title: SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus.
abstract: Glomerular parietal epithelial cells (PECs) are precursors to podocytes in mature glomeruli; however, as progenitors, the distinct intrinsic mechanisms that allow for repeated periods of cell-cycle arrest and re-entry of PECs after glomerulogenesis are unknown. Here, we show that the Src-suppressed protein kinase C substrate (SSeCKS), a multivalent scaffolding A kinase anchoring protein, sequesters cyclin D1 in the cytoplasm of quiescent PECs. SSeCKS expression is induced in embryonic PECs, but not in embryonic podocytes, starting at the S phase of glomerulogenesis, and is constitutively expressed postnatally by PECs, but not podocytes, in normal glomeruli. Cyclin D1 was immunoprecipitated with SSeCKS from capsulated glomeruli containing PECs, whereas decapsulated glomeruli without PECs lacked SSeCKS and cyclin D1. Cell-cell contact inhibition of proliferation in cultured PECs induced SSeCKS expression and binding of cyclin D1 by SSeCKS in the cytoplasm, whereas phosphorylation of SSeCKS by activated protein kinase C disrupted binding, resulting in nuclear translocation of cyclin D1. SSeCKS(-/-) mice showed hyperplasia of PECs in otherwise normal glomeruli and developed significantly worse proteinuric glomerular disease, marked by increased PEC proliferation and expression of nuclear cyclin D1, from nephrotoxic nephritis. These results suggest that SSeCKS controls the localization and activity of cyclin D1 in PECs and influences proliferative injury in the glomerulus.
authors.affiliation: Division of Nephrology and Kidney Research Institute, University of Washington, Health Sciences Center, Seattle, WA, USA.
authors.forename: Bettina
authors.initials: B
authors.lastname: Burnworth
authors.forename: Jeff
authors.initials: J
authors.lastname: Pippin
authors.forename: Prasanthi
authors.initials: P
authors.lastname: Karna
authors.forename: Shin
authors.initials: S
authors.lastname: Akakura
authors.forename: Ron
authors.initials: R
authors.lastname: Krofft
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhang
authors.forename: Kelly
authors.initials: K
authors.lastname: Hudkins
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.forename: Kelly
authors.initials: K
authors.lastname: Smith
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Shankland
authors.forename: Irwin H
authors.initials: IH
authors.lastname: Gelman
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000196:embryology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; C491161:Akap12 protein, mouse; C530105:Ccnd1 protein, mouse; D018797:Cell Cycle Proteins; D019938:Cyclin D1