S100A11 is involved in the regulation of the stability of cell cycle regulator p21CIP1/WAF1 in human keratinocyte HaCaT cells
S100A11 is involved in the regulation of the stability of cell cycle regulator p21CIP1/WAF1 in human keratinocyte HaCaT cells
复制标题
DOI：
10.1111/febs.12378
复制
发表时间：
2013-08-01
期刊：
影响因子：
5.4
通讯作者：
Melle, Christian
中科院分区：
文献类型：
--
作者：
Foertsch, Franziska;Teichmann, Nicole;Melle, Christian
细胞周期蛋白依赖性激酶抑制剂p21（CIP 1/WAF 1）是细胞周期的调节因子。它的转录激活和蛋白质稳定性受到几种不同机制的严格控制。S100 A11是钙结合蛋白S100家族的成员，参与多种生物学过程，包括细胞周期进程和信号转导。在本研究中，我们发现，下调S100 A11的结果在减少人HaCaT角质形成细胞中的p21蛋白。在S100 A11下调的细胞中，p21的降解似乎涉及一种不依赖于泛素的蛋白酶体降解过程。蛋白酶体抑制剂的应用稳定了这些细胞中的p21蛋白。不同的信号转导途径的分析揭示了一个干扰磷脂酰肌醇-3-激酶/Akt途径后S100 A11敲低。我们确定，糖原合成酶激酶-3，这是负调控的磷脂酰肌醇3-激酶/Akt，被激活的细胞具有击倒S100 A11，似乎参与p21蛋白的不稳定。应用糖原合成酶激酶3的特异性抑制剂导致S100 A11下调的HaCaT细胞中p21蛋白水平的增加。糖原合成酶激酶3能够在T57磷酸化p21，这诱导p21蛋白酶体周转。糖原合成酶激酶3位点苏氨酸57突变为丙氨酸（T57 A）在缺乏S100 A11的HaCaT细胞中稳定p21。除p21蛋白表达减少外，S100 A11蛋白表达下调还可诱导HaCaT细胞凋亡。这些观察结果表明，S100 A11参与维持p21蛋白的稳定性，并似乎作为人HaCaT角质形成细胞凋亡的抑制剂。因此，这些数据揭示了调节p21蛋白稳定性的新途径。
The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) is a regulatory factor of the cell cycle. Its transcriptional activation and protein stability are tightly controlled by several distinct mechanisms. S100A11 is a member of the S100 family of Ca2+-binding proteins involved in several biological processes, including cell cycle progression and signal transduction. In the present study, we show that down-regulation of S100A11 results in the reduction of p21 protein in human HaCaT keratinocytes. It appears that a ubiquitin-independent proteasomal degradation process is involved in p21 degradation in S100A11 down-regulated cells. The application of a proteasome inhibitor stabilized p21 protein in these cells. Analysis of distinct signal transduction pathways revealed a disturbed phosphatidylinositol- 3-kinase/Akt pathway after S100A11 knockdown. We determined that the glycogen synthase kinase-3, which is negatively regulated by phosphatidylinositol 3-kinase/Akt, was activated in cells possessing knocked-down S100A11 and appears to be involved in p21 protein destabilization. The application of a specific inhibitor of glycogen synthase kinase 3 resulted in an increase of the p21 protein level in S100A11 down-regulated HaCaT cells. Glycogen synthase kinase 3 is able to phosphorylate p21 at T57, which induces p21 proteasomal turnover. Mutation of the glycogen synthase kinase 3 site threonine 57 into alanine (T57A) stabilizes p21 in HaCaT cells lacking S100A11. Beside decreased p21 protein, down-regulation of S100A11 triggered the induction of apoptosis in HaCaT cells. These observations suggest that S100A11 is involved in the maintenance of p21 protein stability and appears to function as an inhibitor of apoptosis in human HaCaT keratinocyte cells. Thus, the data shed light on a novel pathway regulating p21 protein stability.