Functional analysis of the transforming growth factor beta responsive elements in the WAF1/Cip1/p21 promoter.

Published

Journal Article

The transforming growth factor beta s (TGF-beta s) are a group of multifunctional growth factors that inhibit cell cycle progression in many cell types. The TGF-beta-induced cell cycle arrest has been partially attributed to the regulatory effects of TGF-beta on both the levels and activities of the G1 cyclins and their cyclin-dependent kinase partners. The ability of TGF-beta to inhibit the activity of these kinase complexes derives in part from its regulatory effects on the cyclin-dependent kinase inhibitors, p21/WAF1/Cip1, p27Kip1, and p15. Upon treatment of cells with TGF-beta, these three inhibitors bind to and block the activities of specific cyclin-cyclin-dependent kinase complexes to cause cell cycle arrest. Little is known, however, on the mechanism through which TGF-beta activates these cyclin-dependent kinase inhibitors. In the case of p21, TGF-beta treatment leads to an increase in p21 mRNA. This increase in p21 mRNA is partly due to transcriptional activation of the p21 promoter by TGF-beta. To further define the signaling pathways through which TGF-beta induces p21, we have performed a detailed functional analysis on the p21 promoter. Through both deletion and mutation analysis of the p21 promoter, we have defined a 10-base pair sequence that is required for the activation of the p21 promoter by TGF-beta. In addition, this sequence is sufficient to drive TGF-beta-mediated transcription from a previously nonresponsive promoter. Preliminary gel shift assays demonstrate that this TGF-beta responsive element binds specifically to several proteins in vitro. Two of these proteins are the transcription factors Sp-1 and Sp-3. These studies represent the initial steps toward defining the signaling pathways involved in TGF-beta-mediated transcriptional activation of p21.

Full Text

Duke Authors

Cited Authors

  • Datto, MB; Yu, Y; Wang, XF

Published Date

  • December 1, 1995

Published In

Volume / Issue

  • 270 / 48

Start / End Page

  • 28623 - 28628

PubMed ID

  • 7499379

Pubmed Central ID

  • 7499379

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.270.48.28623

Language

  • eng

Conference Location

  • United States