Matin A, Hung M C
Department of Tumor Biology, University of Texas, M. D. Anderson Cancer Center, Houston 77030.
Cell Growth Differ. 1993 Dec;4(12):1051-6.
The neu gene is amplified and its protein product is overexpressed in certain human tumors. The adenovirus 5 E1a gene product and c-myc repress neu transcription. Moreover, expression of E1a in neu-transformed cells leads to decrease in transformation phenotype and metastatic potential. The simian virus 40 large T antigen (LT) shares structural and functional homology with E1a and c-myc, and all three proteins bind to the retinoblastoma gene product, Rb. We found that LT also represses neu expression at the transcriptional level. However, LT represses neu promoter by a different mechanism compared to E1a and c-myc, because the region of the neu promoter mediating repression by LT (-172 to -79) is downstream from the region responding to E1a and c-myc (-312 to -172). In addition, a LT mutant (K1) unable to complex Rb still represses neu promoter activity, indicating that the Rb binding domain of LT is not required for repression of neu. Since K1, unlike LT, does not transform Rat-1 cells but, like LT, represses the neu promoter, we tested whether K1 functions as a transformation suppressor of activated neu oncogene. Focus-forming assays showed that K1 indeed suppresses the strong cell-transforming activity of activated neu.
neu基因在某些人类肿瘤中发生扩增，其蛋白质产物过度表达。腺病毒5 E1a基因产物和c-myc可抑制neu转录。此外，E1a在neu转化细胞中的表达会导致转化表型和转移潜能降低。猿猴病毒40大T抗原（LT）与E1a和c-myc在结构和功能上具有同源性，并且这三种蛋白质均与视网膜母细胞瘤基因产物Rb结合。我们发现LT也在转录水平上抑制neu表达。然而，与E1a和c-myc相比，LT通过不同的机制抑制neu启动子，因为介导LT抑制作用的neu启动子区域（-172至-79）位于响应E1a和c-myc的区域（-312至-172）的下游。此外，无法与Rb形成复合物的LT突变体（K1）仍然抑制neu启动子活性，这表明LT的Rb结合结构域对于抑制neu并非必需。由于K1与LT不同，它不能转化Rat-1细胞，但与LT一样能抑制neu启动子，因此我们测试了K1是否作为活化的neu癌基因的转化抑制因子发挥作用。集落形成试验表明，K1确实抑制了活化的neu的强大细胞转化活性。
