Search results for: HDAC4 (flag)
#26510776 
2015/10/29
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The effects of a novel aliphatic-chain hydroxamate derivative WMJ-S-001 in HCT116 colorectal cancer cell death.
Hydroxamate derivatives have attracted considerable attention due to their broad pharmacological properties and have been extensively investigated. We recently demonstrated that WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory and anti-angiogenic activities. In this study, we explored the underlying mechanisms by which WMJ-S-001 induces HCT116 colorectal cancer cell death. WMJ-S-001 inhibited cell proliferation and induced cell apoptosis in HCT116 cells. These actions were associated with AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK) activation, p53 phosphorylation and acetylation, as well as the modulation of p21(cip/Waf1), cyclin D1, survivin and Bax. AMPK-p38MAPK signaling blockade reduced WMJ-S-001-induced p53 phosphorylation. Transfection with AMPK dominant negative mutant (DN) reduced WMJ-S-001's effects on p53 and Sp1 binding to the survivn promoter region. Transfection with HDAC3-Flag or HDAC4-Flag also abrogated WMJ-S-001's enhancing effect on p53 acetylation. WMJ-S-001's actions on p21(cip/Waf1), cyclin D1, survivin, Bax were reduced in p53-null HCT116 cells. Furthermore, WMJ-S-001 was shown to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. In summary, the death of HCT116 colorectal cancer cells exposed to WMJ-S-001 may involve AMPK-p38MAPK-p53-survivin cascade. These results support the role of WMJ-S-001 as a potential drug candidate and warrant the clinical development in the treatment of cancer.Yu-Han Huang, Shiu-Wen Huang, Ya-Fen Hsu, George Ou, Wei-Jan Huang, Ming-Jen Hsu
2356 related Products with: The effects of a novel aliphatic-chain hydroxamate derivative WMJ-S-001 in HCT116 colorectal cancer cell death.
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#17975112 2007/11/01
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Nitric oxide modulates chromatin folding in human endothelial cells via protein phosphatase 2A activation and class II histone deacetylases nuclear shuttling.
Nitric oxide (NO) modulates important endothelial cell (EC) functions and gene expression by a molecular mechanism which is still poorly characterized. Here we show that in human umbilical vein ECs (HUVECs) NO inhibited serum-induced histone acetylation and enhanced histone deacetylase (HDAC) activity. By immunofluorescence and Western blot analyses it was found that NO induced class II HDAC4 and 5 nuclear shuttling and that class II HDACs selective inhibitor MC1568 rescued serum-dependent histone acetylation above control level in NO-treated HUVECs. In contrast, class I HDACs inhibitor MS27-275 had no effect, indicating a specific role for class II HDACs in NO-dependent histone deacetylation. In addition, it was found that NO ability to induce HDAC4 and HDAC5 nuclear shuttling involved the activation of the protein phosphatase 2A (PP2A). In fact, HDAC4 nuclear translocation was impaired in ECs expressing small-t antigen and exposed to NO. Finally, in cells engineered to express a HDAC4-Flag fusion protein, NO induced the formation of a macromolecular complex including HDAC4, HDAC3, HDAC5, and an active PP2A. The present results show that NO-dependent PP2A activation plays a key role in class II HDACs nuclear translocation.Barbara Illi, Claudio Dello Russo, Claudia Colussi, Jessica Rosati, Michele Pallaoro, Francesco Spallotta, Dante Rotili, Sergio Valente, Gianluca Ragone, Fabio Martelli, Paolo Biglioli, Christian Steinkuhler, Paola Gallinari, Antonello Mai, Maurizio C Capogrossi, Carlo Gaetano
1816 related Products with: Nitric oxide modulates chromatin folding in human endothelial cells via protein phosphatase 2A activation and class II histone deacetylases nuclear shuttling.
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#17179159 2006/12/19
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Nuclear calcium/calmodulin-dependent protein kinase IIdelta preferentially transmits signals to histone deacetylase 4 in cardiac cells.
Class II histone deacetylases (HDACs) act as repressors of cardiac hypertrophy, an adaptative response of the heart characterized by a reprogramming of fetal cardiac genes. Prolonged hypertrophy often leads to dilated cardiomyopathy and heart failure. Upstream endogenous regulators of class II HDACs that regulate hypertrophic growth are just beginning to emerge. Here we demonstrate that the delta B isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIdeltaB), known to promote cardiac hypertrophy, transmits signals specifically to HDAC4 but not other class II HDACs. CaMKIIdeltaB efficiently phosphorylates both a glutathione S-transferase (GST)-HDAC4 fragment spanning amino acids 207-311 and full-length FLAG-HDAC4 but not the equivalents in HDAC5. Although previous studies in skeletal muscle cells have shown that HDAC4 lacking serine 246 cannot be phosphorylated by CaMKI/IV, a similar mutant is still phosphorylated by CaMKIIdeltaB. Importantly, mutation of serine 210 to alanine totally abolishes phosphorylation of the GST fragment and significantly reduces phosphorylation of full-length HDAC by CaMKIIdeltaB. RNA interference knockdown of CaMKIIdeltaB prevents the effects of hypertrophic stimuli. Overexpression of CaMKIIdeltaB in primary neonatal cardiomyocytes increases the activity of the Mef2 transcription factor and completely rescues HDAC4-mediated repression of MEF2 but only partially rescues inhibition by HDAC5 or the HDAC4 S210A mutant. CaMKIIdeltaB strongly interacts with HDAC4 in cells but not with HDAC5. These results demonstrate that CaMKIIdeltaB preferentially targets HDAC4, and this involves serine 210. These findings identify HDAC4 as a specific downstream substrate of CaMKIIdeltaB in cardiac cells and have broad applications for the signaling pathways leading to cardiac hypertrophy and heart failure.Gillian H Little, Yan Bai, Tyisha Williams, Coralie Poizat