Markovics Jennifer A, Carroll Patrick A, Robles M Teresa Sáenz, Pope Hannah, Coopersmith Craig M, Pipas James M
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
J Virol. 2005 Jun;79(12):7492-502. doi: 10.1128/JVI.79.12.7492-7502.2005.
Transgenic mice expressing simian virus 40 large T antigen in enterocytes develop intestinal hyperplasia that progresses to dysplasia with age. Hyperplasia is dependent on T antigen binding to the retinoblastoma (pRb) family of tumor suppressor proteins. Mice expressing a truncated T antigen that inactivates the pRb-family, but is defective for binding p53, exhibit hyperplasia but do not progress to dysplasia. We hypothesized that the inhibition of the pRb family leads to entry of enterocytes into the cell cycle, resulting in hyperplasia, while inactivation of p53 is required for progression to dysplasia. Therefore, we examined T antigen/p53 complexes from the intestines of transgenic mice. We found that T antigen did not induce p53 stabilization, and we could not detect T antigen/p53 complexes in villus enterocytes. In contrast, T antigen expression led to a large increase in the levels of the cyclin-dependent kinase inhibitor p21. Furthermore, mice in which pRb was inactivated by a truncated T antigen in a p53 null background exhibited intestinal hyperplasia but no progression to dysplasia. These data indicate that loss of p53 function does not play a role in T antigen-induced dysplasia in the intestine. Rather, some unknown function of T antigen is essential for progression beyond hyperplasia.
在肠细胞中表达猿猴病毒40大T抗原的转基因小鼠会出现肠道增生，随着年龄增长会发展为发育异常。增生依赖于T抗原与肿瘤抑制蛋白视网膜母细胞瘤（pRb）家族的结合。表达截短型T抗原的小鼠，该抗原可使pRb家族失活，但与p53结合存在缺陷，表现出增生但不会发展为发育异常。我们推测，pRb家族的抑制导致肠细胞进入细胞周期，从而导致增生，而p53失活是发展为发育异常所必需的。因此，我们检测了转基因小鼠肠道中的T抗原/p53复合物。我们发现T抗原不会诱导p53稳定，并且在绒毛肠细胞中检测不到T抗原/p53复合物。相反，T抗原的表达导致细胞周期蛋白依赖性激酶抑制剂p21的水平大幅增加。此外，在p53基因敲除背景下，通过截短型T抗原使pRb失活的小鼠表现出肠道增生，但没有发展为发育异常。这些数据表明，p53功能丧失在T抗原诱导的肠道发育异常中不起作用。相反，T抗原的某些未知功能对于超越增生阶段至关重要。
