Human carcinoma cell lines are frequently refractory to the antiproliferative effect of the autocrine growth inhibitor transforming growth factor β1 (TGF-β1) 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-β1. A murine p53 complementary DNA carrying an activating point mutation was introduced into TGF-β1-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-β1 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-β1 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-β1 by interfering with its signaling pathway.
Supported in part by USPHS Grant CA 41556 of the National Cancer Institute.