Constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis.
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.
Xu
X
X
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92307, USA.
Heidenreich
O
O
Kitajima
I
I
McGuire
K
K
Li
Q
Q
Su
B
B
Nerenberg
M
M
D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology / Q000821:virology; D016356:Gene Products, tax / Q000502:physiology; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000209:etiology* / Q000473:pathology; D008214:Lymphocytes / Q000201:enzymology / Q000473:pathology / Q000821:virology; D048670:MAP Kinase Kinase 4; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases; D009363:Neoplasm Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D016356:Gene Products, tax; D009363:Neoplasm Proteins; D011494:Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases