TOPOLOGICAL CONTROL OF P21(WAF1 CIP1) EXPRESSION IN NORMAL AND NEOPLASTIC TISSUES/

The p53-regulated gene product p21(WAF1/CIP1) is the prototype of a fa mily of small proteins that negatively regulate the cell cycle. To lea rn more about p21(WAF1/CIP1) regulation in vivo, monoclonal antibodies were developed for immunohistochemistry. These revealed that p21(WAF1 /CIP1) expression followed radiation-induced DNA damage in human skin in a pattern consistent with its regulation by p53. A detailed compari son of the human, rat, and mouse p21(WAF1/CIP1) promoter sequences rev ealed that this induction was probably mediated by conserved p53-bindi ng sites upstream of the transcription start site. In unirradiated tis sues, p21(WAF1/CIP1) expression was apparently independent of p53 and was observed in a variety of cell types. Moreover, there was a strikin g compartmentalization of p21(WAF1/CIP1) expression throughout the gas trointestinal tract that correlated with proliferation rather than dif ferentiation. As epithelial cells migrated up the crypts, the Ki67-exp ressing proliferating compartment near the crypt base ended abruptly, with the coincident appearance of a nonproliferating compartment expre ssing p21(WAF1/CIP1). In colored neoplasms, this distinct compartmenta lization was largely abrogated. Cell cycle inhibitors are thus subject to precise topological control, and escape from this regulation may b e a critical feature of neoplastic transformation.