TIP30 interacts with an estrogen receptor alpha-interacting coactivator CIA and regulates c-myc transcription.
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.
Jiang
Chao
C
Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha 68198-7696, USA.
Ito
Mitsuhiro
M
Piening
Valerie
V
Bruck
Kristy
K
Roeder
Robert G
RG
Xiao
Hua
H
D000123:Acetyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D047628:Estrogen Receptor alpha; D005091:Exons / Q000235:genetics; D005260:Female; D016259:Genes, myc / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056918:Nuclear Receptor Coactivators; D011233:Precipitin Tests / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D047628:Estrogen Receptor alpha; C418222:NCOA5 protein, human; D056918:Nuclear Receptor Coactivators; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D014157:Transcription Factors; D000123:Acetyltransferases; C111246:HTATIP2 protein, human