Abstract
Deregulation of c-myc expression is implicated in the pathogenesis of many neoplasias. Estrogen receptor alpha (ERalpha) can increase the rate of c-myc transcription through the recruitment of a variety of cofactors to the promoter, yet the precise roles of these cofactors in transcription and tumorigenesis are largely unknown. We show here that a putative tumor suppressor TIP30, also called CC3 or Htatip2, interacts with an ERalpha-interacting coactivator CIA. Using chromatin immunoprecipitation assays, we demonstrate that TIP30 and CIA are distinct cofactors that are dynamically associated with the promoter and downstream regions of the c-myc gene in response to estrogen. Both TIP30 and CIA are recruited to the c-myc gene promoter by liganded ERalpha in the second transcription cycle. TIP30 overexpression represses ERalpha-mediated c-myc transcription, whereas TIP30 deficiency enhances c-myc transcription in both the absence and presence of estrogen. Ectopic CIA cooperates with TIP30 to repress ERalpha-mediated c-myc transcription. Moreover, virgin TIP30 knockout mice exhibit increased c-myc expression in mammary glands. Together, these results reveal an important role for TIP30 in the regulation of ERalpha-mediated c-myc transcription and suggest a mechanism for tumorigenesis promoted by TIP30 deficiency.
Highlights
Deregulation of c-myc expression is implicated in the pathogenesis of many neoplasias
Virgin TIP30 knockout mice exhibit increased c-myc expression in mammary glands. These results reveal an important role for TIP30 in the regulation of ER␣-mediated c-myc transcription and suggest a mechanism for tumorigenesis promoted by TIP30 deficiency
TIP30 and CIA are associated with the c-myc promoter in the absence of E2 and associated with the promoter and transcribed regions in the second transcription cycle in the presence of E2, suggesting that they are present in the same transcription complexes (Fig. 2)
Summary
Deregulation of c-myc expression is implicated in the pathogenesis of many neoplasias. Both TIP30 and CIA are recruited to the c-myc gene promoter by liganded ER␣ in the second transcription cycle.
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