Dataset Information

Receptor-independent protein kinase C alpha (PKCalpha) signaling by calpain-generated free catalytic domains induces HDAC5 nuclear export and regulates cardiac transcription.

ABSTRACT: Receptor-mediated activation of protein kinase (PK) C is a central pathway regulating cell growth, homeostasis, and programmed death. Recently, we showed that calpain-mediated proteolytic processing of PKC? in ischemic myocardium activates PKC signaling in a receptor-independent manner by releasing a persistent and constitutively active free catalytic fragment, PKC?-CT. This unregulated kinase provokes cardiomyopathy, but the mechanisms remain unclear. Here, we demonstrate that PKC?-CT is a potent regulator of pathological cardiac gene expression. PKC?-CT constitutively localizes to nuclei and directly promotes nucleo-cytoplasmic shuttling of HDAC5, inducing expression of apoptosis and other deleterious genes. Whereas PKD activation is required for HDAC5 nuclear export induced by unprocessed PKCs activated by phorbol ester, PKC?-CT directly drives HDAC cytosolic relocalization. Activation of MEF2-dependent inflammatory pathway genes by PKC?-CT can induce a cell-autonomous transcriptional response that mimics, but anticipates, actual inflammation. Because calpain-mediated processing of PKC isoforms occurs in many tissues wherein calcium is increased by stress or injury, our observation that the catalytically active product of this interaction is a constitutively active transcriptional regulator has broad ramifications for understanding and preventing the pathological transcriptional stress response.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3143653 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Receptor-independent protein kinase C alpha (PKCalpha) signaling by calpain-generated free catalytic domains induces HDAC5 nuclear export and regulates cardiac transcription.

Zhang Yan Y Matkovich Scot J SJ Duan Xiujun X Diwan Abhinav A Kang Min-Young MY Dorn Gerald W GW

The Journal of biological chemistry 20110603 30

Receptor-mediated activation of protein kinase (PK) C is a central pathway regulating cell growth, homeostasis, and programmed death. Recently, we showed that calpain-mediated proteolytic processing of PKCα in ischemic myocardium activates PKC signaling in a receptor-independent manner by releasing a persistent and constitutively active free catalytic fragment, PKCα-CT. This unregulated kinase provokes cardiomyopathy, but the mechanisms remain unclear. Here, we demonstrate that PKCα-CT is a pote ...[more]

PMID: 21642422

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Project description:Class IIa histone deacetylase (HDAC) isoforms such as HDAC5 are critical signal-responsive repressors of maladaptive cardiomyocyte hypertrophy, through nuclear interactions with transcription factors including myocyte enhancer factor-2. β-Adrenoceptor (β-AR) stimulation, a signal of fundamental importance in regulating cardiac function, has been proposed to induce both phosphorylation-independent nuclear export and phosphorylation-dependent nuclear accumulation of cardiomyocyte HDAC5. The relative importance of phosphorylation at Ser259/Ser498 versus Ser279 in HDAC5 regulation is also controversial. We aimed to determine the impact of β-AR stimulation on the phosphorylation, localization, and function of cardiomyocyte HDAC5 and delineate underlying molecular mechanisms. A novel 3-dimensional confocal microscopy method that objectively quantifies the whole-cell nuclear/cytoplasmic distribution of green fluorescent protein tagged HDAC5 revealed the β-AR agonist isoproterenol to induce β1-AR-mediated and protein kinase A-dependent HDAC5 nuclear accumulation in adult rat cardiomyocytes, which was accompanied by dephosphorylation at Ser259/279/498. Mutation of Ser259/Ser498 to Ala promoted HDAC5 nuclear accumulation and myocyte enhancer factor-2 inhibition, whereas Ser279 ablation had no such effect and did not block isoproterenol-induced nuclear accumulation. Inhibition of the Ser/Thr phosphatase PP2A blocked isoproterenol-induced HDAC5 dephosphorylation. Co-immunoprecipitation revealed a specific interaction of HDAC5 with the PP2A targeting subunit B55α, as well as catalytic and scaffolding subunits, which increased >3-fold with isoproterenol. Knockdown of B55α in neonatal cardiomyocytes attenuated isoproterenol-induced HDAC5 dephosphorylation. β-AR stimulation induces HDAC5 nuclear accumulation in cardiomyocytes by a mechanism that is protein kinase A-dependent but requires B55α-PP2A-mediated dephosphorylation of Ser259/Ser498 rather than protein kinase A-mediated phosphorylation of Ser279.

Dataset Information

Receptor-independent protein kinase C alpha (PKCalpha) signaling by calpain-generated free catalytic domains induces HDAC5 nuclear export and regulates cardiac transcription.

Publications

Receptor-independent protein kinase C alpha (PKCalpha) signaling by calpain-generated free catalytic domains induces HDAC5 nuclear export and regulates cardiac transcription.

Similar Datasets

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