Historically, the TFIID complex has been viewed as part of the general transcriptional apparatus; however, recent studies demonstrate that it is flexible in its constituents and has tissue-specific functions. The gonadal-enriched TFIID subunit TAF4B is required for murine fertility and mediates estrogen-induced proliferation of ovarian granulosa cells. These results prompted the hypothesis that TAF4B is part of an ovarian estrogen signaling pathway. Furthermore, the fact that ovarian tumors rely on deregulation of the same growth and apoptotic signaling pathways that regulate folliculogenesis suggested that TAF4B may also affect ovarian tumorigenesis. To determine whether TAF4B is involved in ovarian estrogen response, I first tested whether Taf4b is itself estrogen responsive. Indeed, Taf4b mRNA and TAF4B protein were upregulated in normal mouse ovaries and mouse ovarian tumors exposed to exogenous estrogens. This response occurred primarily via ERβ; however, ERα could maintain Taf4b levels in ERβ’s absence. Bioinformatic promoter analysis allowed the identification of a putative estrogen response element in the Taf4b promoter. The significance of these results was explored by comparing estrogen-dependent transcriptional responses in Taf4b-knockout versus wildtype ovaries. Microarray analysis revealed a small number of genes differing in their response to estrogen in the absence of TAF4B. Together with the estrogen responsiveness of TAF4B, these results illustrate the involvement of TAF4B in ovarian estrogen response. To complement this genome-wide approach, ovarian tumor development was examined in Taf4b-knockout and wildtype mice. Preliminary data suggest that Taf4b-knockout mice can develop tumors; however, background strain effects of the Taf4b mouse line precluded determining the effect of TAF4B on estrogen-induced changes in tumor onset and survival. In addition to TAF4B, I show that other TFIID subunits, especially TAF2, are amplified or upregulated in many high-grade serous ovarian cancers. A cell-based assay was established to identify TAF inhibitors that could potentially be used to disrupt TFIID in human ovarian cancer. Together, the results presented demonstrate that TAFs should be examined more closely for their specific roles in ovarian cancer and for how their deregulation can be targeted in future therapeutics.
Ribeiro, Jennifer R.,
"Molecular and Functional Roles of TAF4B in Ovarian Health and Disease"
(2014).
Pathobiology Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z02N50NN
