PT  - JOURNAL ARTICLE
AU  - Takagi, Yoshikazu
AU  - Du, Jun
AU  - Ma, Xiu-Yang
AU  - Nakashima, Izumi
AU  - Nagase, Fumihiko
TI  - Phorbol 12-Myristate 13-Acetate Protects Jurkat Cells from Methylglyoxal-Induced Apoptosis by Preventing c-Jun N-Terminal Kinase-Mediated Leakage of Cytochrome <em>c</em> in an Extracellular Signal-Regulated Kinase-Dependent Manner
AID  - 10.1124/mol.65.3.778
DP  - 2004 Mar 01
TA  - Molecular Pharmacology
PG  - 778--787
VI  - 65
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/65/3/778.short
4100  - http://molpharm.aspetjournals.org/content/65/3/778.full
SO  - Mol Pharmacol2004 Mar 01; 65
AB  - Methylglyoxal (MG) is an endogenous metabolite that increases in the blood and tissues of diabetic patients and is believed to be linked to the development of chronic complications of diabetes. We showed previously that Jurkat cells treated with MG rapidly undergo apoptosis via c-Jun N-terminal kinase (JNK) activation. In this study, we examined whether phorbol 12-myristate 13-acetate (PMA) can prevent MG-induced apoptosis in Jurkat cells. The results showed the following: 1) PMA can prevent MG-induced apoptosis; 2) triggering of this antiapoptotic signal depends on the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathway; 3) PMA inhibits MG-induced activation of caspase-3 and caspase-9, release of cytochrome c, and decline of mitochondrial membrane potential, but it does not affect MG-induced JNK activation; 4) the ERK pathway modulates outer mitochondrial membrane permeability and regulates the mitochondrial death machinery; and 5) activated ERK prevents JNK-induced leakage of cytochrome c from isolated mitochondria. Taken together, these results suggest that PMA-induced ERK activation can protect Jurkat cells from methylglyoxal-induced apoptosis and that activated ERK exerts its antiapoptotic effects on mitochondria by inhibiting activated JNK-induced permeabilization of the outer mitochondrial membrane.