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Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1-binding sites

L Kivinen1, M Tsubari, T Haapajärvi

  • 1Haartman Institute, Department of Virology, University of Helsinki, Finland.

Oncogene
|December 22, 1999
PubMed

Insights

Ras, a key growth regulator, potently induces the cell cycle inhibitor p21 through both transcriptional and posttranscriptional mechanisms, impacting cell growth regulation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • The regulation of p21Cip1/Waf1 (p21), a cyclin-dependent kinase inhibitor, by upstream signaling pathways like Raf and MAPKK is known.
  • However, the precise mechanisms and extent of Ras-mediated regulation of p21 remain incompletely understood.

Purpose of the Study:

  • To investigate the role of Ras in inducing p21 expression.
  • To elucidate the transcriptional and posttranscriptional mechanisms underlying Ras-induced p21.
  • To identify the specific regulatory elements and transcription factors involved in Ras-mediated p21 transcriptional activation.

Main Methods:

  • Utilized conditional and transient Ras-expression models in cellular systems.
  • Investigated posttranscriptional regulation via the mitogen-activated protein kinase (MAPK) pathway.
  • Analyzed transcriptional activation by examining the p21 promoter region (-83 to -54 bp) using mutations and electrophoretic mobility shift assays (EMSAs).

Main Results:

  • Ras was demonstrated to induce p21 expression.
  • Posttranscriptional induction of p21 by Ras in conditionally expressing cells occurs via the MAPK pathway.
  • High-level transient Ras expression leads to transcriptional activation of p21, mediated by a GC-rich promoter region (-83 to -54 bp) containing Sp1 transcription factor binding sites.
  • Simultaneous mutation of Sp1-binding sites 2 and 4 abolished Ras-induced promoter activity.
  • EMSAs confirmed binding of Sp1 and Sp3 transcription factors to Sp1-binding site 2.

Conclusions:

  • Ras acts as a significant inducer of p21 at both transcriptional and posttranscriptional levels.
  • The findings clarify the intricate regulatory network connecting Ras signaling to cell cycle control through p21.
  • This study highlights the importance of the Sp1 transcription factor family in mediating Ras-induced p21 transcription.

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