Regulation of cell proliferation and apoptosis through fibrocystin-prosaposin interaction.
Mutations in PKHD1 (polycystic kidney and hepatic disease gene 1) gene cause the autosomal recessive polycystic kidney disease (ARPKD). It is widely accepted that cystogenesis is owing to aberrant cell proliferation and apoptosis, increased fluid secretion, and extracellular matrix abnormality. Fibrocystin/polyductin (FPC), the encoded protein product by PKHD1, is a single transmembrane protein and believed to be a novel receptor-like molecule. FPC has been located mainly on the plasma membrane and cilium/basal body. However, its biological functions remain poorly understood. To investigate the roles of FPC in the pathogenesis of ARPKD, we searched for FPC-interacting proteins by yeast two-hybrid assay, and found a novel partner, prosaposin. Prosaposin is a glycoprotein with multiple functions. With GST pull-down assay and co-immunoprecipitation, we confirmed the interaction between FPC and prosaposin. In order to study the effects of FPC-prosaposin interaction on cell proliferation and apoptosis, we have made stable cell lines in which FPC was overexpressed or knocked down alone or in combination with prosaposin overexpression. By MTT assay, we found that FPC knockdown and prosaposin overexpression increased cell proliferation, respectively, while overexpression of FPC C-tail did the opposite. With apoptosis assay, we found that overexpression of FPC C-tail promoted cell apoptosis. However, overexpression of prosaposin significantly enhanced cell survival in FPC knockdown cells. All these findings indicated that FPC and prosaposin may play significant roles in regulation of cell proliferation and apoptosis. Taken together, we have disclosed a novel signaling pathway of FPC, which may be important for the pathogenesis of ARPKD.
Sun
Liping
L
Shenzhen People's Hospital, Jinan University, China.
Wang
Shixuan
S
Hu
Chaofeng
C
Zhang
Xinzhou
X
D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002923:Cilia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005796:Genes; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics