Modulation of mitogen-activated protein kinases and phosphorylation of Bcl-2 by vinblastine represent persistent forms of normal fluctuations at G2-M1.
Microtubule inhibitors, widely used in cancer chemotherapy, induce G2-M arrest and apoptosis and have in common the ability to stimulate Raf-1/Bcl-2 phosphorylation and activate c-Jun NH2-terminal protein kinase (JNK). These signal transduction pathways are thought to be activated in response to microtubule damage to promote apoptosis. However, Bcl-2 phosphorylation has been reported to occur at G2-M in nonapoptotic cells, raising the possibility that this and perhaps other signaling pathways altered by microtubule inhibitors reflect perturbations of normal mitotic events. In this study, we sought to test this hypothesis. We show that Bcl-2 phosphorylation and JNK activation, as well as extracellular response kinase and p38 inactivation, occur not only in response to vinblastine but also as discrete transient events at G2-M phase in untreated synchronized KB-3 cells. Thus, modulation of these pathways is not a response to microtubule damage; rather they occur normally at G2-M, and it is the extent, duration, and/or irreversible nature of the signals that distinguish a preapoptotic cell from one destined to divide. These findings provide novel insight into the relationship between mitotic and apoptotic signaling and the mechanism of action of antimitotic drugs.
Fan
M
M
Department of Biochemistry, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Du
L
L
Stone
A A
AA
Gilbert
K M
KM
Chambers
T C
TC
D051698:Activating Transcription Factor 2; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007624:KB Cells; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology*; D051020:bcl-X Protein; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D051020:bcl-X Protein; D014747:Vinblastine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases