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The c-Jun NH₂-terminal Protein Kinase/AP-1 Pathway Is Required for Efficient Apoptosis Induced by Vinblastine¹

Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199 [M. F., M. E. G., T. C. C.], and Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, NIH, Bethesda, Maryland 20850 [M. J. B.]

Vinblastine is an important antitumor agent that induces G₂-M arrest and subsequent apoptosis in a wide variety of cell lines, but the molecular mechanisms that link mitotic arrest and apoptosis are poorly understood. The AP-1 transcription factor has been implicated in many critical cellular processes, including apoptosis, and is a major target of the c-Jun NH₂-terminal kinase signaling pathway that is activated by vinblastine and other microtubule inhibitors. In this study we sought to determine the role of c-Jun NH₂-terminal kinase/AP-1 in the response of KB3 carcinoma cells to vinblastine. For this purpose, we generated KB3 cell lines that stably expressed the c-Jun dominant-negative deletional mutant TAM67, which lacks the NH₂-terminal transactivation domain. KB3-TAM67 cell lines displayed normal growth kinetics and essentially unaltered basal AP-1 activity, but vinblastine-induced phosphorylation of c-Jun and activating transcription factor-2, and AP-1 activation, were strongly inhibited. KB3-TAM67 cell lines arrested normally at G₂-M in response to vinblastine, but were significantly more resistant to the drug, exhibiting markedly delayed apoptosis and increased overall survival, relative to control cells. To investigate the underlying mechanisms, differential expression of apoptotic regulatory genes was monitored by immunoblot and cDNA microarray analysis. We found that vinblastine treatment caused down-regulation of p53 and its target p21 and up-regulation of tumor necrosis factor , Bak, and several other genes in control but not in KB3-TAM67 cells, identifying these genes as putative targets of vinblastine-inducible AP-1. These results demonstrate that vinblastine-inducible AP-1 plays a destructive, proapoptotic role and may do so by regulating the expression of a specific subset of target genes that promotes efficient apoptotic cell death following mitotic arrest.

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