Downregulation of p38 kinase pathway by cAMP response element-binding protein protects HL-60 cells from iron chelator-induced apoptosis.
The signaling mechanisms that control apoptotic events evoked by iron chelators are largely unknown. We found that cAMP response element-binding protein (CREB) is cleaved during iron chelator deferoxamine (DFO)-induced apoptosis, and that the cleavage is largely prevented by the cell-permeable analog of cAMP, dibutyryl-cAMP (dbcAMP), a known CREB activator. In addition, dbcAMP profoundly reduced DFO-induced apoptosis along with significant suppression of caspase-3 and -8 activation and inhibition of loss of mitochondrial potential. These results led us to investigate whether CREB activation is functionally connected with the MAPK family members because we previously demonstrated that p38 kinase is involved in iron chelator-induced apoptosis of HL-60 cells. dbcAMP by itself rapidly induced CREB phosphorylation but dramatically inhibited DFO-induced phosphorylation of all three MAPK family members. However, disruption of CREB expression by antisense oligodeoxyribonucleotide (AS-ODN) only restored p38 kinase activation, and simultaneously attenuated dbcAMP-induced protection of HL-60 cells from DFO-induced cell death. Conversely, inhibition of p38 kinase activity by SB203580 significantly reduced DFO-induced CREB cleavage as well as apoptosis, indicating a cross-talk between CREB and p38 kinase. Collectively, these results demonstrate that cAMP-dependent CREB activation plays an important role in protecting HL-60 cells from iron chelator-induced apoptosis, presumably through downregulation of p38 kinase.
Choi
Suck Chei
SC
Digestive Disease Research Institute, Wonkwang University School of Medicine, Iksan, Chonbuk, South Korea.
Kim
Bum Su
BS
Song
Moon Young
MY
Choi
Eun Young
EY
Oh
Hyun Mee
HM
Lyou
June Hyung
JH
Han
Weon Cheol
WC
Moon
Hyung Bae
HB
Kim
Tae Hyeon
TH
Oh
Jae Min
JM
Chung
Hun Taeg
HT
Jun
Chang Duk
CD
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007502:Iron Chelating Agents; D020319:Oligodeoxyribonucleotides, Antisense; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D003676:Deferoxamine