MAP/ERK Kinase Kinase 1 (MEKK1) Mediates Transcriptional Repression by Interacting with Polycystic Kidney Disease-1 (PKD1) Promoter-bound p53 Tumor Suppressor Protein

• Published in: The Journal of biological chemistry 2010-12, Vol.285 (50), p.38818-38831
• Main Authors: Islam, M. Rafiq, Jimenez, Tamara, Pelham, Christopher, Rodova, Marianna, Puri, Sanjeev, Magenheimer, Brenda S., Maser, Robin L., Widmann, Christian, Calvet, James P.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Cell Nucleus - metabolism; Chlorocebus aethiops; Corepressor Transcription; COS Cells; Gene Expression Regulation, Enzymologic; Gene Regulation; Humans; MAP Kinase Kinase Kinase 1 - metabolism; MAP Kinases (MAPKs); Mekk1; Mice; Microscopy, Fluorescence - methods; Molecular Sequence Data; Mutagenesis; Oxidative Stress; p53; PKD1; Polycystic Kidney Disease; Promoter Regions, Genetic; Promoters; Transcription Regulation; Transcription, Genetic; TRPP Cation Channels - metabolism; Tumor Necrosis Factor (TNF); Tumor Necrosis Factor-alpha - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.145284

Mitogen-activated protein kinase (MAPK) cascades regulate a wide variety of cellular processes that ultimately depend on changes in gene expression. We have found a novel mechanism whereby one of the key MAP3 kinases, Mekk1, regulates transcriptional activity through an interaction with p53. The tumor suppressor protein p53 down-regulates a number of genes, including the gene most frequently mutated in autosomal dominant polycystic kidney disease (PKD1). We have discovered that Mekk1 translocates to the nucleus and acts as a co-repressor with p53 to down-regulate PKD1 transcriptional activity. This repression does not require Mekk1 kinase activity, excluding the need for an Mekk1 phosphorylation cascade. However, this PKD1 repression can also be induced by the stress-pathway stimuli, including TNFα, suggesting that Mekk1 activation induces both JNK-dependent and JNK-independent pathways that target the PKD1 gene. An Mekk1-p53 interaction at the PKD1 promoter suggests a new mechanism by which abnormally elevated stress-pathway stimuli might directly down-regulate the PKD1 gene, possibly causing haploinsufficiency and cyst formation.