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PMID: 10200270 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 8 ·1999-04-13 ·Pages 4378-83

Kelavkar UP, Badr KF

Abstract

Human 15-lipoxygenase (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 degrees C and in wild-type conformation when grown at 32 degrees C. Transfection of h15-LO promoter constructs (driving luciferase reporter) into (10)1val cells and into p53-deficient (10)1 cells resulted in a marked increase in h15-LO promoter activity in (10)1val cells at 39 degrees C, but not at 32 degrees 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 degrees C and 39 degrees 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-LO (mouse analog of h15-LO) mRNA and protein when grown at 39 degrees C compared with cells grown at 32 degrees 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.

MeSH Terms
Animals Arachidonate 12-Lipoxygenase/genetics Arachidonate 15-Lipoxygenase/genetics Cells, Cultured Embryo, Mammalian Enhancer Elements, Genetic Fibroblasts/cytology,metabolism Gene Deletion Genes, p53 Humans Luciferases/genetics Mice Mice, Inbred BALB C Promoter Regions, Genetic RNA, Messenger/genetics Recombinant Fusion Proteins/biosynthesis Transcription, Genetic Transfection Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
RNA, Messenger Recombinant Fusion Proteins Tumor Suppressor Protein p53 Arachidonate 12-Lipoxygenase Arachidonate 15-Lipoxygenase Luciferases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Kelavkar U P
Renal Division and Center for Glomerulonephritis, Emory University, Atlanta, GA 30322, USA.
Badr K F
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.8.4378
Published
1999-04-13
Pages
4378-83
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC16340
Subset
IM
Grants
NIDDK NIH HHS · 2RO1DK43883 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.8.4378 PMC Full Text View journal details
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