SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus
SSeCKS sequesters cyclin D1 in glomerular parietal epithelial cells and influences proliferative injury in the glomerulus
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DOI：
10.1038/labinvest.2011.199
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发表时间：
2012-04-01
影响因子：
5
通讯作者：
Nelson, Peter J.
中科院分区：
文献类型：
--
作者：
Burnworth, Bettina;Pippin, Jeff;Nelson, Peter J.
肾小球壁上皮细胞（佩奇）是成熟肾小球中足细胞的前体;然而，作为祖细胞，允许佩奇在肾小球形成后重复细胞周期停滞和重新进入的独特内在机制尚不清楚。在这里，我们表明，Src抑制蛋白激酶C底物（SSeCKS），多价支架A激酶锚定蛋白，隔离细胞周期蛋白D1在细胞质中的静止佩奇。SSeCKS的表达诱导胚胎佩奇，但不是在胚胎足细胞，在S期肾小球发生，并组成性表达出生后的佩奇，但不是足细胞，在正常肾小球。细胞周期蛋白D-1与SSeCKS从含有佩奇的囊化肾小球免疫沉淀，而无佩奇的去囊化肾小球缺乏SSeCKS和细胞周期蛋白D1。细胞-细胞接触抑制培养的佩奇增殖诱导SSeCKS的表达和细胞周期蛋白D1的SSeCKS在细胞质中的结合，而SSeCKS的磷酸化激活的蛋白激酶C破坏结合，导致细胞周期蛋白D1的核转位。SSeCKS-/-小鼠在其他正常肾小球中表现出佩奇增生，并发生了明显更严重的蛋白尿性肾小球疾病，其特征是PEC增殖增加和核细胞周期蛋白D-1表达增加，来自肾毒性肾炎。这些结果表明，SSeCKS控制佩奇中细胞周期蛋白D1的定位和活性，并影响肾小球的增殖性损伤。实验室调查（2012）92，499-510; doi：10.1038/labinvest.2011.199;在线发表2012年1月16日
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 D-1 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 D-1, 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. Laboratory Investigation (2012) 92, 499-510; doi:10.1038/labinvest.2011.199; published online 16 January 2012