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Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues.

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/CIP1 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/CIP1 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/CIP1. 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.

Pubmed ID: 7796420


  • el-Deiry WS
  • Tokino T
  • Waldman T
  • Oliner JD
  • Velculescu VE
  • Burrell M
  • Hill DE
  • Healy E
  • Rees JL
  • Hamilton SR


Cancer research

Publication Data

July 1, 1995

Associated Grants

  • Agency: NCI NIH HHS, Id: CA43460
  • Agency: NCI NIH HHS, Id: CA62924
  • Agency: NIGMS NIH HHS, Id: GM07184

Mesh Terms

  • Adenoma
  • Animals
  • Antibodies, Monoclonal
  • Base Sequence
  • Carcinoma
  • Colorectal Neoplasms
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA Primers
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • RNA, Messenger
  • Rats
  • Sequence Alignment
  • Sequence Homology, Nucleic Acid
  • Skin
  • Transcription, Genetic
  • Tumor Suppressor Protein p53