Nishigaki Kazuo, Hanson Charlotte, Jelacic Tanya, Thompson Delores, Ruscetti Sandra
Laboratory of Cancer Prevention, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15488-93. doi: 10.1073/pnas.0506570102. Epub 2005 Oct 13.
Friend spleen focus-forming virus (SFFV) causes rapid erythroleukemia in mice due to expression of its unique envelope glycoprotein, gp55. Erythroid cells expressing SFFV gp55 proliferate in the absence of their normal regulator erythropoietin (Epo) because of constitutive activation of Epo signal transduction pathways. Although SFFV infects many cell types, deregulation of cell growth occurs only when SFFV infects erythroid cells, suggesting that these cells express unique proteins that the virus requires to mediate its biological effects. Not only do erythroid cells express the Epo receptor (EpoR), but those from mice susceptible to SFFV-induced erythroleukemia also express a short form of the receptor tyrosine kinase Stk (sf-Stk). In erythroid cells, SFFV gp55 interacts with the EpoR complex and sf-Stk, leading to activation of the kinase and constitutive activation of signal transducing molecules. In this study, we demonstrate that SFFV gp55 can also deregulate the growth of nonerythroid cells when it is coexpressed with sf-Stk. Expression of SFFV gp55 in rodent fibroblasts engineered to express sf-Stk induced their transformation, as demonstrated by focus formation and anchorage-independent growth in vitro. This transformation by SFFV gp55 requires the kinase activity of sf-Stk and the presence of its extracellular domain but not expression of the EpoR or the tyrosine kinase Jak2, which is required for activation of signal transduction pathways through the EpoR. Thus, expression of SFFV gp55 in nonerythroid cells coexpressing sf-Stk results in their uncontrolled growth, demonstrating a previously unrecognized mechanism for retrovirus transformation of rodent fibroblasts and providing insight into SFFV-induced disease.
Friend脾集落形成病毒（SFFV）可在小鼠中引发快速的红白血病，这是由于其独特的包膜糖蛋白gp55的表达所致。表达SFFV gp55的红系细胞在缺乏其正常调节因子促红细胞生成素（Epo）的情况下仍能增殖，这是因为Epo信号转导通路的组成性激活。尽管SFFV可感染多种细胞类型，但只有当SFFV感染红系细胞时才会出现细胞生长失调，这表明这些细胞表达了病毒介导其生物学效应所需的独特蛋白质。红系细胞不仅表达Epo受体（EpoR），而且来自易患SFFV诱导的红白血病的小鼠的红系细胞还表达一种受体酪氨酸激酶Stk的短形式（sf-Stk）。在红系细胞中，SFFV gp55与EpoR复合物和sf-Stk相互作用，导致激酶激活和信号转导分子的组成性激活。在本研究中，我们证明当SFFV gp55与sf-Stk共表达时，它也能使非红系细胞的生长失调。在经过基因工程改造以表达sf-Stk的啮齿动物成纤维细胞中，SFFV gp55的表达诱导了它们的转化，这通过体外集落形成和不依赖贴壁生长得以证明。SFFV gp55的这种转化需要sf-Stk的激酶活性及其细胞外结构域的存在，但不需要EpoR或酪氨酸激酶Jak2的表达，而Jak2是通过EpoR激活信号转导通路所必需的。因此，在共表达sf-Stk的非红系细胞中SFFV gp55的表达导致它们不受控制地生长，这揭示了逆转录病毒转化啮齿动物成纤维细胞的一种先前未被认识的机制，并为深入了解SFFV诱导的疾病提供了线索。
