Effects of mutant p53 expression on human 15-lipoxygenasepromoter activity and murine 12/15-lipoxygenase gene expression: Evidence that 15- lipoxygenase is a mutator gene

U. P. Kelavkar, K. F. Badr

Research output: Contribution to journalArticle

Abstract

Human 15-1ipoxygenase (h15-LO) is present on chromosome 17p13.3 in close proximity to the tumor-suppressor gene, p53. 15-LO is implicated in antiinflammation, membrane remodeling, and cancer development/metastasis. The murine BALB/c embryo fibroblast cell line, (10)1val, expresses p53 in mutant (mt) conformation when grown at 39°C and in wild-type conformation when grown at 32°C. Transfection of h15-LO promoter constructs (driving luciferase reporter) into (10)lval cells and into p53-deficient (10)1 cells resulted in a marked increase in h15-LO promoter activity in (10)1val cells at 39°C, but not at 32°C, or as compared with (10)1 cells. Transfection of h15-LO promoter deletion constructs, however, resulted in total loss of activity in both cell types at 32°C and 39°C. Cotransfection of (10)1 cells with h15-LO promoter (driving luciferase reporter) along with increasing levels of a mt p53 expression vector demonstrated dose-dependent capacity of mt p53 to induce 15-LO promoter activity. No effect was observed with wild- type p53. In contrast to h15-LO promoter activity, (10)1val cells had significantly lower levels of endogenous (murine) 12/15-L0 (mouse analog of h15-LO) mRNA and protein when grown at 39°C compared with cells grown at 32°C. Our data support the hypothesis that loss of a tumor-suppressor gene (p53), or 'gain-of-function activities' resulting from the expression of its mutant forms, regulates 15-LO promoter activity in man and in mouse, albeit in directionally opposite manners. The studies define a direct link between 15-LO activity and an established tumor-suppressor gene located in close chromosomal proximity.

Original languageEnglish (US)
Pages (from-to)4378-4383
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number8
DOIs
StatePublished - Apr 13 1999
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • General

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