THE REGION OF THE HPV E7 ONCOPROTEIN HOMOLOGOUS TO ADENOVIRUS E1A AND SV40 LARGE T-ANTIGEN CONTAINS SEPARATE DOMAINS FOR RB BINDING AND CASEIN KINASE-II PHOSPHORYLATION
THE REGION OF THE HPV E7 ONCOPROTEIN HOMOLOGOUS TO ADENOVIRUS E1A AND SV40 LARGE T-ANTIGEN CONTAINS SEPARATE DOMAINS FOR RB BINDING AND CASEIN KINASE-II PHOSPHORYLATION
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DOI：
10.1002/j.1460-2075.1990.tb08091.x
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发表时间：
1990-01-01
期刊：
影响因子：
11.4
通讯作者：
VOUSDEN, KH
中科院分区：
文献类型：
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作者：
BARBOSA, MS;EDMONDS, C;VOUSDEN, KH
一些生殖器人乳头瘤病毒（HPV）类型，如16和18，与恶性宫颈肿瘤高度相关，而其他类型，如HPV 6，在这些恶性肿瘤中很少发现。HPV 6、16和18的E7癌蛋白各有一个17个氨基酸的区域，与腺病毒E1 a和SV 40 LT具有惊人的同源性。E1 a、LT和HPV 16的E7癌蛋白在体外都与细胞Rb蛋白结合，并且对于E1 a和LT，该同源区域含有与Rb相互作用所必需的序列。我们现已发现，在HPV 16 E7中，该区域（氨基酸21-37）含有两种独立的生物化学活性，每种活性都有助于E7介导的转化。Rb结合定位于该区域的N末端，而C末端显示作为酪蛋白激酶（CK）II的底物，其磷酸化丝氨酸-31和丝氨酸-32。两个丝氨酸的非磷酸化氨基酸的替代导致转化活性的降低，并取消磷酸化，但不影响Rb结合。还检查了HPV 6和HPV 18的E7蛋白的Rb结合和CK II磷酸化。HPV 16和18 E7与Rb的结合相似，但HPV 6 E7始终结合较少。磷酸化速率也不同，HPV 18 E7比HPV 16 E7快2倍，HPV 16 E7又比HPV 6 E7快2倍。我们的结论是Rb结合磷酸化的E7的CKII是独立的活动，需要有效的转化E7，这些活动直接相关的相对致癌潜力，这些病毒。
Some genital human papillomavirus (HPV) types, such as 16 and 18, are highly associated with malignant cervical tumors while others, such as HPV 6, are only rarely found in these malignancies. The E7 oncoproteins of HPV 6, 16 and 18 each have a 17 amino acid region with striking homology to adenovirus E1a and SV40 LT. E1a, LT and the E7 oncoprotein of HPV16 all bind the cellular Rb protein in vitro, and for E1a and LT this region of homology contains sequences essential for interaction with Rb. We have now found that in HPV 16 E7 this region (amino acids 21-37) contains two separate biochemical activities, each of which contributes to E7-mediated transformation. Rb binding was localized to the N terminus of this region, while the C terminus was shown to serve as a substrate for casein kinase (CK) II, which phosphorylated serine-31 and serine-32. Replacement of the two serines by non-phosphorylatable amino acids led to a reduction in transforming activity and abolished phosphorylation but did not affect Rb binding. Rb binding and CK II phosphorylation were also examined for the E7 proteins of HPV 6 and HPV 18. HPV 16 and 18 E7 bound similar amouns of Rb, but HPV 6 E7 consistently bound less. Phosphorylation rates also varied, with HPV 18 E7 being 2-fold faster than HPV 16 E7, which in turn was 2-fold faster than HPV 6 E7. We conclude that Rb binding the phoshorylation of E7 by CKII are independent activities which are required for efficient transformation by E7 and that these activities correlate directly with the relative oncogenic potential of these viruses.