Activation of p53-p21waf1 pathway in response to disruption of cell-matrix interactions.
The proliferation of most cells is strictly dependent on cell-matrix interactions, a phenomenon called anchorage dependence. Because tumor cells often are independent of this regulation, it is important to characterize the molecular pathways that control cellular proliferation after detachment of cells from their matrix. In this report, we investigated a possible role of p53 and one of its target genes, p21(waf1/cip1), as components of anchorage-dependent cell growth control. We found that p53 protein is rapidly activated upon the disruption of cellular attachment. This led to p21 transcriptional activation via two p53-binding sites in its promoter. Elevated p21 protein levels blocked transcription and activity of the cell cycle-regulator cyclin A, and cells became arrested in G1 of the cell cycle. Under the same conditions, fibroblasts from p53 knock-out mice did not activate p21 and did not down-regulate cyclin A expression but rather induced another cell cycle inhibitor, p27. Thus, our results characterize a chain of events, starting from the activation of p53 and proceeding via p21 to cyclin A, that is activated in response to the loss of cellular adherence. This p53-regulated pathway may constitute one of a few redundant systems to ensure proper cell control in multicellular organisms.
Wu
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Department of Molecular Microbiology and Immunology, and K. Norris, Jr. Comprehensive Cancer Center, University of Southern California Medical School, HMR-405, Los Angeles, California 90033, USA.
Schönthal
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AH
D000818:Animals; D002460:Cell Line; D019925:Cyclin A / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493957:Cdkn1a protein, mouse; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53