Progesterone regulates transcription of the p21(WAF1) cyclin-dependent kinase inhibitor gene through Sp1 and CBP/p300

Owen, GI; Richer, JK; Tung, L; Takimoto, G; Horwitz, KB

Abstract

Progesterone has biphasic effects on proliferation of breast cancer cells; it stimulates growth in the first cell cycle, then arrests cells at G(1)/S of the second cycle accompanied by up-regulation of the cyclin-dependent kinase inhibitor, p21. We now show that progesterone regulates transcription of the p21 promoter by an unusual mechanism. This promoter lacks a canonical progesterone response element. Instead, progesterone receptors (PRs) interact with the promoter through the transcription factor Spl at the third and fourth of six Spl binding sites located downstream of nucleotide 154. Mutation of Spl site 3 eliminates basal transcription, and mutation of sites 3 and 4 eliminates transcriptional up-regulation by progesterone. Progesterone-mediated transcription is further prevented by overexpression of E1A, suggesting that CBP/p300 is required. Indeed, in HeLa cells, Spl and CBP/p300 associate with stably integrated flag-tagged PRs in a multiprotein complex. Since many signals converge on p21, cross-talk between PRs and other factors co-localized on the p21 promoter, may explain how progesterone can be either proliferative or differentiative in different target cells.

Más información

Título según WOS: ID WOS:000073224200082 Not found in local WOS DB
Título de la Revista: JOURNAL OF BIOLOGICAL CHEMISTRY
Volumen: 273
Número: 17
Editorial: Elsevier
Fecha de publicación: 1998
Página de inicio: 10696
Página final: 10701
DOI:

10.1074/jbc.273.17.10696

Notas: ISI