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MEKK1 Mediates Transcriptional Repression of PKD1 by Interacting with Promoter‐Bound p53 Tumor Suppressor Protein
Author(s) -
Islam M Rafiq,
Jimenez Tamara,
Pelham Chris,
Rodova Marianna,
Puri Sanjeev,
Magenheimer Brenda,
Maser Robin,
Widmann Christian,
Calvet James
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.699.8
MAPK cascades are involved in a wide variety of cellular functions that ultimately depend on changes in gene expression. We found full‐length Mekk1 markedly reduced transcriptional activity from a 200 bp proximal PKD1 promoter‐luciferase construct. However, inhibitors of ERK, p38, and JNK, and Kinase‐inactive Mekk1 failed to block this Mekk1‐mediated effect, excluding the involvement phosphorylation cascade. The Mekk1 effect was attenuated by cotransfection of a dominant negative p53 construct, p53 siRNA and mutation in the p53 element in the promoter or in p53‐null HCT116 cells, implicating involvement of p53 in this repression. Mekk1 was shown to be present in the nucleus and to co‐immunoprecipitate with p53. ChIP assays demonstrated p53‐dependent Mekk1 binding to the PKD1 promoter. Transient or stable transfection of kinase‐active or kinase‐inactive Mekk1 constructs as well as PMA, H 2 O 2 , and TNFalpha treatments significantly decreased endogenous PKD1 mRNA levels, and also IEX‐1 and the bradykinin B2 receptor mRNAs, known to be downregulated by p53. These results have identified a novel transcriptional mechanism whereby Mekk1, regulates transcriptional activity through an interaction with p53 that does not require Mekk1 kinase activity. A functional Mekk1‐p53 interaction at p53‐regulated promoters suggests a new mechanism by which stress‐pathway stimuli can directly affect p53 function. Supported by NIDDK.

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