Pan Wei, Datta Abhishek, Adami Guy R, Raychaudhuri Pradip, Bagchi Srilata
Center for the Molecular Biology of Oral Diseases, College of Dentistry (M/C 860), University of Illinois at Chicago, 801S Paulina Street, Chicago, IL 60612, USA.
Oncogene. 2003 Aug 21;22(35):5496-503. doi: 10.1038/sj.onc.1206857.
The E7 oncoprotein encoded by high-risk types of human papillomavirus (HPV) plays a significant role in the development of HPV-related cancers. E7 is a potent stimulator of S phase and host DNA replication. These functions of E7 are linked to the deregulation of the Rb family of proteins. For example, E7 binds and induces proteolysis of Rb through the ubiquitin-proteasome pathway. Despite advances in our understanding of E7, reagents that inhibit E7 with promise in therapy have not been developed or identified. Here, we provide evidence that the tumor suppressor ARF can inhibit E7. We show that the expression of ARF causes a relocalization of E7 from the nucleoplasm to the nucleolus. Two distinct regions in ARF overlapping with the MDM2-binding sites are necessary for the relocalization of E7. Furthermore, we show that ARF blocks the proteolysis of Rb induced by E7. In addition, ARF expression inhibits DNA replication induced by E7. Although it is not known whether the endogenous ARF, which is expressed at a low level, interferes with E7, our results suggest that ARF is an effective inhibitor of E7. We speculate that ARF or an ARF-derived molecule might have a significant impact in therapy against HPV-related tumors.
高危型人乳头瘤病毒（HPV）编码的E7癌蛋白在HPV相关癌症的发展中起重要作用。E7是S期和宿主DNA复制的有效刺激因子。E7的这些功能与Rb蛋白家族的失调有关。例如，E7通过泛素-蛋白酶体途径结合并诱导Rb的蛋白水解。尽管我们对E7的理解有所进展，但尚未开发或鉴定出在治疗中有望抑制E7的试剂。在此，我们提供证据表明肿瘤抑制因子ARF可以抑制E7。我们表明ARF的表达导致E7从核质重新定位到核仁。ARF中与MDM2结合位点重叠的两个不同区域对于E7的重新定位是必需的。此外，我们表明ARF阻断E7诱导的Rb的蛋白水解。另外，ARF表达抑制E7诱导的DNA复制。虽然尚不清楚低水平表达的内源性ARF是否会干扰E7，但我们的结果表明ARF是E7的有效抑制剂。我们推测ARF或源自ARF的分子可能在针对HPV相关肿瘤的治疗中产生重大影响。
