Regulation of Estrogen-Responsive Gene Expression and Tumor Suppression by Transcriptional Cofactors
Annual rept. 1 May 2003-30 Apr 2004
NEBRASKA UNIV MEDICAL CENTER OMAHA
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The growth and metastatic potential of breast cancer cells are regulated by estrogen, a ligand of the estrogen receptors ERs 1, 2. The ERs facilitate major effects of estrogen in cells through interactions with transcriptional cofactors to regulate transcription of ER- targeting genes. We previously identified two human cofactors TIP30 and CIA Coativator Independent of AF2 that can specifically regulate ERalpha-mediated transcription. TIP3O, also called CC3 or Htatip2, is a tumor suppressor that can promote apoptosis and inhibits angiogensis, through the regulation of transcription 3-5. TIP3O interacts with an ERalpha-interacting coactivator CIA 6,7. Therefore, we hypothesized that overexpression of both TIP3O and CIA will inhibit transcription of ER-target genes such as c-Myc and Cyclin D1 and overexpression of TIP3O and CIA in ER-negative MDA-MB-231 breast cancer cells suppresses cell growth. We proposed to determine the effects of TIP3O and CIA on expression of ERalpha-responsive genes, such as c-Myc and Cyclin Dl in the first year. Now, we show that TIP3O overexpression represses ERalpha-mediated c-myc transcription, whereas TIP3O deficiency enhances c-myc transcription in the absence and presence of estrogen. Ectopic CIA cooperates with TIP3O to repress ERalpha-mediated c-myc transcription. Using chromatin immunoprecipitation ChIP assays 8, we demonstrate that TIP3O and CIA are distinct cofactors that are dynamically associated with transcription initiation and elongation complexes in response to estrogen. Both TIP3O and CIA are recruited to the C-myc gene promoter by liganded ERalpha in the second transcription cycle. Overexpression of TIP30 and CIA in ER-negative MDA-MB-231 breast cancer cells suppresses cell growth.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research