Kralova Jarmila, Liss Andrew S, Bargmann William, Pendleton Cullen, Varadarajan Janani, Ulug Emin, Bose Henry R
Section of Molecular Genetics and Microbiology and the Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712-1095, USA.
J Virol. 2002 Dec;76(23):11960-70. doi: 10.1128/jvi.76.23.11960-11970.2002.
The v-rel oncogene encoded by reticuloendotheliosis virus is the acutely transforming member of the Rel/NF-kappaB family of transcription factors. v-Rel is a truncated and mutated form of c-Rel and transforms cells by inducing the aberrant expression of genes regulated by Rel/NF-kappaB proteins. The expression of ch-IAP1, a member of the inhibitor-of-apoptosis family, is highly elevated in cells expressing v-Rel and contributes to the immortalization of cells transformed by this oncoprotein. In this study we demonstrate that the elevated expression of ch-IAP1 in v-Rel-expressing cells is due to an increased rate of transcription. The ch-IAP1 promoter was isolated, and four Rel/NF-kappaB binding sites were identified upstream of the transcription start site. Two kappaB sites proximal to the transcription start site were required for v-Rel to activate the ch-IAP1 promoter. While c-Rel also utilized these sites, a third more-distal kappaB site was required for its full activation of the ch-IAP1 promoter. Differences in the transactivation domains of v-Rel and c-Rel are responsible for their different abilities to utilize these sites and account for their differential activation of the ch-IAP1 promoter. Although c-Rel was a more potent activator of the ch-IAP1 promoter than v-Rel in transient reporter assays, cells stably overexpressing c-Rel failed to maintain high levels of ch-IAP1 expression. The reduction of ch-IAP1 expression in these cells correlated with the efficient regulation of c-Rel by IkappaBalpha. The ability of v-Rel to escape IkappaBalpha regulation allows for the gradual and sustained elevation of ch-IAP1 expression directly contributing to the transforming properties of v-Rel.
由网状内皮增生症病毒编码的v-rel癌基因是Rel/NF-κB转录因子家族的急性转化成员。v-Rel是c-Rel的截短和突变形式，通过诱导由Rel/NF-κB蛋白调控的基因异常表达来转化细胞。凋亡抑制因子家族成员ch-IAP1在表达v-Rel的细胞中表达水平显著升高，并有助于该癌蛋白转化的细胞永生化。在本研究中，我们证明ch-IAP1在表达v-Rel的细胞中表达升高是由于转录速率增加。分离出ch-IAP1启动子，并在转录起始位点上游鉴定出四个Rel/NF-κB结合位点。v-Rel激活ch-IAP1启动子需要转录起始位点附近的两个κB位点。虽然c-Rel也利用这些位点，但其完全激活ch-IAP1启动子还需要第三个更远端的κB位点。v-Rel和c-Rel反式激活结构域的差异导致它们利用这些位点的能力不同，并解释了它们对ch-IAP1启动子的差异激活。尽管在瞬时报告基因分析中c-Rel比v-Rel是更强的ch-IAP1启动子激活剂，但稳定过表达c-Rel的细胞未能维持ch-IAP1的高水平表达。这些细胞中ch-IAP1表达的降低与IκBα对c-Rel的有效调控相关。v-Rel逃避IκBα调控的能力使得ch-IAP1表达逐渐持续升高，直接促成了v-Rel的转化特性。
