SOC1 inhibits HPV-E7-mediated transformation by inducing degradation of E7 protein
SOC1 inhibits HPV-E7-mediated transformation by inducing degradation of E7 protein
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DOI：
10.1038/sj.onc.1207453
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发表时间：
2004-04-15
期刊：
影响因子：
8
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
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作者：
Kamio, M;Yoshida, T;Yoshimura, A
人乳头瘤病毒 (HPV) 是一种小型双链 DNA 病毒，可感染粘膜和皮肤上皮并诱发宫颈癌。研究表明，干扰素 (IFN) γ 通过抑制 HPV E7 的表达来抑制 HPV 感染细胞的增殖。在这里，我们发现 IFNgamma 不仅会抑制 E7 转录，还会诱导蛋白酶体依赖性降解。细胞因子信号传导抑制因子-1 (SOCS1)/JAB 是一种细胞因子信号传导抑制因子，已知由 IFNγ 诱导，并作为针对各种造血致癌蛋白的抑癌基因发挥作用。 SOCS1 包含 SOCS-box，它可以将泛素转移酶募集到与 SOCS1 相互作用的分子中。我们发现SOCS1与HPV E7蛋白相互作用，并以SOCS盒依赖性方式诱导E7泛素化和降解。 SOCS1 过表达还增加了 Rb 蛋白水平并抑制了感染 HPV 的宫颈癌细胞系的增殖。此外，与野生型成纤维细胞相比，携带E7基因的逆转录病毒载体感染的SOCS1缺陷型成纤维细胞中，E7蛋白水平较高，Rb蛋白水平较低。 E7 在 SOCS1 缺陷的成纤维细胞中诱导不依赖贴壁的生长，但在野生型细胞中则不然。这些数据表明SOCS1在调节E7蛋白水平及其转化潜力中发挥重要作用，并且可能成为HPV介导的肿瘤的新治疗工具。
Human papilloma viruses (HPVs) are small double-stranded DNA viruses that infect mucosal and cutaneous epithelium and induce cervical cancer. It has been shown that interferon (IFN)gamma suppresses proliferation of HPV-infected cells by suppressing expression of HPV E7. Here, we found that IFNgamma induces not only suppression of E7 transcription but also proteasome-dependent degradation. Suppressor of cytokine signaling-1 (SOCS1)/JAB, a suppressor of cytokine signaling, is known to be induced by IFNgamma, and functions as an antioncogene against various hematopoietic oncogenic proteins. SOCS1 contains the SOCS-box, which is shown to recruit ubiquitin transferase to the molecules that interact with SOCS1. We found that SOCS1 interacted with HPV E7 protein and induced ubiquitination and degradation of E7 in a SOCS-box-dependent manner. SOCS1 overexpression also increased Rb protein levels and suppressed proliferation of cervical cancer cell lines infected with HPV. Moreover, E7 protein levels were higher and Rb protein levels were lower in SOCS1-deficient fibroblasts infected with retrovirus vector carrying E7 gene than in wild-type fibroblasts. E7 induced anchorage-independent growth in SOCS1-deficient fibroblasts, but not in wild-type cells. These data suggested that SOCS1 plays an important role in regulating the levels of E7 protein and their transforming potential, and could be a new therapeutic tool for HPV-mediated tumors.