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Aberrant Polycystin-1 Expression Results in Modification of Activator Protein-1 Activity, whereas Wnt Signaling Remains Unaffected\ud

By N.H. Le, P. van der Bent, G. Huls, M. van de Wetering, M. Loghman-Adham, A.C.M. Ong, J.P. Calvet, H. Clevers, M.H. Breuning, H. van Dam and D.J.M. Peters


Polycystin-1, the polycystic kidney disease 1 gene\ud product, has been implicated in several signaling complexes\ud that are known to regulate essential cellular\ud functions. We investigated the role of polycystin-1 in\ud Wnt signaling and activator protein-1 (AP-1) activation.\ud To this aim, a membrane-targeted construct encoding\ud the conserved C-terminal region of mouse polycystin-\ud 1 reported to mediate signal transduction\ud activity was expressed in human embryonic and renal\ud epithelial cells. To ensure specificity and minimal cotransfection\ud effects, we focused our study on the endogenous\ud proteins that actually transduce the signals,\ud -catenin and T-cell factor/lymphoid-enhancing factor\ud for Wnt signaling and (phosphorylated) c-Jun, ATF2,\ud and c-Fos for AP-1. Our data indicate that the C-terminal\ud region of polycystin-1 activates AP-1 by inducing\ud phosphorylation and expression of at least c-Jun and\ud ATF2, whereas c-Fos was not affected. Under our\ud experimental conditions, polycystin-1 did not modulate\ud Wnt signaling. AP-1 activity was aberrant in\ud human autosomal dominant polycystic kidney disease\ud (ADPKD) renal cystic epithelial cells and in renal epithelial\ud cells expressing transgenic full-length polycystin-\ud 1, resulting in decreased Jun-ATF and increased\ud Jun-Fos activity, whereas Wnt signaling remained unaffected.\ud Since our data indicate that aberrant polycystin-\ud 1 expression results in altered AP-1 activity,\ud polycystin-1 may be required for adequate AP-1\ud activity

Year: 2004
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