Xu X, Heidenreich O, Kitajima I, McGuire K, Li Q, Su B, Nerenberg M
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92307, USA.
Oncogene. 1996 Jul 4;13(1):135-42.
Human T cell leukemia virus type I (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy, also called tropical spastic paraparesis (HAM/TSP). Both clinical and in vitro evidence have demonstrated that the virus or its transactivator Tax, are transforming. However, transformation appears to require additional, as yet poorly characterized, genetic changes in infected cells. JNK is a recently characterized member of the MAP kinase family. Its signaling cascade is distinct from other members and has been demonstrated to play an important role in T-cell activation, at least partially through its downstream targets, c-jun and ATF-2. Here we demonstrate constitutive activation of the JNK cascade in human lymphocytes transformed in vitro by HTLV-1 and also in Tax transformed murine fibroblasts. Such activation is not induced by Tax expression alone, and occurs only when infected lymphocytes become IL-2 independent or immortalized. Constitutive JNK activation was also found in leukocytes isolated from ATL patients. The acquisition of constitutive JNK activation may represent an important later event in HTLV-1 tumorigenesis.
人类嗜T细胞病毒I型（HTLV-1）是成人T细胞白血病（ATL）和HTLV-1相关脊髓病（也称为热带痉挛性截瘫，HAM/TSP）的病原体。临床和体外证据均表明，该病毒或其反式激活因子Tax具有转化作用。然而，转化似乎需要受感染细胞发生额外的、目前特征尚不明确的基因变化。JNK是丝裂原活化蛋白激酶（MAP激酶）家族中最近被鉴定的成员。其信号级联与其他成员不同，并且已证明至少部分地通过其下游靶点c-jun和ATF-2在T细胞活化中起重要作用。在此，我们证明在体外被HTLV-1转化的人淋巴细胞以及Tax转化的小鼠成纤维细胞中JNK级联的组成性激活。这种激活不是仅由Tax表达诱导的，并且仅在受感染的淋巴细胞变得不依赖白细胞介素-2或永生化时发生。在从ATL患者分离的白细胞中也发现了组成性JNK激活。组成性JNK激活的获得可能代表HTLV-1肿瘤发生过程中一个重要的后期事件。
