Regulation of EGF Receptor Signaling by Histone Deacetylase 6 (HDAC6)-Mediated Reversible Acetylation

Background: Histone deacetylase (HDAC) 6 inhibitors have demonstrated significant protective effects in traumatic injuries. However, their roles in neuroprotection and underlying mechanisms are poorly understood. This study sought to investigate the neuroprotective effects of Tubastatin A (Tub-A), an HDAC6 inhibitor, during oxygenglucose deprivation (OGD) in HT22 hippocampal cells. Methods: HT22 hippocampal cells were exposed to OGD. Cell viability and cytotoxicity were assessed by cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assay. Cellular apoptosis was assessed by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mitochondria membrane potential was detected using JC-1 dye. Expressions of acetylated α-tubulin, α-tubulin, cytochrome c, VDAC, Bax, Bcl- 2, cleaved caspase 3, phosphorylated Akt, Akt, phosphorylated GSK3β and GSK3β were analyzed by Western blot analysis. Results: Tub-A induced acetylation of α-tubulin, demonstrating appropriate efficacy. Tub-A significantly increased cell viability and attenuated LDH release after exposure to OGD. Furthermore, Tub-A treatment blunted the increase in TUNEL-positive cells following OGD and preserved the mitochondrial membrane potential. Tub-A also attenuated the release of cytochrome c from the mitochondria into the cytoplasm and suppressed the ratio of Bax/Bcl-2 and cleaved caspase 3. This was mediated, in part, by the increased phosphorylation of Akt and GSK3β signaling pathways. Conclusion: HDAC 6 inhibition, using Tub-A, protects against OGD-induced injury in HT22 cells by modulating Akt/GSK3β signaling and inhibiting mitochondria-mediated apoptosis.

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Downregulation of EGF Receptor Signaling in Pancreatic Islets Causes Diabetes Due to Impaired Postnatal -Cell Growth

Diabetes ◽

10.2337/db06-0413 ◽

2006 ◽

Vol 55 (12) ◽

pp. 3299-3308 ◽

Cited By ~ 58

Author(s):

P. J. Miettinen ◽

J. Ustinov ◽

P. Ormio ◽

R. Gao ◽

J. Palgi ◽

...

Keyword(s):

Cell Growth ◽

Pancreatic Islets ◽

Egf Receptor ◽

Receptor Signaling

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A patent review of histone deacetylase 6 inhibitors in neurodegenerative diseases (2014-2019)

Expert Opinion on Therapeutic Patents ◽

10.1080/13543776.2019.1708901 ◽

2019 ◽

Vol 30 (2) ◽

pp. 121-136 ◽

Cited By ~ 11

Author(s):

Sida Shen ◽

Alan P. Kozikowski

Keyword(s):

Neurodegenerative Diseases ◽

Histone Deacetylase ◽

Histone Deacetylase 6 ◽

Patent Review

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Targeted Expression of the Class II Phosphoinositide 3-Kinase in Drosophila melanogaster Reveals Lipid Kinase-Dependent Effects on Patterning and Interactions with Receptor Signaling Pathways

Molecular and Cellular Biology ◽

10.1128/mcb.24.2.796-808.2004 ◽

2004 ◽

Vol 24 (2) ◽

pp. 796-808 ◽

Cited By ~ 22

Author(s):

Lindsay K. MacDougall ◽

Mary Elizabeth Gagou ◽

Sally J. Leevers ◽

Ernst Hafen ◽

Michael D. Waterfield

Keyword(s):

Drosophila Melanogaster ◽

Signaling Pathways ◽

Egf Receptor ◽

Adaptor Protein ◽

Class Ii ◽

Notch Receptor ◽

Mitogen Activated Protein Kinase ◽

Class I ◽

Wing Venation ◽

Receptor Signaling

ABSTRACT Phosphoinositide 3-kinases (PI3Ks) can be divided into three distinct classes (I, II, and III) on the basis of their domain structures and the lipid signals that they generate. Functions have been assigned to the class I and class III enzymes but have not been established for the class II PI3Ks. We have obtained the first evidence for a biological function for a class II PI3K by expressing this enzyme during Drosophila melanogaster development and by using deficiencies that remove the endogenous gene. Wild-type and catalytically inactive PI3K_68D transgenes have opposite effects on the number of sensory bristles and on wing venation phenotypes induced by modified epidermal growth factor (EGF) receptor signaling. These results indicate that the endogenous PI3K_68D may act antagonistically to the EGF receptor-stimulated Ras-mitogen-activated protein kinase pathway and downstream of, or parallel to, the Notch receptor. A class II polyproline motif in PI3K_68D can bind the Drk adaptor protein in vitro, primarily via the N-terminal SH3 domain of Drk. Drk may thus be important for the localization of PI3K_68D, allowing it to modify signaling pathways downstream of cell surface receptors. The phenotypes obtained are markedly distinct from those generated by expression of the Drosophila class I PI3K, which affects growth but not pattern formation.

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