Basic fibroblast growth factor inhibits p38-mediated cell differentiation and growth inhibition by activin A but not by histone deacetylase inhibitors in CML cells.
The p38 mitogen-activated protein kinase (p38) is involved in multiple cellular functions such as cell proliferation and differentiation. Previously, we found that activin A mediated hemoglobin synthesis and cell growth inhibition through p38, whereas, basic fibroblast growth factor (bFGF) inactivated p38 to antagonize the activin A effects. In this study, we selected three structurally different histone deacetylase (HDAC) inhibitors, apicidin, MS275, and sodium butyrate that activate p38, to probe the signal pathway from activin A to p38 in chronic myeloid leukemia (CML)-derived K562 cells. HDAC inhibitors and activin A showed additive p38 phosphorylation. The enhanced phosphorylation of p38 was correlated with increased cell differentiation and decreased cell proliferation. The use of p38 inhibitor SB203580 in conjunction with activin A or with the HDAC inhibitors inhibited cell differentiation and restored cell proliferation, indicating that activin A and the HDAC inhibitors exert their effects through p38 activation. However, bFGF did not affect HDAC inhibitors-induced cell differentiation or growth inhibition. Western blots showed that p38 phosphorylation remained at similar levels with or without bFGF in the presence of HDAC inhibitors. Thus, the HDAC inhibitors activate p38 in a manner different from the activin A pathway. Furthermore, mRNA expressions for activin type I, IB, II, and IIB receptors remained constant in the presence of activin A, bFGF, or both activin A and bFGF. These results indicate that bFGF does not directly act on p38 nor on the mRNA expression levels of activin receptors but inhibit activin A activation of p38 upstream of p38 in K562 cells.
Chen
Chun-Hsin
CH
Department of Psychiatry, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
Lin
John Yi-Chung
JY
Liu
Fu-Hwa
FH
Chang
Ju-Ling
JL
Huang
Huei-Mei
HM
D028341:Activins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; C422405:activin A; D016222:Fibroblast Growth Factor 2; D028341:Activins; D048051:p38 Mitogen-Activated Protein Kinases