Activation of ERK during DNA damage-induced apoptosis involves protein kinase Cdelta.
We have previously shown that protein kinase C (PKC) acts upstream of caspases to regulate cisplatin-induced apoptosis. Since extracellular signal-regulated kinases (ERKs) have also been implicated in DNA damage-induced apoptosis, we have examined if ERK signaling pathway acts downstream of PKC in the regulation of cisplatin-induced apoptosis. PKC activator PDBu induced ERK1/2 phosphorylation which was inhibited by general PKC inhibitor bisindolylmaleimide and Gö 6983 as well as the MEK inhibitor U0126 but not by the PKCdelta inhibitor rottlerin. Cisplatin caused a concentration-dependent activation of ERK1/2 in HeLa cells. The level of ERK2 was decreased in HeLa cells that acquired resistance to cisplatin (HeLa/CP). The MEK inhibitor U0126 inhibited cisplatin-induced ERK activation and attenuated cisplatin-induced cell death. Inhibition of PKCdelta by rottlerin or depletion of PKCdelta by siRNA inhibited cisplatin-induced ERK activation. These results suggest that cisplatin-induced DNA damage results in activation of ERK1/2 via PKCdelta.
Basu
Alakananda
A
Department of Molecular Biology and Immunology, Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. abasu@hsc.unt.edu
Tu
Haidi
H
D017209:Apoptosis; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D015398:Signal Transduction / Q000187:drug effects
C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D002945:Cisplatin