Ojala P M, Yamamoto K, Castaños-Vélez E, Biberfeld P, Korsmeyer S J, Mäkelä T P
Haartman Institute & Biocentrum Helsinki, University of Helsinki, PO Box 21, Haartmaninkatu 3, 00014 Helsinki, Finland.
Nat Cell Biol. 2000 Nov;2(11):819-25. doi: 10.1038/35041064.
v-cyclin encoded by Kaposi's sarcoma herpesvirus/human herpesvirus 8 (KSHV or HHV8) associates with cellular cyclin-dependent kinase 6 (CDK6) to form a kinase complex that promotes cell-cycle progression, but can also induce apoptosis in cells with high levels of CDK6. Here we show that whereas HHV8-encoded v-Bcl-2 protects against this apoptosis, cellular Bcl-2 has lost its anti-apoptotic potential as a result of an inactivating phosphorylation in its unstructured loop region. Moreover, we identify Bcl-2 as a new substrate for v-cyclin-CDK6 in vitro, and show that it is present in a complex with CDK6 in cell lysates. A Bcl-2 mutant with a S70A S87A double substitution in the loop region is not phosphorylated and provides resistance to apoptosis, indicating that inactivation of Bcl-2 by v-cyclin-CDK6 may be required for the observed apoptosis. Furthermore, the identification of phosphorylated Bcl-2 in HHV8-positive Kaposi's sarcoma indicates that HHV8-mediated interference with host apoptotic signalling pathways may encourage the development of Kaposi's sarcoma.
由卡波西肉瘤疱疹病毒/人类疱疹病毒8型（KSHV或HHV8）编码的v - 细胞周期蛋白与细胞周期蛋白依赖性激酶6（CDK6）结合形成激酶复合物，该复合物促进细胞周期进程，但也可在CDK6水平高的细胞中诱导凋亡。我们在此表明，虽然HHV8编码的v - Bcl - 2可防止这种凋亡，但细胞Bcl - 2由于其无结构环区域的失活磷酸化而失去了其抗凋亡潜力。此外，我们在体外确定Bcl - 2是v - 细胞周期蛋白 - CDK6的新底物，并表明它存在于细胞裂解物中与CDK6的复合物中。在环区域具有S70A S87A双取代的Bcl - 2突变体不被磷酸化并提供抗凋亡能力，表明v - 细胞周期蛋白 - CDK6使Bcl - 2失活可能是观察到的凋亡所必需的。此外，在HHV8阳性的卡波西肉瘤中鉴定出磷酸化的Bcl - 2表明HHV8介导的对宿主凋亡信号通路的干扰可能促进卡波西肉瘤的发展。
