al-Salameh A M, Cloyd M W
Department of Microbiology, University of Texas Medical Branch, Galveston 77550.
J Virol. 1992 Oct;66(10):6125-32. doi: 10.1128/JVI.66.10.6125-6132.1992.
Naturally occurring recombinant murine leukemia viruses (MuLVs), termed mink cell focus-inducing (MCF) viruses, are the proximal leukemogens in spontaneous thymic lymphomas of AKR mice. The mechanism by which these viruses transform lymphocytes is not clear. Previous studies have implicated either integrational activation of proto-oncogenes, chronic autocrine immune stimulation, and/or autocrine stimulation of growth factor receptors (e.g., interleukin 2 receptors) via binding of the viral env glycoprotein (gp70) to these receptors. Any one of these events could also involve activation of second messenger signaling pathways in the cell. We examined whether infection with oncogenic AKR-247 MCF MuLV induced transmembrane signaling cascades in thymocytes of AKR mice. Cyclic AMP levels were not changed, but there was enhanced turnover of phosphatidylinositol phosphates, with concomitant increases in diacyglycerol and inositol 1,4,5-triphosphate. Thus, phospholipase C activity was increased. Protein kinase C activity was also elevated in comparison to that in uninfected thymocytes. The above events occurred in parallel with MCF expression in the thymus and were chronically maintained thereafter. No changes in phospholipid turnover occurred in an organ which did not replicate the MCF virus (spleen) or in thymocytes of AKR mice infected with a thymotropic, nononcogenic MCF virus (AKV-1-C36). Therefore, only the oncogenic MCF virus induced phosphatidylinositol signal transduction. Flow cytometric comparison of cell surface gp70 revealed that AKR-247 MCF virus-infected thymocytes expressed more MCF virus gp70 than did thymocytes from AKV-1-C36 MCF virus-infected mice, suggesting that certain threshold quantities of MCF virus env glycoproteins may be involved in this signaling. This type of signal transduction is not induced by stimulation of the interleukin 2 receptor but is involved in certain oncogene systems (e.g., ras and fms). Its chronic induction by oncogenic MCF MuLV may thus initiate thymocyte transformation.
天然存在的重组鼠白血病病毒（MuLVs），即所谓的貂细胞集落诱导（MCF）病毒，是AKR小鼠自发性胸腺淋巴瘤中的近端致白血病原。这些病毒转化淋巴细胞的机制尚不清楚。先前的研究表明，原癌基因的整合激活、慢性自分泌免疫刺激和/或通过病毒env糖蛋白（gp70）与这些受体结合对生长因子受体（如白细胞介素2受体）的自分泌刺激都可能起作用。这些事件中的任何一个也可能涉及细胞中第二信使信号通路的激活。我们研究了致癌性AKR - 247 MCF MuLV感染是否会在AKR小鼠的胸腺细胞中诱导跨膜信号级联反应。环磷酸腺苷水平没有变化，但磷脂酰肌醇磷酸的周转增强，同时二酰基甘油和肌醇1,4,5 - 三磷酸增加。因此，磷脂酶C活性增加。与未感染的胸腺细胞相比，蛋白激酶C活性也升高。上述事件与胸腺中MCF的表达同时发生，并在此后长期维持。在不复制MCF病毒的器官（脾脏）或感染嗜胸腺、非致癌性MCF病毒（AKV - 1 - C36）的AKR小鼠的胸腺细胞中，磷脂周转没有变化。因此，只有致癌性MCF病毒诱导磷脂酰肌醇信号转导。细胞表面gp70的流式细胞术比较显示，AKR - 247 MCF病毒感染的胸腺细胞比AKV - 1 - C36 MCF病毒感染小鼠的胸腺细胞表达更多的MCF病毒gp70，这表明一定阈值量的MCF病毒env糖蛋白可能参与了这种信号传导。这种类型的信号转导不是由白细胞介素2受体的刺激诱导的，而是参与某些癌基因系统（如ras和fms）。因此，致癌性MCF MuLV对其的长期诱导可能引发胸腺细胞转化。
