The Kaposi's sarcoma-associated herpesvirus K-bZIP protein represses transforming growth factor β signaling through interaction with CREB-binding protein
The Kaposi's sarcoma-associated herpesvirus K-bZIP protein represses transforming growth factor β signaling through interaction with CREB-binding protein
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DOI：
10.1038/sj.onc.1208059
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发表时间：
2004-10
期刊：
影响因子：
8
通讯作者：
M. Tomita;J. Choe;T. Tsukazaki;N. Mori
中科院分区：
文献类型：
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作者：
M. Tomita;J. Choe;T. Tsukazaki;N. Mori
卡波西肉瘤（KS）相关疱疹病毒（KSHV）参与KS、原发性渗出性淋巴瘤和多中心Castleman病的发病机制。K-bZIP是由KSHV的开放阅读框K8编码的蛋白质，属于碱性区-亮氨酸拉链转录因子家族。我们通过研究K-bZIP是否通过转化生长因子β（TGF-β）干扰信号传导（TGF-β抑制多种细胞类型的增殖），研究了KSHV诱导肿瘤发生的机制。K-bZIP抑制TGF-β诱导的Smad介导的转录活性，并拮抗TGF-β的生长抑制作用。由于已知K-bZIP和Smad均与CREB结合蛋白（CBP）相互作用，因此检查了CBP对K-bZIP抑制Smad介导的转录激活的作用。缺少CBP结合位点的K-bZIP突变体不能抑制TGF-β诱导的或Smad 3介导的转录活性。CBP的过表达恢复了K-bZIP诱导的Smad 3介导的转录活性抑制。竞争性相互作用研究表明，K-bZIP抑制了Smad 3与CBP的相互作用。这些结果表明，K-bZIP通过其与CBP的结合，通过干扰CBP募集到TGF-β响应元件上的转录起始复合物中来破坏TGF-β信号传导。我们提出了一种可能性，即K-bZIP可能通过抑制TGF-β信号传导促进细胞存活的能力而促进肿瘤发生。
Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is involved in the pathogenesis of KS, primary effusion lymphoma, and multicentric Castleman's disease. K-bZIP, the protein encoded by the open reading frame K8 of KSHV, is a member of the basic region-leucine zipper family of transcription factors. We studied the mechanisms that underlie KSHV-induced oncogenesis by investigating whether K-bZIP perturbs signaling through transforming growth factor β (TGF-β), which inhibits proliferation of a wide range of cell types. K-bZIP repressed TGF-β-induced, Smad-mediated transcriptional activity and antagonized the growth-inhibitory effects of TGF-β. Since both K-bZIP and Smad are known to interact with CREB-binding protein (CBP), the effect of CBP on inhibition of Smad-mediated transcriptional activation by K-bZIP was examined. K-bZIP mutants, which lacked the CBP-binding site, could not repress TGF-β-induced or Smad3-mediated transcriptional activity. Overexpression of CBP restored K-bZIP-induced inhibition of Smad3-mediated transcriptional activity. Competitive interaction studies showed that K-bZIP inhibited the interaction of Smad3 with CBP. These results suggest that K-bZIP, through its binding to CBP, disrupts TGF-β signaling by interfering with the recruitment of CBP into transcription initiation complexes on TGF-β-responsive elements. We propose a possibility that K-bZIP may contribute to oncogenesis through its ability to promote cell survival by repressing TGF-β signaling.