Wild-type p53 demonstrates functional dominance in a human colon carcinoma cell line in which it induces reversible growth arrest.
We have introduced an inducible wild-type p53 allele into the human SW480 colon cancer cell line, which bears an endogenous mutant p53 allele. The expression of inducible wild-type p53 is under basal repression by the lac repressor and is induced by isopropyl-beta-thiogalactopyranoside. The addition of isopropyl-beta-thiogalactopyranoside induces expression of wild-type p53 transcript and protein at a level no greater than that of the endogenous mutant p53. This level of wild-type p53 induction is sufficient both to induce expression of WAF1/CIP1 and to induce G1 cell cycle arrest. This p53-induced growth arrest is reversible after 6 days of continuous p53 expression, indicating that apoptosis is not induced. These results demonstrate that in a human colon epithelial cell background, wild-type p53 is functionally dominant over this mutant p53 and thus provides a mechanism for the observed inactivation of both copies of the p53 gene in most colon cancers. Moreover, despite the well-documented role of apoptosis in maintaining homeostasis in the nontransformed colon epithelium, these results demonstrate that restoration of wild-type p53 expression is insufficient to trigger apoptosis of transformed colonic cells.
Yang
B
B
Departments of Molecular Biology & Microbiology and Medicine, Case Western Reserve University and Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Stambrook
P J
PJ
Markowitz
S D
SD
D002453:Cell Cycle / Q000235:genetics* / Q000502:physiology; D002455:Cell Division; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000235:genetics; D016193:G1 Phase / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005799:Genes, Dominant / Q000235:genetics; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012097:Repressor Proteins; D007544:Isopropyl Thiogalactoside