Ran suppresses paclitaxel-induced apoptosis in human glioblastoma cells.
Yeast-based functional screening of a human glioblastoma cDNA library identified ras-related nuclear protein (Ran) as a novel suppressor of Bcl-2-associated X protein (Bax), a pro-apoptotic member of the Bcl-2 family of proteins. Yeast cells that expressed human Ran were resistant to Bax-induced cell death. In U373MG glioblastoma cells, stable overexpression of Ran significantly attenuated apoptotic cell death induced by the chemotherapeutic agent paclitaxel. FACS analysis demonstrated that Ran is involved in paclitaxel-induced cell cycle arrest. Stable overexpression of Ran also markedly inhibited the phosphorylation of Bcl-2 by paclitaxel, and inhibited the translocation of Bax, the release of cytochrome c and activation of caspase-3. Paclitaxel-induced phosphorylation of c-JUN N-terminal kinase (JNK), but not p38, extracellular signal-regulated kinase and Akt, was markedly suppressed in U373MG cells that stably expressed Ran. These results suggest that Ran suppresses paclitaxel-induced cell death through the downregulation of JNK-mediated signal pathways.
Woo
Im Sun
IS
Department of Pharmacology, Gyeongsang Institute of Health Science, Gyeongsang National University School of Medicine, Jinju 660-751, South Korea.
Jang
Han-Su
HS
Eun
So Young
SY
Kim
Hyo Jung
HJ
Ham
Sun Ah
SA
Kim
Hye Jung
HJ
Lee
Jae Heun
JH
Chang
Ki Churl
KC
Kim
Jin-Hoi
JH
Han
Chang Woo
CW
Seo
Han Geuk
HG
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D015723:Gene Library; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D017239:Paclitaxel / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D020931:ran GTP-Binding Protein