Liu Yingwang, Heilman Susan A, Illanes Diego, Sluder Greenfield, Chen Jason J
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605-2324, USA.
Cancer Res. 2007 Mar 15;67(6):2603-10. doi: 10.1158/0008-5472.CAN-06-3436.
Polyploidy is often an early event during cervical carcinogenesis, and it predisposes cells to aneuploidy, which is thought to play a causal role in tumorigenesis. Cervical and anogenital cancers are induced by the high-risk types of human papillomavirus (HPV). The HPV E6 oncoprotein induces polyploidy in human keratinocytes, yet the mechanism is not known. It was believed that E6 induces polyploidy by abrogating the spindle checkpoint after mitotic stress. We have tested this hypothesis using human keratinocytes in which E6 expression induces a significant amount of polyploidy. We found that E6 expression does not affect the spindle checkpoint. Instead, we provide direct evidence that E6 is capable of abrogating the subsequent G(1) arrest after adaptation of the mitotic stress. E6 targets p53 for degradation, and previous studies have shown an important role for p53 in modulation of the G(1) arrest after mitotic stress. Importantly, we have discovered that E6 mutants defective in p53 degradation also induce polyploidy, although with lower efficiency. These results suggest that E6 is able to induce polyploidy via both p53-dependent and p53-independent mechanisms. Therefore, our studies highlight a novel function of HPV E6 that may contribute to HPV-induced carcinogenesis and improve our understanding of the onset of the disease.
多倍体通常是子宫颈癌发生过程中的早期事件，它使细胞易于发生非整倍体，而非整倍体被认为在肿瘤发生中起因果作用。子宫颈癌和肛门生殖器癌是由高危型人乳头瘤病毒（HPV）诱发的。HPV E6癌蛋白可在人角质形成细胞中诱导多倍体形成，但其机制尚不清楚。人们曾认为E6通过在有丝分裂应激后废除纺锤体检查点来诱导多倍体形成。我们使用E6表达可诱导大量多倍体形成的人角质形成细胞对这一假说进行了验证。我们发现E6表达并不影响纺锤体检查点。相反，我们提供了直接证据表明E6能够在适应有丝分裂应激后废除随后的G(1)期阻滞。E6靶向p53使其降解，并且先前的研究已表明p53在调节有丝分裂应激后的G(1)期阻滞中起重要作用。重要的是，我们发现p53降解缺陷的E6突变体也能诱导多倍体形成，尽管效率较低。这些结果表明E6能够通过p53依赖和p53非依赖机制诱导多倍体形成。因此，我们的研究突出了HPV E6的一种新功能，这可能有助于HPV诱导的致癌作用，并增进我们对该疾病发病机制的理解。
