Histone deacetylase 1 and 2 differentially regulate apoptosis by opposing effects on extracellular signal-regulated kinase 1/2

Histone deacetylases (HDACs) are epigenetic regulators that are important for the control of various pathophysiological events. We found that HDAC inhibitors completely abolished transforming growth factor- β 1 (TGF- β 1)-induced apoptosis in AML-12 and primary mouse hepatocytes. Expression of a dom...

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Bibliographic Details
Published in:Cell death & disease Vol. 1; no. 5; p. e44
Main Authors: Lei, W-W, Zhang, K-H, Pan, X-C, Wang, D-M, Hu, Y, Yang, Y-N, Song, J-G
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.05.2010
Springer Nature B.V
Nature Publishing Group
Subjects:
631/45/607/1164
631/45/607/275
631/80/82/23
Animals
Antibodies
Apoptosis - drug effects
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell Line
Cell Survival - drug effects
Enzyme Activation - drug effects
Hepatocytes - cytology
Hepatocytes - drug effects
Hepatocytes - enzymology
Histone Deacetylase 1 - metabolism
Histone Deacetylase 2 - metabolism
Histone Deacetylase Inhibitors - pharmacology
Humans
Immunology
Life Sciences
Mice
Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 - metabolism
Models, Biological
Original
original-article
Phosphorylation - drug effects
Transforming Growth Factor beta1 - pharmacology
1
HDAC2
TGF
ERK1/2
HDAC1
apoptosis
signalling
ISSN:2041-4889, 2041-4889
Online Access:Get full text
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Summary:Histone deacetylases (HDACs) are epigenetic regulators that are important for the control of various pathophysiological events. We found that HDAC inhibitors completely abolished transforming growth factor- β 1 (TGF- β 1)-induced apoptosis in AML-12 and primary mouse hepatocytes. Expression of a dominant-negative mutant of HDAC1 or downregulation of HDAC1 by RNAi both suppressed TGF- β 1-induced apoptosis. In addition, overexpression of HDAC1 enhanced TGF- β 1-induced apoptosis, and the rescue of HDAC1 expression in HDAC1 RNAi cells restored the apoptotic response of cells to TGF- β 1. These data indicate that HDAC1 functions as a proapoptotic factor in TGF- β 1-induced apoptosis. In contrast, downregulation of HDAC2 by RNAi increased spontaneous apoptosis and markedly enhanced TGF- β 1-induced apoptosis, suggesting that HDAC2 has a reciprocal role in controlling cell survival. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) by MEK1 inhibitor PD98059 or expression of a kinase-dead mutant of MEK1 restored the apoptotic response to TGF- β 1 in HDAC1 RNAi cells. Strikingly, HDAC2 RNAi caused an inhibition of ERK1/2, and the spontaneous apoptosis can be abolished by reactivation of ERK1/2. Taken together, our data demonstrate that HDAC1 and 2 reciprocally affect cell viability by differential regulation of ERK1/2; these observations provide insight into the roles and potential mechanisms of HDAC1 and 2 in apoptosis.
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ISSN:2041-4889
2041-4889
DOI:10.1038/cddis.2010.21