Kim Arianna L, Gautier Jean, Bickers David R, Athar Mohammad
Department of Dermatology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
Biochem Biophys Res Commun. 2002 Nov 1;298(3):377-82. doi: 10.1016/s0006-291x(02)02435-x.
Ubiquitination of cyclin D1 signals for its proteosomal degradation. To assess the possibility that reduced cyclin D1 proteolysis is a putative mechanism for its accumulation during UVB-induced skin tumorigenesis, ubiquitination activity of cyclin D1 was assessed in UVB-induced murine SCCs. Cyclin D1 was rapidly ubiquitinated by control skin extract, whereas ubiquitination of cyclin D1 was significantly reduced in SCCs. Mutant cyclin D1, in which residues important for GSK3beta-mediated degradation of cyclin D1 are altered to non-phosphorylatable alanine, was not ubiquitinated. We also observed phosphorylation-dependent inactivation of GSK3beta in SCCs. Our results indicate reduced ubiquitination of cyclin D1 in UVB-induced murine SCCs and suggest that inactivation of GSK3beta-dependent cyclin D1 degradation pathway contributes to the accumulation of cyclin D1 in UVB-induced murine SCCs.
细胞周期蛋白D1的泛素化标志着其通过蛋白酶体进行降解。为了评估细胞周期蛋白D1蛋白水解减少是否是其在紫外线诱导的皮肤肿瘤发生过程中积累的一种潜在机制，我们在紫外线诱导的小鼠鳞状细胞癌中评估了细胞周期蛋白D1的泛素化活性。细胞周期蛋白D1可被对照皮肤提取物迅速泛素化，而在鳞状细胞癌中细胞周期蛋白D1的泛素化显著减少。突变型细胞周期蛋白D1中对糖原合成酶激酶3β（GSK3β）介导的细胞周期蛋白D1降解起重要作用的残基被改变为不可磷酸化的丙氨酸，该突变型细胞周期蛋白D1未被泛素化。我们还观察到在鳞状细胞癌中GSK3β存在磷酸化依赖性失活。我们的结果表明在紫外线诱导的小鼠鳞状细胞癌中细胞周期蛋白D1的泛素化减少，提示GSK3β依赖性细胞周期蛋白D1降解途径的失活导致了细胞周期蛋白D1在紫外线诱导的小鼠鳞状细胞癌中的积累。
