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, ␤-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.Progressive development of fluid-filled cysts in autosomal dominant polycystic kidney disease (ADPKD) 1 results in chronic renal failure. In the majority of patients, the disease can be accounted for by a mutation in the PKD1 gene (1, 2), whereas a minority suffers from a mutation in the PKD2 gene (3, 4). The precise function of polycystin-1 and polycystin-2, the proteins encoded by the PKD1 and PKD2 gene, respectively, remains to be elucidated. Polycystin-1 is predicted to be a transmembrane protein of ϳ460 kDa. The large extracellular N terminus contains multiple domains thought to be involved in cell-cell and cell-matrix interactions. The intracellular C terminus of polycystin-1 contains putative phosphorylation sites and a coiled-coil domain that can mediate protein-protein interactions.Several studies have implicated a role for polycystin-1 in signal transduction. Overexpression of the C-terminal region of polycystin-1 in human embryonic kidney 293T (HEK293T) cells has been shown to activate the Wnt signaling pathway (5) and the activator protein-1 (AP-1) transcription factor complex (6, 7). Furthermore, overexpression of a full-length polycystin-1 construct has been reported to activate the Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling pathway (8). These signaling pathways are all involved in key cellular processes such as proliferation and differentiation, cell cycle regulation, and cell survival. Since these cellular processes are essential for normal function, the signaling pathways governing them are tightly regulated. We ...

Autosomal dominant polycystic kidney disease is a common inherited disorder that predominantly manifests with the formation of fluid-filled cysts in both kidneys. The disease can be accounted for by a mutation in either the PKD1 or the PKD2 gene. It was demonstrated previously that aberrant expression of the PKD1 gene product, polycystin-1, results in modification of activator protein-1 (AP-1) transcription factor activity in cultured renal epithelial cells. Here, it is reported that activity of the AP-1 components c-Jun, ATF2, and c-Fos is altered in renal cystic tissue of patients with autosomal dominant polycystic kidney disease and of hypomorphic Pkd1 mice with polycystic kidney disease. Data were obtained using immunohistochemical and Western blot analysis. Significant upregulation of Thr71-and Thr69/71-phosphorylated ATF2 and Ser73-phosphorylated c-Jun and increased c-Fos were detected in small cysts and (dilated) ducts and tubules surrounded by fibrotic interstitium. The data indicate that various AP-1 components are constitutively activated in polycystic kidney disease and suggest that aberrant AP-1 activity is relevant for cyst formation.

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The disease loci for X-linked Retinoschisis (RS), Keratosis follicularis spinulosa decalvans (KFSD), and Coffin-Lowry syndrome (CLS) have been localized to the same, small region in Xp22 on the human X Chromosome (Chr). To generate a high-resolution map of the available contig in this area, we have used the YAC fragmentation vectors pBP108/ADE2 and pBP109/ADE2 and generated fragmented YACs from a 2.5-Mb YAC (y939H7) spanning the mentioned disease gene candidate regions. Forty-seven fragmented YACs were generated and analyzed, ranging in size from 170 kb to over 2400 kb. The resulting YAC fragmentation panel was used to construct a detailed restriction map of the region and has been used to bin clones and markers. As a deletion panel, it will present a valuable resource for further mapping.