TY - JOUR
T1 - Aberrant polycystin-1 expression results in modification of activator protein-1 activity, whereas Wnt signaling remains unaffected
AU - Le, Ngoc Hang
AU - Van Der Bent, Paola
AU - Huls, Gerwin
AU - Van De Wetering, Marc
AU - Loghman-Adham, Mahmoud
AU - Ong, Albert C.M.
AU - Calvet, James P.
AU - Clevers, Hans
AU - Breuning, Martijn H.
AU - Van Dam, Hans
AU - Peters, Dorien J.M.
PY - 2004/6/25
Y1 - 2004/6/25
N2 - Polycystin-1, the polycystic kidney disease 1 gene product, has been implicated in several signaling complexes that are known to regulate essential cellular functions. We investigated the role of polycystin-1 in Wnt signaling and activator protein-1 (AP-1) activation. To this aim, a membrane-targeted construct encoding the conserved C-terminal region of mouse polycystin-1 reported to mediate signal transduction activity was expressed in human embryonic and renal epithelial cells. To ensure specificity and minimal cotransfection effects, we focused our study on the endogenous proteins that actually transduce the signals, β-catenin and T-cell factor/lymphoid- enhancing factor for Wnt signaling and (phosphorylated) c-Jun, ATF2, and c-Fos for AP-1. Our data indicate that the C-terminal region of polycystin-1 activates AP-1 by inducing phosphorylation and expression of at least c-Jun and ATF2, whereas c-Fos was not affected. Under our experimental conditions, polycystin-1 did not modulate Wnt signaling. AP-1 activity was aberrant in human autosomal dominant polycystic kidney disease (ADPKD) renal cystic epithelial cells and in renal epithelial cells expressing transgenic full-length polycystin-1, resulting in decreased Jun-ATF and increased Jun-Fos activity, whereas Wnt signaling remained unaffected. Since our data indicate that aberrant polycystin-1 expression results in altered AP-1 activity, polycystin-1 may be required for adequate AP-1 activity.
AB - Polycystin-1, the polycystic kidney disease 1 gene product, has been implicated in several signaling complexes that are known to regulate essential cellular functions. We investigated the role of polycystin-1 in Wnt signaling and activator protein-1 (AP-1) activation. To this aim, a membrane-targeted construct encoding the conserved C-terminal region of mouse polycystin-1 reported to mediate signal transduction activity was expressed in human embryonic and renal epithelial cells. To ensure specificity and minimal cotransfection effects, we focused our study on the endogenous proteins that actually transduce the signals, β-catenin and T-cell factor/lymphoid- enhancing factor for Wnt signaling and (phosphorylated) c-Jun, ATF2, and c-Fos for AP-1. Our data indicate that the C-terminal region of polycystin-1 activates AP-1 by inducing phosphorylation and expression of at least c-Jun and ATF2, whereas c-Fos was not affected. Under our experimental conditions, polycystin-1 did not modulate Wnt signaling. AP-1 activity was aberrant in human autosomal dominant polycystic kidney disease (ADPKD) renal cystic epithelial cells and in renal epithelial cells expressing transgenic full-length polycystin-1, resulting in decreased Jun-ATF and increased Jun-Fos activity, whereas Wnt signaling remained unaffected. Since our data indicate that aberrant polycystin-1 expression results in altered AP-1 activity, polycystin-1 may be required for adequate AP-1 activity.
UR - http://www.scopus.com/inward/record.url?scp=3042641823&partnerID=8YFLogxK
U2 - 10.1074/jbc.M312183200
DO - 10.1074/jbc.M312183200
M3 - Article
C2 - 15087466
AN - SCOPUS:3042641823
SN - 0021-9258
VL - 279
SP - 27472
EP - 27481
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 26
ER -