c-Jun NH2-terminal kinase/c-Jun signaling promotes survival and metastasis of B lymphocytes transformed by Theileria.
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.
Lizundia
Regina
R
Institut Cochin, Département de Maladies Infectieuses, Paris, France.
Chaussepied
Marie
M
Huerre
Michel
M
Werling
Dirk
D
Di Santo
James P
JP
Langsley
Gordon
G
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism / Q000469:parasitology* / Q000473:pathology; D002417:Cattle; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016797:Theileria parva / Q000502:physiology*; D013801:Theileriasis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; C064655:V(D)J recombination activating protein 2; D048031:JNK Mitogen-Activated Protein Kinases