Effects of p53 mutants on wild-type p53-mediated transactivation are cell type dependent

K. Forrester, S. E. Lupold, V. L. Ott, C. H. Chay, V. Band, X. W. Wang, C. C. Harris

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

The spectrum of p53 mutations differs among human cancer types. We have hypothesized that the p53 mutational spectrum observed in particular tumor types reflects the functional ability of different p53 mutants to modulate wild-type (WT) p53-dependent gene transcription. Missense p53 mutants representing several mutational hotspot codons were cotransfected with WT p53 and analysed for their effects on p53-dependent transactivation of a reporter construct containing a specific p53 binding sequence (PG13-CAT) in human tumor cell lines lacking endogenous p53. Our results show that the ability of p53 mutants to inhibit WT p53-mediated transactivation is cell type dependent. In cell lines derived from a lung adenocarcinoma and a mesothelioma, the transactivation function of WT p53 was strongly inhibited by all p53 mutants examined. However, in cell lines derived from a prostate carcinoma and an osteosarcoma, the mutants examined generally had only minimal dominant negative effects. In cell lines derived from a hepatocellular carcinoma and an ovarian carcinoma, two mutants (248(trp) and 273(his)) enhanced WT p53 mediated-transactivation of the reporter construct. Additional mutants retained the ability to inhibit WT p53-mediated transactivation in these cell lines. In addition, in a series of four breast tumor cell lines, the p53 mutants examined had similar effects on WT p53 transactivation ability including enhanced transactivation activity in the 273(his) cotransfectants. The p53 mutants mere incapable of transactivating the PG13-CAT reporter in the absence of WT p53 expression. Therefore, the dominant negative effects of p53 mutants on WT p53 function may vary depending on the particular cell type. In addition, mutants with stronger inhibitory capabilities may confer a selective advantage during the tumorigenic process.

Original languageEnglish (US)
Pages (from-to)2103-2111
Number of pages9
JournalOncogene
Volume10
Issue number11
StatePublished - 1995

Keywords

  • Cell type specificity
  • Transactivation
  • p53
  • p53 mutants

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Effects of p53 mutants on wild-type p53-mediated transactivation are cell type dependent'. Together they form a unique fingerprint.

  • Cite this

    Forrester, K., Lupold, S. E., Ott, V. L., Chay, C. H., Band, V., Wang, X. W., & Harris, C. C. (1995). Effects of p53 mutants on wild-type p53-mediated transactivation are cell type dependent. Oncogene, 10(11), 2103-2111.