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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1995-07, Vol.55 (13), p.2910-2919
Main Authors: 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
Format: Article
Language:English
Subjects:
Adenoma - genetics
Animals
Antibodies, Monoclonal - immunology
Base Sequence
Carcinoma - genetics
Colorectal Neoplasms - genetics
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - genetics
Cyclins - metabolism
DNA Primers - chemistry
Female
Gene Expression Regulation, Neoplastic
Humans
Immunoenzyme Techniques
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Molecular Sequence Data
Promoter Regions, Genetic
Rats
RNA, Messenger - genetics
Sequence Alignment
Sequence Homology, Nucleic Acid
Skin - metabolism
Transcription, Genetic
Tumor Suppressor Protein p53 - physiology
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Summary: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.
ISSN:0008-5472