PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2.
Autosomal dominant polycystic kidney disease is characterized by cyst formation in the kidney and other organs and results from mutations of PKD1 or PKD2. Previous studies suggest that their gene products have an important role in growth regulation. We now show that expression of polycystin-1 activates the JAK-STAT pathway, thereby upregulating p21(waf1) and inducing cell cycle arrest in G0/G1. This process requires polycystin-2, a channel protein, as an essential cofactor. Mutations that disrupt polycystin-1/2 binding prevent activation of the pathway. Mouse embryos lacking Pkd1 have defective STAT1 phosphorylation and p21(waf1) induction. These results suggest that one function of the polycystin-1/2 complex is to regulate the JAK/STAT pathway and explain how mutations of either gene can result in dysregulated growth.
Bhunia
Anil Kumar
AK
Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Piontek
Klaus
K
Boletta
Alessandra
A
Liu
Lijuan
L
Qian
Feng
F
Xu
Pei Ning
PN
Germino
F Joseph
FJ
Germino
Gregory G
GG
D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D016193:G1 Phase / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics; D050396:TRPP Cation Channels; D015534:Trans-Activators / Q000235:genetics
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D053614:Janus Kinase 2; D008565:Membrane Proteins; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050396:TRPP Cation Channels; D015534:Trans-Activators; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse