Mutant p53 tumor suppressor gene causes resistance to transforming growth factor beta 1 in murine keratinocytes.
Human carcinoma cell lines are frequently refractory to the antiproliferative effect of the autocrine growth inhibitor transforming growth factor beta 1 (TGF-beta 1) and often express mutant forms of the tumor suppressor gene p53. Therefore, we wished to determine whether mutant p53 affects the cellular response to TGF-beta 1. A murine p53 complementary DNA carrying an activating point mutation was introduced into TGF-beta 1-sensitive BALB/MK mouse epidermal keratinocytes by retroviral infection. Mp53 transformed cells displayed a spindle-type morphology and expressed between 0.02 and 0.7 ng of mutant p53/mg total protein. Furthermore, whereas TGF-beta 1 caused approximately 90% maximal inhibition of DNA synthesis of parental BALB/MK cells, the Mp53 transformants were inhibited by less than 70%. The median inhibiting dose of TGF-beta 1 was 4.07 +/- 1 (SE) pM for BALB/MK cells, but ranged from 2.4 to 11.2 pM and from 11.7 to 40 pM for two different sets of Mp53 transformants, and increased as a function of the amounts of mutant p53 protein that were expressed. Our findings suggest that mutant forms of p53 inhibit the antiproliferative effect of TGF-beta 1 by interfering with its signaling pathway.
Reiss
M
M
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Vellucci
V F
VF
Zhou
Z L
ZL
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D004351:Drug Resistance / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016158:Genes, p53; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D016212:Transforming Growth Factor beta