Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway.
c-Raf-1 (Raf-1) is a central component of signal transduction pathways stimulated by various growth factors, protein kinase C, and other protein kinases. Raf-1 activation is thought to be initiated at the plasma membrane after its recruitment by Ras. Raf-1 activation is associated primarily with proliferation and cell survival, but it has also been implicated in apoptosis. Raf-1 has also been shown to form complexes with both R-Ras and Bcl-2, raising the possibility that this component of cellular Raf-1 plays a role in apoptosis. Recently, taxol was reported to induce Bcl-2 phosphorylation and inactivation. We have previously demonstrated Raf-1 activation following taxol in MCF7 cells. We now present evidence that taxol fails to stimulate either apoptosis or phosphorylation of Bel-2 in the absence of Raf-1. Moreover, Raf-1 activation by taxol coincided with Bel-2 phosphorylation, showing similar dose and time dependence. Thus, our data support a role for a distinct subcellular component of Raf-1, which is taxol but not phorbol myristate acetate sensitive, in mediating an apoptotic pathway involving Bc1-2.
Blagosklonny
M V
MV
Clinical Pharmacology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Schulte
T
T
Nguyen
P
P
Trepel
J
J
Neckers
L M
LM
D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001943:Breast Neoplasms; D002460:Cell Line; D004789:Enzyme Activation; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D017239:Paclitaxel / Q000633:toxicity*; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D017346:Protein Serine-Threonine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000302:isolation & purification / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D019908:Proto-Oncogene Proteins c-raf; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D013755:Tetradecanoylphorbol Acetate; D017239:Paclitaxel