Yu D, Suen T C, Yan D H, Chang L S, Hung M C
Department of Tumor Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Proc Natl Acad Sci U S A. 1990 Jun;87(12):4499-503. doi: 10.1073/pnas.87.12.4499.
Amplification/overexpression of the human neu protooncogene has been frequently found in human primary breast and ovarian cancers and is correlated with the number of axillary lymph nodes positive for metastasis in breast cancer patients. Identification of the factors controlling transcription of the neu gene is essential for understanding the mechanisms of neu gene regulation and its role in tumorigenicity. The adenovirus early region 1A (E1A) gene products are pleiotropic transcription regulators of viral and cellular genes and have been identified as a viral suppressor gene for metastasis. Here we demonstrate that transcription of neu can be strongly repressed by the E1A gene products. The 13S and 12S products of E1A gene are effective at repressing neu transcription and the transcriptional repression requires the conserved region 2 of the E1A proteins. The target for E1A repression was localized within a 139-base-pair DNA fragment in the upstream region of the neu promoter. In addition, competition experiments suggest that the sequence TGGAATG, within the 139-base-pair fragment, is an important element for the E1A-induced repression. These results indicate that E1A negatively regulates neu gene expression at the transcriptional level by means of a specific DNA element.
人类neu原癌基因的扩增/过表达在人类原发性乳腺癌和卵巢癌中经常被发现，并且与乳腺癌患者腋窝淋巴结转移阳性的数量相关。鉴定控制neu基因转录的因子对于理解neu基因调控机制及其在肿瘤发生中的作用至关重要。腺病毒早期区域1A（E1A）基因产物是病毒和细胞基因的多效性转录调节因子，并且已被鉴定为转移的病毒抑制基因。在这里，我们证明E1A基因产物可以强烈抑制neu的转录。E1A基因的13S和12S产物在抑制neu转录方面是有效的，并且转录抑制需要E1A蛋白的保守区域2。E1A抑制的靶标定位于neu启动子上游区域的一个139个碱基对的DNA片段内。此外，竞争实验表明，139个碱基对片段内的序列TGGAATG是E1A诱导抑制的重要元件。这些结果表明，E1A通过特定的DNA元件在转录水平上负调控neu基因表达。
