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

Oncogene volume 18, pages 6252–6261 (1999)Cite this article

Abstract

p21Cip1/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.

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Acknowledgements

Supported by the Academy of Finland, Finnish Cancer Organizations, Emil Aaltonen Foundation, Finnish Medical Society Duodecim, Instrumentarium Scientific Fund and Biocentrum Helsinki. We thank Juha Saharinen for good advice on PCR.

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Authors and Affiliations

  1. Department of Virology, Haartman Institute, University of Helsinki, FIN-00014, Helsinki, PO Box 21, (Haartmaninkatu 3), Finland

    Laura Kivinen, Minna Tsubari, Tarja Haapajärvi & Marikki Laiho

  2. Department of Pharmacology, Duke University Medical Center, Durham, North Carolina, 27710, NC, USA

    Michael B Datto & Xiao-Fan Wang

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  1. Laura Kivinen
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Kivinen, L., Tsubari, M., Haapajärvi, T. et al. Ras induces p21Cip1/Waf1 cyclin kinase inhibitor transcriptionally through Sp1-binding sites. Oncogene 18, 6252–6261 (1999). https://doi.org/10.1038/sj.onc.1203000

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