PMID- 17543571
OWN - NLM
STAT- MEDLINE
DCOM- 20070927
LR  - 20091119
IS  - 1357-2725 (Print)
IS  - 1357-2725 (Linking)
VI  - 39
IP  - 9
DP  - 2007
TI  - ERK1/2 inactivation and p38 MAPK-dependent caspase activation during guanosine 
      5'-triphosphate-mediated terminal erythroid differentiation of K562 cells.
PG  - 1685-97
AB  - Since differentiation therapy is one of the promising strategies for treatment of 
      leukemia, universal efforts have been focused on finding new differentiating 
      agents. In that respect, it was recently shown that guanosine 5'-triphosphate 
      (GTP) induced the differentiation of K562 cells, suggesting its possible 
      efficiency in treatment of chronic myelogenous leukemia (CML). However, further 
      investigations are required to verify this possibility. Here, the effects of GTP 
      on activation of mitogen-activated protein kinases (MAPKs) and caspases in K562 
      cells were examined. Exposure of K562 cells to 100muM GTP markedly inhibited 
      growth (4-70%) and increased percent glycophorin A positive cells after 1-6 days. 
      GTP-induced terminal erythroid differentiation of K562 cells was accompanied with 
      activation of three key caspases, i.e., caspase-3, -6 and -9. More detailed 
      studies revealed that mitochondrial pathway is activated along with 
      down-regulation of Bcl-xL and releasing of cytochrome c into cytosol. Among 
      MAPKs, ERK1/2and p38 were modulated after GTP treatment. Western blot analyses 
      showed that sustained phosphorylation of p38 MAPK was accompanied by a decrease 
      in ERK1/2 activation. These modulatory effects of GTP were observed at early 
      exposure times before the onset of differentiation (3h), and followed for 24-96h. 
      Interestingly, inhibition of p38 MAPK pathway by SB202190 impeded GTP-mediated 
      caspases activation and differentiation in K562 cells, suggesting that p38 MAPK 
      may act upstream of caspases in our system. These results point to a pivotal role 
      for p38 MAPK pathway during GTP-mediated erythroid differentiation of K562 cells 
      and will hopefully have important impact on pharmaceutical evaluation of GTP for 
      CML treatment in differentiation therapy approaches.
FAU - Moosavi, Mohammad Amin
AU  - Moosavi MA
AD  - Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 
      13145-1384, Tehran, Iran.
FAU - Yazdanparast, Razieh
AU  - Yazdanparast R
FAU - Lotfi, Abbas
AU  - Lotfi A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070504
PL  - Netherlands
TA  - Int J Biochem Cell Biol
JT  - The international journal of biochemistry & cell biology
JID - 9508482
RN  - 0 (Protein Kinase Inhibitors)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Caspases/*metabolism
MH  - Cell Differentiation/*drug effects
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Enzyme Activation/drug effects
MH  - Erythroid Cells/cytology/drug effects/*enzymology
MH  - Guanosine Triphosphate/*pharmacology
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - K562 Cells
MH  - Mitochondria/drug effects/metabolism
MH  - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/*metabolism
MH  - Mitogen-Activated Protein Kinase 3/antagonists & inhibitors/*metabolism
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Time Factors
MH  - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
EDAT- 2007/06/05 09:00
MHDA- 2007/09/28 09:00
CRDT- 2007/06/05 09:00
PHST- 2007/01/31 00:00 [received]
PHST- 2007/04/15 00:00 [revised]
PHST- 2007/04/16 00:00 [accepted]
PHST- 2007/06/05 09:00 [pubmed]
PHST- 2007/09/28 09:00 [medline]
PHST- 2007/06/05 09:00 [entrez]
AID - S1357-2725(07)00130-6 [pii]
AID - 10.1016/j.biocel.2007.04.016 [doi]
PST - ppublish
SO  - Int J Biochem Cell Biol. 2007;39(9):1685-97. doi: 10.1016/j.biocel.2007.04.016. 
      Epub 2007 May 4.