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c-Jun NH₂-Terminal Kinase/c-Jun Signaling Promotes Survival and Metastasis of B Lymphocytes Transformed by Theileria

¹ Institut Cochin, Département de Maladies Infectieuses, Faculté de Médecine René Descartes, Université Paris Descartes, INSERM U567, CNRS UMR 8104, ² Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Département de Pathogenèse Microbienne, ³ Unité des Cytokines et Développement Lymphoïde, INSERM U668, Département d'Immunologie, Institut Pasteur, Paris Cedex 15, France; and ⁴ The Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire, United Kingdom

Requests for reprints: Gordon Langsley, Institut Cochin, Département de Maladie Infectieuse, Paris, F-75014 France. Phone: 33-1-40-51-65-92; Fax: 11-33-1-40-51-65-70; E-mail: langsley{at}cochin.inserm.fr.

Theileria parasites infect and transform bovine lymphocytes resulting in tumors with metastatic/invasive potential. Importantly, cellular transformation is reversed upon drug-induced parasite death, and the infected lymphocyte dies of apoptosis within 48 hours. Theileria-dependent transformation leads to the constitutive activation of c-Jun NH₂-terminal kinase (both JNK1 and JNK2) and permanent induction of activator protein-1. Inactivation of JNK (following transfection of dominant-negative mutants, or treatment with a JNK-specific inhibitor) leads to lymphocyte apoptosis, suggesting an antiapoptotic role for JNK activation in Theileria-induced B cell transformation. Theileria-induced JNK activation also leads to constitutive c-Jun phosphorylation, and inhibition of c-Jun and activator protein-1 transactivation following the expression of a dominant-negative mutant of c-Jun sensitizes Theileria-transformed B cells to apoptosis, but does not significantly affect their proliferation. Thus, JNK activation and c-Jun induction have overlapping, but nonidentical antiapoptotic roles in Theileria-induced B cell transformation. Increased sensitivity to apoptosis may be related to the fact that the expression levels of antiapoptotic proteins such as Mcl-1 and c-IAP are reduced upon c-Jun inhibition. In addition, decreased c-Jun expression correlates with the impaired ability of transfected B cells to degrade synthetic matrix in vitro, and their injection into lymphoid mice gives rise to significantly less and smaller tumors. Combined, these data argue for a role for JNK and c-Jun induction in the survival and metastasis of Theileria-transformed B cells. The similarity between Theileria-transformed B cells with human B lymphomas argues that exploiting the reversible nature of Theileria-induced transformation could throw light on the mechanisms underlying human malignancies. (Cancer Res 2006; 66(12): 6105-10)