Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells

Michaelis, Martin; Suhan, Tatyana; Michaelis, Uwe; Beek, K; Rothweiler, Florian; Tausch, Lars; Werz, Oliver; Eikel, Daniel; Zörnig, Martin; Nau, Heinz; Fleming, Ingrid; Doerr, Hans Wilhelm; Činátl, Jindřich

doi:10.1038/sj.cdd.4401759

Cited by 79 publications

(88 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, our report is the first to demonstrate that HDACs can modulate a number of intracellular signalling cascades in response to growth factors. This appeared to be a TGF-β-specific effect, because in the absence of the growth factor HDAC inhibitors activated MAPK signalling, as previously noted for VPA (Michaelis et al, 2006). Furthermore, when examining IL-1 activation of MAPK we found no repression by TSA, albeit in cultured human articular chondrocytes (Supp.…”

Section: Discussionmentioning

confidence: 68%

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Barter¹,

Pybus²,

Litherland³

et al. 2010

Matrix Biology

View full text Add to dashboard Cite

a b s t r a c t a r t i c l e i n f oHistone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-β signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-β-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-β, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-β induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-β induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-β-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semiselective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-β-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-β. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-β and for the subsequent gene induction dependent on these signalling pathways.

show abstract

Section: Discussionmentioning

confidence: 68%

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Barter¹,

Pybus²,

Litherland³

et al. 2010

Matrix Biology

View full text Add to dashboard Cite

show abstract

“…Pettersson et al (31) also suggested that the activation of ERK was essential for the retinoid-induced apoptosis of breast cancer cells. Michaelis et al (13) reported that valproic acid increases the level of ERK 1/2 phosphorylation in human umbilical vein endothelial cells. These results provide evidence for a novel signaling pathway that mediates apicidininduced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…1A). Apicidin is a novel cyclic tetrapeptide with potent broadspectrum anti-protozoal activity against apicomplexan parasites and anti-proliferative activity against various cancer cell lines (13,14). However, the precise mechanism of how apicidin regulates apoptosis in ras-activated human breast epithelial cells is not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

Park

Im²,

Kim³

et al. 2008

Int J Mol Med

View full text Add to dashboard Cite

Abstract. The cellular susceptibility of cancer cells to histone deacetylase (HDAC) inhibitors is increased by the etopic expression of oncogenic Ras. However, the ability of HDAC inhibitors to regulate the apoptotic pathway in human breast cancer cells is still not completely understood. In this study, the anti-proliferative effects of apicidin were compared in Hras-transformed human breast epithelial (MCF10A-ras) and non-transformed epithelial (MCF10A) cells. MCF10A-ras cells showed a significantly higher growth rate than MCF10A cells. Apicidin significantly increased the levels of acetylated histone H3 and H4 in both cell lines. Western blot analysis and flow cytometry were used to determine if the anti-proliferative effects of apicidin in MCF10A and MCF10A-ras cells could be mediated by modulating the cell cycle. Apicidin attenuated the expression of cyclin E and CDK2 in MCF10A cells, decreased cyclin D1 and cyclin E levels in MCF10A-ras cells, and increased the levels of CDK inhibitors, p21WAF1/Cip1 and p27Kip1 , in both cell lines. Notably, the levels of hyperphosphorylation of the Rb protein levels were lower in the MCF10A-ras cells after apicidin treatment. Studies on the regulation of apoptosis showed that apicidin induces the upregulation of p53 and the downstream activation of ERK in MCF10A-ras cells. The up-regulation of p53 promoted Bax expression leading to activation of caspases-9 and -6, and eventually to apoptosis in MCF10A-ras cells. In addition, apicidin significantly increased the levels of ERK1/2 phosphorylation in MCF10A-ras cells. Therefore, the apicidinmediated ERK pathway appears to play an important role in modulating the pro-apoptotic pathway in MCF10A-ras cells.

show abstract

“…Cell cycle was determined using a commercial kit (BD Biosciences, San Jose, CA) according to the manufacturer's instructions as described previously [33].…”

Section: Cell Cycle Analysismentioning

confidence: 99%

The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3β

Ogbomo

Biru

Michaelis

et al. 2011

Biochemical Pharmacology

View full text Add to dashboard Cite

Please cite this article as: Ogbomo H, Biru T, Michaelis M, Loeschmann N, Doerr HW, Cinatl Jr. J, The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3␤, Biochemical Pharmacology (2008Pharmacology ( ), doi:10.1016Pharmacology ( /j.bcp.2010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

show abstract

Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells

Cited by 79 publications

References 35 publications

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Effects of apicidin, a histone deacetylase inhibitor, on the regulation of apoptosis in H-ras-transformed breast epithelial cells

The anti-tumoral drug enzastaurin inhibits natural killer cell cytotoxicity via activation of glycogen synthase kinase-3β

Contact Info

Product

Resources

About