Viral Skin Carcinogenesis Group, Division Viral Transformation Mechanisms, German Cancer Research Center (DKFZ), DKFZ-Charité, Heidelberg, Germany.
PLoS One. 2011;6(11):e27655. doi: 10.1371/journal.pone.0027655. Epub 2011 Nov 16.
Ultraviolet irradiation (UV) is the major risk factor for the development of skin cancer. Moreover, increasing evidence suggests cutaneotropic human papillomaviruses (HPV) from the beta genus to play a causal role as a co-factor in the development of cutaneous squamous cell carcinoma. Homeodomain-interacting protein kinase 2 (HIPK2) operates as a potential suppressor in skin tumorigenesis and is stabilized by UV-damage. HIPK2 is an important regulator of apoptosis, which forms a complex with the tumor suppressor p53, mediating p53 phosphorylation at Ser 46 and thus promoting pro-apoptotic gene expression. In our study, we demonstrate that cutaneous HPV23 E6 protein directly targets HIPK2 function. Accordingly, HPV23 E6 interacts with HIPK2 both in vitro and in vivo. Furthermore, upon massive UVB-damage HPV23 E6 co-localizes with endogenous HIPK2 at nuclear bodies. Functionally, we demonstrate that HPV23 E6 inhibits HIPK2-mediated p53 Ser 46 phosphorylation through enforcing dissociation of the HIPK2/p53 complex. In addition, HPV23 E6 co-accumulates with endogenous HIPK2 upon UV damage suggesting a mechanism by which HPV23 E6 keeps HIPK2 in check after UV damage. Thus, cutaneous HPV23 E6 prevents HIPK2-mediated p53 Ser 46 phosphorylation, which may favour survival of UV-damaged keratinocytes and skin carcinogenesis by apoptosis evasion.
紫外线照射（UV）是皮肤癌发展的主要危险因素。此外，越来越多的证据表明，β属的皮肤嗜性人乳头瘤病毒（HPV）作为皮肤鳞状细胞癌发生的协同因素起因果作用。同源结构域相互作用蛋白激酶 2（HIPK2）作为皮肤肿瘤发生的潜在抑制因子，通过 UV 损伤稳定。HIPK2 是细胞凋亡的重要调节剂，它与肿瘤抑制因子 p53 形成复合物，介导 p53 在丝氨酸 46 处磷酸化，从而促进促凋亡基因的表达。在我们的研究中，我们证明了皮肤 HPV23 E6 蛋白直接靶向 HIPK2 功能。因此，HPV23 E6 在体外和体内均与 HIPK2 相互作用。此外，在大量 UVB 损伤下，HPV23 E6 与内源性 HIPK2 在内核体中共同定位。功能上，我们证明 HPV23 E6 通过强制分离 HIPK2/p53 复合物来抑制 HIPK2 介导的 p53 丝氨酸 46 磷酸化。此外，HPV23 E6 在 UV 损伤后与内源性 HIPK2 共同积累，这表明 HPV23 E6 在 UV 损伤后通过保持 HIPK2 的抑制作用来阻止 HIPK2 介导的 p53 丝氨酸 46 磷酸化的机制。因此，皮肤 HPV23 E6 可防止 HIPK2 介导的 p53 丝氨酸 46 磷酸化，这可能通过逃避细胞凋亡来促进 UV 损伤的角质细胞存活和皮肤癌变。
