ERK1/2 activation attenuates TRAIL-induced apoptosis through the regulation of mitochondria-dependent pathway.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) functions as an extracellular signal, which triggers apoptosis in tumor cells. In order to characterize the molecular events involved in TRAIL cytotoxic signaling, we attempted to determine the role of extracellular signal-regulated kinase 1/2 (ERK1/2), as well as its downstream targets in TRAIL-treated HeLa cells. Here we demonstrate that TRAIL exposure resulted in the activation of ERK1/2, and the elevation of anti-apoptotic Bcl-2 protein levels. ERK1/2 inhibition with PD98059 promoted cell death via the down-regulation of Bcl-2 protein levels, together with increasing mitochondrial damage, including the collapse of mitochondrial membrane potential, the release of cytochrome c from mitochondria to cytoplasm and caspase activity. These results suggest that the ERK1/2 activation is a kind of survival mechanism to struggle against TRAIL-induced stress condition in early stage, via activating cellular defense mechanisms like as the up-regulation of the Bcl-2/Bax ratio, as well as several mitochondrial events.
Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, 221 Huksuk-dong, Dongjak-ku, Seoul 156-756, Republic of Korea.
Do Yeon
DY
Lee
Myoung Woo
MW
Lee
Hyun Jung
HJ
Lee
Yoo Hun
YH
Noh
Soon Cheol
SC
Park
Moo Yeol
MY
Lee
Kyung Yong
KY
Kim
Won Bok
WB
Lee
Sung Su
SS
Kim
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases