Ras induces p21(Cip1/Waf1) cyclin kinase inhibitor transcriptionally through Sp1-binding sites

Laura Kivinen, Minna Tsubari, Tarja Haapajärvi, Michael B. Datto, Xiao Fan Wang, Marikki Laiho

Research output: Contribution to journalArticlepeer-review

Abstract

p21(Cip/Waf1) cyclin-dependent kinase inhibitor (p21) is inducible by Raf and mitogen-activated protein kinase kinase (MAPKK), but the level of regulation is unknown, We show here by conditional and transient Ras-expression models that Ras induces p21. Induction of p21 in conditionally Ras-expressing cells is posttranscriptional utilizing mitogen-activated protein kinase (MAPK) pathway. Transient, high-level Ras-expression induces transcriptional activation of p21 mediated by a GC-rich region in p21 promoter -83-54 bp relative to the transcription initiation site containing binding sites for Sp1-family transcription factors. Mutation of either Sp1-binding site 2 or 4 in this region decreases the magnitude of induction of promoter activity by Ras, but only the simultaneous mutation of both sites abolishes fully the induction. Electrophoretic mobility shift assays using an oligonucleotide corresponding to Sp1-binding site 2 indicate that both Sp1 and Sp3 transcription factors bind to this region. The results demonstrate that the central cytosolic growth regulator Ras is a potent transcriptional and posttranscriptional inducer of the nuclear growth inhibitor p21.

Original languageEnglish (US)
Pages (from-to)6252-6261
Number of pages10
JournalOncogene
Volume18
Issue number46
DOIs
StatePublished - Nov 4 1999

Keywords

  • Ras
  • Transcriptional activation
  • p21(Cip/Waf1)

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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