The polycystic kidney disease 1 gene product mediates protein kinase C α-dependent and c-Jun N-terminal kinase-dependent activation of the transcription factor AP-1

Thierry Arnould, Emily Kim, Leonidas Tsiokas, Friederike Jochimsen, Wolfram Grüning, James D. Chang, Gerd Walz

Research output: Contribution to journalArticlepeer-review

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disorder that accounts for 8-10% of end stage renal disease. PKD1, one of two recently isolated ADPKD gene products, has been implicated in cell-cell and cell-matrix interactions. However, the signaling pathway of PKD1 remains undefined. We found that the C-terminal 226 amino acids of PKD1 transactivate an AP-1 promoter construct in human embryonic kidney cells (293T). PKD1-induced transcription is specific for AP-1; promoter constructs containing cAMP response element-binding protein, c-Fos, c-Myc, or NFκB- binding sites are unaffected by PKD1. In vitro kinase assays revealed that PKD1 triggers the activation of c-Jun N-terminal kinase (JNK), but not of mitogen-activated protein kinases p38 or p44. Dominant-negative Rac-1 and Cdc42 mutations abrogated PKD1-mediated JNK and AP-1 activation, suggesting a critical role for small GTP-binding proteins in PKD1-mediated signaling. Several protein kinase C (PKC) inhibitors decreased PKD1-mediated AP-1 activation. Conversely, expression of the C-terminal domain of PKD1 increased PKC activity in 293T cells. A dominant-negative PKC α, but not a dominant- negative PKC β or δ, abrogated PKD1-mediated AP-1 activation. These findings indicate that small GTP-binding proteins and PKC α mediate PKD1- induced JNK/AP-1 activation, together comprising a signaling cascade that may regulate renal tubulogenesis.

Original languageEnglish
Pages (from-to)6013-6018
Number of pages6
JournalJ. Biol. Chem.
Volume273
Issue number11
DOIs
Publication statusPublished - 13 Mar 1998

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