene expression patterns that lead to over-proliferation of granulosa cells. To test this hypothesis, we propose to look at the effects of over-expression of TAF4b on gene expression and proliferation in cultured mouse granulosa cells. We also will test the effects of over-expressing TAF4b in vivo by producing transgenic mice that express exogenous TAF4b protein in the ovary. Ovarian histology combined with proliferation assays of transgenic ovaries will be used to examine whether TAF4b over-expression leads to granulosa tumor formation in the ovary. Together, these studies will compare TAF4b-dependent expression patterns in vitro and in vivo and will yield fundamental mechanism of gene expression required for normal cellular proliferation. More importantly, these studies will be the first steps towards the understanding whether elevated TAF4b levels may be associated with ovarian cancer in women. Ovarian cancer is the fifth leading cause of cancer deaths among women in the United States. Ap-proximately five to ten percent of these ovarian cancer patients suffer from granulosa-derived tumors of the ovary. The study of fundamental growth control of granulosa cells regulated by TAF4b may yield important genetic pathways that are dysregualated in granulosa-derived ovarian cancer. The transgenic mice produced for these studies may also yield new mouse models of granulosa tumor formation. Such animal models may ultimately yield useful tools in the diagnostic or therapeutic treatment of this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015578-10
Application #
7959355
Study Section
Special Emphasis Panel (ZRR1-RI-8 (01))
Project Start
2009-03-01
Project End
2010-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
10
Fiscal Year
2009
Total Cost
$233,467
Indirect Cost
Name
Brown University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Lovasco, Lindsay A; Gustafson, Eric A; Seymour, Kimberly A et al. (2015) TAF4b is required for mouse spermatogonial stem cell development. Stem Cells 33:1267-76
Ribeiro, Jennifer R; Freiman, Richard N (2014) Estrogen signaling crosstalk: Implications for endocrine resistance in ovarian cancer. J Steroid Biochem Mol Biol 143:160-73
Casella, Cinzia; Miller, Daniel H; Lynch, Kerry et al. (2014) Oxysterols synergize with statins by inhibiting SREBP-2 in ovarian cancer cells. Gynecol Oncol 135:333-41
Grive, Kathryn J; Seymour, Kimberly A; Mehta, Rajvi et al. (2014) TAF4b promotes mouse primordial follicle assembly and oocyte survival. Dev Biol 392:42-51
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Minhas, Hassan M; Pescosolido, Matthew F; Schwede, Matthew et al. (2013) An unbalanced translocation involving loss of 10q26.2 and gain of 11q25 in a pedigree with autism spectrum disorder and cerebellar juvenile pilocytic astrocytoma. Am J Med Genet A 161A:787-91
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Li, Hua; Jogl, Gerwald (2013) Crystal structure of decaprenylphosphoryl-?- D-ribose 2'-epimerase from Mycobacterium smegmatis. Proteins 81:538-43
Tomimaru, Yoshito; Koga, Hironori; Yano, Hirohisa et al. (2013) Upregulation of T-cell factor-4 isoform-responsive target genes in hepatocellular carcinoma. Liver Int 33:1100-12
Tomimaru, Yoshito; Koga, Hironori; Shin, Tai Ho et al. (2013) The SxxSS motif of T-cell factor-4 isoforms modulates Wnt/?-catenin signal activation in hepatocellular carcinoma cells. Cancer Lett 336:359-69

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