TY - JOUR
T1 - 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
AU - Arnould, Thierry
AU - Kim, Emily
AU - Tsiokas, Leonidas
AU - Jochimsen, Friederike
AU - Grüning, Wolfram
AU - Chang, James D.
AU - Walz, Gerd
PY - 1998/3/13
Y1 - 1998/3/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0032513031&partnerID=8YFLogxK
U2 - 10.1074/jbc.273.11.6013
DO - 10.1074/jbc.273.11.6013
M3 - Article
C2 - 9497315
SN - 1083-351X
VL - 273
SP - 6013
EP - 6018
JO - J. Biol. Chem.
JF - J. Biol. Chem.
IS - 11
ER -