Distinctive Cellular Roles for Novel Protein Kinase C Isoenzymes

Perletti, Gian Paolo; Dm, Terrian

doi:10.2174/138161206777947498

Cited by 12 publications

(19 citation statements)

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“…3A). Many different PKC isoforms have been identified in mammals (22,23); of these, the α, δ, and ε isoforms are dominantly expressed in BAECs (24). We designed and validated siRNAs to knock down these PKC isoforms ( Fig.…”

Section: H 2 O 2 Induces Marcks Phosphorylation and Translocation Inmentioning

confidence: 99%

MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability

Jin

Lin

Golan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Impairment of endothelial barrier function is implicated in many vascular and inflammatory disorders. One prevalent mechanism of endothelial dysfunction is an increase in reactive oxygen species under oxidative stress. Previous reports have demonstrated that hydrogen peroxide (H 2 O 2 ), a highly stable reactive oxygen species that modulates physiological signaling pathways, also enhances endothelial permeability, but the mechanism of this effect is unknown. Here, we identify the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) as a key mediator of the H 2 O 2 -induced permeability change in bovine aortic endothelial cells. MARCKS knockdown and H 2 O 2 treatment alter the architecture of the actin cytoskeleton in endothelial cells, and H 2 O 2 induces the phosphorylation and translocation of MARCKS from the cell membrane to the cytosol. Using pharmacological inhibitors and small interference RNA constructs directed against specific proteins, we uncover a signaling cascade from Rac1 to Abl1, phospholipase Cγ1, and PKCδ that is triggered by H 2 O 2 and leads to MARCKS phosphorylation. Our findings establish a distinct role for MARCKS in the regulation of H 2 O 2 -induced permeability change in endothelial cells, and suggest potential new therapeutic targets for the treatment of disorders involving oxidative stress and altered endothelial permeability.

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Section: H 2 O 2 Induces Marcks Phosphorylation and Translocation Inmentioning

confidence: 99%

MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability

Jin

Lin

Golan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…However, many studies have implicated downregulation, rather than activation, of PKCδ in sporadic human colonic cancer in resistance to apoptosis and differentiation [9, 10]. Transient overexpression of PKCδ has been linked to tumor-suppressive functions, including suppression of anchorage-independent cell growth [11], reversal of colonic epithelial cells transformation via Src [12], and inhibition of neoplastic phenotype via p53 [13]. Therefore, PKCδ is thought of as a tumor suppressor.…”

Section: Introductionmentioning

confidence: 99%

A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin

Wang

Liou

et al. 2014

Oncotarget

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Accumulation of genetic and epigenetic changes contributes to cancer development and progression. Compared with gene mutations or deletions, epigenetic changes are reversible, which alter the chromatin structure remodeling instead of changes in DNA sequence, and therefore become a promising strategy for chemotherapy. Histone deacetylases (HDACs) are a class of enzymes that responsible for the epigenetic regulation of gene expression. MPT0G030 is a potent and selective class I HDAC inhibitor which showed broad-spectrum cytotoxicity against various human cancer cell lines. in vitro fluorometric HDAC activity assay showed that MPT0G030 effectively inhibited Class I HDACs (HDAC1~3), which were overexpressed in many malignant neoplasms. Interestingly, MPT0G030 not only induced histone acetylation and tumor suppressor p21 transcription, but also redistributed E-cadherin and activated Protein Kinase C δ (PKCδ), which was linked to cell apoptosis and differentiation. Further, activation of PKCδ was demonstrated to be modulated through HDAC1. The in vivo anticancer activity of MPT0G030 and the importance of PKCδ were confirmed in the HT-29 tumor xenograft models. Taken together, those results indicate that MPT0G030, a class I HDAC inhibitor, has great potential as a new drug candidate for cancer therapy.

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“…PKCδ is also a positive regulator of cell growth. It can function as an antiapoptotic protein and can contribute to cell transformation and metastasis [1, 7, 33, 34]. We have shown that acquisition of resistance by HeLa cells to the chemotherapeutic drug cisplatin was associated with loss of regulation of PKCδ [35, 36].…”

Section: Introductionmentioning

confidence: 99%

Regulation of protein kinase Cδ downregulation by protein kinase Cε and mammalian target of rapamycin complex 2

Basu¹,

Sridharan²,

Persaud³

2009

Cellular Signalling

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Phosphorylation and dephosphorylation of PKCs can regulate their activity, stability and function. We have previously shown that downregulation of PKCδ by tumor promoting phorbol esters was compromised when HeLa cells acquired resistance to cisplatin (HeLa/CP). In the present study, we have used these cells to understand the mechanism of PKCδ downregulation. A brief treatment of HeLa cells with phorbol 12,13-dibutyrate (PDBu) induced phosphorylation of PKCδ at the activation loop (Thr505), turn motif (Ser643), hydrophobic motif (Ser662) and Tyr-311 sites to a greater extent in HeLa/CP cells compared to HeLa cells. Prolonged treatment with PDBu led to downregulation of PKCδ in HeLa but not in HeLa/CP cells. The PKC inhibitor Gö 6983 inhibited PDBu-induced downregulation of PKCδ, decreased Thr505 phosphorylation and increased PKCδ tyrosine phosphorylation at Tyr-311 site. However, knockdown of c-Abl, c-Src, Fyn and Lyn had little effect on PKCδ downregulation and Tyr311 phosphorylation. Pretreatment with the phosphatidylinositol 3-kinase inhibitor Ly294002 and mTOR inhibitor rapamycin restored the ability of PDBu to downregulate PKCδ in HeLa/CP cells. Knockdown of mTOR and rictor but not raptor facilitated PKCδ downregulation. Depletion of PKCε also enhanced PKCδ downregulation by PDBu. These results suggest that downregulation of PKCδ is regulated by PKCε and mammalian target of rapamycin complex 2 (mTORC2).

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Distinctive Cellular Roles for Novel Protein Kinase C Isoenzymes

Cited by 12 publications

References 0 publications

MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability

MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability

A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin

Regulation of protein kinase Cδ downregulation by protein kinase Cε and mammalian target of rapamycin complex 2

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