Casanovas Oriol, Jaumot Montserrat, Paules Ana-Belén, Agell Neus, Bachs Oriol
Departament de Biologia Cel lular i Anatomia Patològica, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Casanova 143, 08036, Spain.
Oncogene. 2004 Sep 30;23(45):7537-44. doi: 10.1038/sj.onc.1208040.
Cyclin D3 plays a critical role in maturation of precursor T cells and their levels are tightly regulated during this process. Alteration of cyclin D3 levels has been proposed to be important in the development of different human cancers, including malignancies of the lymphoid system. Thus, we have analysed the mechanisms involved in the regulation of cyclin D3 levels. Our results indicate that cyclin D3 is degraded via proteasome and that Thr-283 is essential for its degradation. Wild-type cyclin D3 but not the Thr-283A mutant accumulated ubiquitylated forms after treatment with proteasome inhibitors. We also observed that different type of stresses promote the Thr-283-dependent in vivo degradation of cyclin D3. The analysis of the kinases involved in Thr-283 phosphorylation indicates that all the members of the p38SAPK family of serine-threonine kinases are able to phosphorylate cyclin D3 at this specific site. Moreover, we found that the overexpression of p38alphaSAPK2 induce the decrease of cyclin D3 in vivo. These results indicate that p38SAPK might be involved in the regulation of cyclin D3 levels and suggest that this mechanism is involved in the maturation of precursor T-cells. Alterations of this mechanism might be important for oncogenesis.
细胞周期蛋白D3在前体T细胞成熟过程中起关键作用，且在此过程中其水平受到严格调控。细胞周期蛋白D3水平的改变被认为在包括淋巴系统恶性肿瘤在内的不同人类癌症的发生发展中具有重要意义。因此，我们分析了细胞周期蛋白D3水平调控所涉及的机制。我们的结果表明，细胞周期蛋白D3通过蛋白酶体降解，且苏氨酸283（Thr-283）对其降解至关重要。用蛋白酶体抑制剂处理后，野生型细胞周期蛋白D3而非Thr-283A突变体积累了泛素化形式。我们还观察到不同类型的应激促进细胞周期蛋白D3在体内依赖于Thr-283的降解。对参与Thr-283磷酸化的激酶的分析表明，丝氨酸-苏氨酸激酶p38SAPK家族的所有成员都能够在这个特定位点磷酸化细胞周期蛋白D3。此外，我们发现p38αSAPK2的过表达在体内诱导细胞周期蛋白D3水平降低。这些结果表明p38SAPK可能参与细胞周期蛋白D3水平的调控，并提示该机制参与前体T细胞的成熟。这一机制的改变可能对肿瘤发生具有重要意义。
