Lee L A, Dolde C, Barrett J, Wu C S, Dang C V
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.
J Clin Invest. 1996 Apr 1;97(7):1687-95. doi: 10.1172/JCI118595.
Recent studies indicate that the transcription factor c-Myc contributes to oncogenesis by altering the expression of genes involved in cell proliferation, but its precise function in neoplasia remains ambiguous. The ability of c-Myc to bind the sequence CAC(G/A)TG and transactivate appears to be linked to its transforming activity; however, c-Myc also represses transcription in vitro through a pyrimidine-rich cis element termed the initiator (Inr). In transfection experiments using the adenoviral major late (adML) promoter, which contains two Myc binding sites and an Inr, we determined that c-Myc represses transcription through the initiator in vivo. This activity requires the dimerization domain and amino acids 106 to 143, which are located within the transactivation domain and are necessary for neoplastic transformation. We studied a lymphoma-derived c-Myc substitution mutation at 115-Phe, which is within the region required for transcriptional suppression, and found the mutant more effective than wild-type c-Myc in transforming rodent fibroblasts and in suppressing the adML promoter. Our studies of both loss-of-function and gain-of-function c-Myc mutations suggest a link between c-Myc-mediated neoplastic transformation and transcriptional repression through the Inr.
最近的研究表明，转录因子c-Myc通过改变参与细胞增殖的基因表达来促进肿瘤发生，但其在肿瘤形成中的精确功能仍不明确。c-Myc结合序列CAC(G/A)TG并反式激活的能力似乎与其转化活性相关；然而，c-Myc在体外也通过一个富含嘧啶的顺式元件（称为起始子，Inr）来抑制转录。在使用腺病毒主要晚期（adML）启动子的转染实验中，该启动子包含两个Myc结合位点和一个Inr，我们确定c-Myc在体内通过起始子抑制转录。这种活性需要二聚化结构域以及位于反式激活结构域内的106至143位氨基酸，而这些氨基酸对于肿瘤转化是必需的。我们研究了淋巴瘤来源的c-Myc在115位苯丙氨酸处的替代突变，该位点位于转录抑制所需区域内，发现该突变体在转化啮齿动物成纤维细胞和抑制adML启动子方面比野生型c-Myc更有效。我们对功能丧失和功能获得性c-Myc突变的研究表明，c-Myc介导的肿瘤转化与通过Inr的转录抑制之间存在联系。
