Kralova J, Liss A S, Bargmann W, Bose H R
Department of Microbiology and the Institute for Cellular and Molecular Biology, University of Texas at Austin, 78712-1095, USA.
Mol Cell Biol. 1998 May;18(5):2997-3009. doi: 10.1128/MCB.18.5.2997.
v-rel is the oncogenic member of the Rel/NF-kappaB family of transcription factors. The mechanism by which v-Rel induces transformation of avian lymphoid cells and fibroblasts is not precisely known. However, most models propose that v-rel disrupts the normal transcriptional regulatory network. In this study we evaluated the role of AP-1 family members in v-Rel-mediated transformation. The overexpression of v-Rel, c-Rel, and c-Rel delta resulted in a prolonged elevation of c-fos and c-jun expression and in a sustained repression of fra-2 at both the mRNA and protein levels in fibroblasts and lymphoid cells. Moreover, the transforming abilities of these Rel proteins correlated with their ability to alter the expression of these AP-1 factors. v-Rel exhibited the most pronounced effect, whereas c-Rel, with poor transforming ability, elicited only moderate changes in AP-1 levels. Furthermore, c-Rel delta, which exhibits enhanced transforming potential relative to c-Rel, induced intermediate changes in AP-1 expression. To directly evaluate the role of AP-1 family members in the v-Rel transformation process, a supjun-1 transdominant mutant was used. The supjun-1 mutant functions as a general inhibitor of AP-1 activity by inhibiting AP-1-mediated transactivation and by reducing AP-1 DNA-binding activity. Coinfection or sequential infection of fibroblasts or lymphoid cells with viruses carrying rel oncogenes and supjun-1 resulted in a reduction of the transformation efficiency of the Rel proteins. The expression of supjun-1 inhibited the ability of v-Rel transformed lymphoid cells and fibroblasts to form colonies in soft agar by over 70%. Furthermore, the expression of supjun-1 strongly interfered with the ability of v-Rel to morphologically transform avian fibroblasts. This is the first report showing that v-Rel might execute its oncogenic potential through modulating the activity of early response genes.
v-Rel是转录因子Rel/NF-κB家族中的致癌成员。v-Rel诱导禽类淋巴细胞和成纤维细胞转化的机制尚不完全清楚。然而，大多数模型认为v-Rel破坏了正常的转录调控网络。在本研究中，我们评估了AP-1家族成员在v-Rel介导的转化中的作用。v-Rel、c-Rel和c-Relδ的过表达导致成纤维细胞和淋巴细胞中c-fos和c-jun表达的长期升高以及fra-2在mRNA和蛋白质水平上的持续抑制。此外，这些Rel蛋白的转化能力与其改变这些AP-1因子表达的能力相关。v-Rel表现出最显著的效果，而转化能力较差的c-Rel仅引起AP-1水平的适度变化。此外，相对于c-Rel具有增强转化潜力的c-Relδ诱导了AP-1表达的中间变化。为了直接评估AP-1家族成员在v-Rel转化过程中的作用，使用了supjun-1反式显性突变体。supjun-1突变体通过抑制AP-1介导的反式激活和降低AP-1 DNA结合活性，作为AP-1活性的一般抑制剂发挥作用。携带rel癌基因和supjun-1的病毒共感染或顺序感染成纤维细胞或淋巴细胞导致Rel蛋白的转化效率降低。supjun-1的表达抑制了v-Rel转化的淋巴细胞和成纤维细胞在软琼脂中形成集落的能力超过70%。此外，supjun-1的表达强烈干扰了v-Rel对禽类成纤维细胞进行形态转化的能力。这是第一份表明v-Rel可能通过调节早期反应基因的活性来发挥其致癌潜力的报告。
