Aberrant polycystin-1 expression results in modification of activator protein-1 activity, whereas Wnt signaling remains unaffected.
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, beta-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.
Le
Ngoc Hang
NH
Department of Human Genetics, Leiden University Medical Center, Leiden 2333 AL, The Netherlands.
van der Bent
Paola
P
Huls
Gerwin
G
van de Wetering
Marc
M
Loghman-Adham
Mahmoud
M
Ong
Albert C M
AC
Calvet
James P
JP
Clevers
Hans
H
Breuning
Martijn H
MH
van Dam
Hans
H
Peters
Dorien J M
DJ
D051698:Activating Transcription Factor 2; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004285:Dogs; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D050396:TRPP Cation Channels; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D051153:Wnt Proteins; D051176:beta Catenin
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D050396:TRPP Cation Channels; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C497105:ATF2 protein, human; C497106:Atf2 protein, mouse; C497107:Atf2 protein, rat; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat