细胞周期再进入存在于亨廷顿病(HD)等多种神经退行性疾病，以Rb磷酸化、cyclins和CDKs异常上调为特征。钙反应性反式激活子（CREST）通过影响p53活性，调节Rb磷酸化而阻滞细胞周期和促神经元分化。我们前期发现， HD致病蛋白突变亨廷顿蛋白（mHtt）可产生被钙蛋白酶(calpain)抑制剂阻断的下调全长CREST水平、产生CREST片段的作用；过表达CREST可减轻mHtt毒性,提示mHtt通过影响calpain对CREST酶切而抑制CREST稳细胞周期、促神经元分化功能，致HD细胞周期再进入。为此，本项目分析酶切CREST的calpain类型与mHtt的影响及其机制，鉴定mHtt诱导calpain对CREST切割的酶切位点，明确mHtt下调CREST机制；并从影响Rb磷酸化的上游机制，解析mHtt引起的CREST的钙蛋白酶切在HD细胞周期再进入及神经退行性变中的作用及其机制。

Cell cycle re-entry, which is characterized with the abnormal upregulation in phosphorylation of retinoblastoma protein (Rb),levels of cyclins and CDKs, is found in several neurodegenerative diseases like Huntington's disease (HD). Calcium-responsive transactivator (CREST) may arrest cell cycle and promote differentiation of neuronal cells through regulating activity of p53 to integrating the phosphorylation of Rb. We found previously that mutant huntingtin (mHtt) causing HD decreased full-length CREST and produced CREST fragments, which could be blocked by inhibitor of calpains, and that the cell toxcity of mHtt could be blocked by overexpression of CREST. It is thus indicated that mHtt may inhibit the functions of CREST stabling cell cycle and promoting neuronal differentiation through affecting cleavage of CREST by calpains, which leads to cell cycle re-entry in HD. The present project will analyze the types of calpain cleaving CREST, the effect of mHtt on the calpain cleavage, identifying the cleavage site of the mHtt-induced calpain on the CREST. Furthemore, from upstream mechanism affecting Rb phosphorylation, the role and the underling mechanism of CREST cleavage by calpain induced by mHtt in cell cycle re-entry and neurodegeneration will also be analyzed.