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Repression of the Polycystic Kidney Disease‐1 (PKD1) Promoter by MEKK1 is mediated by p53
Author(s) -
Islam M. Rafiqul,
Rodova Marianna,
Puri Sanjeev,
Magenheimer Brenda,
Maser Robin,
Widmann Christian,
Calvet Janes,
Jimenez Tamara
Publication year - 2008
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.22.1_supplement.782.23
Subject(s) - pkd1 , psychological repression , hek 293 cells , transfection , promoter , polycystic kidney disease , microbiology and biotechnology , chemistry , biology , kidney , gene , endocrinology , gene expression , biochemistry
We found that PMA and constitutively active MEKK1 (CAM) significantly reduced transcriptional activity (upto 90%) from the 200 bp proximal PKD1 (Polycystic Kidney Disease 1) promoter in HEK293T. Semi‐quantitative RT‐PCR showed decreased levels of endogenous PKD1 mRNA in PMA treated and CAM transfected HEK293T cells. ChIP‐PCR assay suggested MEKK1 interacts with the proximal promoter, however, the binding is indirect as purified CAM‐GST was unable to bind in EMSA assay. JNK inhibitors had no effect in the CAM‐mediated repression, rather surprisingly, a kinase‐inactive MEKK1 repressed the proximal promoter similar to CAM. The suppression of the transcriptional reduction by CAM was observed in HEK293T cells co‐transfected with p53siRNA or dominant negative p53. Furthermore, in HCT116 cells lacking p53, the 200 bp proximal promoter could not be repressed by either CAM. Co‐precipitation of p53 with CAM, or vice‐versa and their co‐nuclear localization indicated their interaction. Taken together, these data indicate that repression of the PKD1 promoter by CAM is mediated through p53, and suggest that PMA‐MEKK1 pathway may play a role in PKD1 regulation. The work is supported by NIH fund.