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 RIS Download
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