Topological Control of p21WAF1/CIP1 Expression in Normal and Neoplastic Tissues

Wafik S. El-Deiry, Takashi Tokino, Todd Waldman, Jon D. Oliner, Victor E. Velculescu, Marilee Burrell, David E. Hill, Eugene Healy, Jonathan L. Rees, Stanley R. Hamilton, Kenneth W. Kinzler, Bert Vogelstein

Research output: Contribution to journalArticle

Abstract

The p53-regulated gene product p21WAF1/CIP1 is the prototype of a family of small proteins that negatively regulate the cell cycle. To learn more about p21WAF1/CIP1 regulation in vivo, monoclonal antibodies were developed for immunohistochemistry. These revealed that p21WAF1/CIPI, expression followed radiation-induced DNA damage in human skin in a pattern consistent with its regulation by p53. A detailed comparison of the human, rat, and mouse p21WAF1/CIP1 promoter sequences revealed that this induction was probably mediated by conserved p53-binding sites upstream of the transcription start site. In unirradiated tissues, p21WAF1/CIPI expression was apparently independent of p53 and was observed in a variety of cell types. Moreover, there was a striking compartmentalization of p21WAF1/CIP1 expression throughout the gastrointestinal tract that correlated with proliferation rather than differentiation. As epithelial cells migrated up the crypts, the Ki67-expressing proliferating compartment near the crypt base ended abruptly, with the coincident appearance of a nonproliferating compartment expressing p21WAF1/CIPI. In colonic neoplasms, this distinct compartmentalization was largely abrogated. Cell cycle inhibitors are thus subject to precise topological control, and escape from this regulation may be a critical feature of neoplastic transformation.

Original languageEnglish (US)
Pages (from-to)2910-2919
Number of pages10
JournalCancer Research
Volume55
Issue number13
StatePublished - Jul 1 1995

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

El-Deiry, W. S., Tokino, T., Waldman, T., Oliner, J. D., Velculescu, V. E., Burrell, M., Hill, D. E., Healy, E., Rees, J. L., Hamilton, S. R., Kinzler, K. W., & Vogelstein, B. (1995). Topological Control of p21WAF1/CIP1 Expression in Normal and Neoplastic Tissues. Cancer Research, 55(13), 2910-2919.