Protein kinase C, an elusive therapeutic target?

Mochly‐Rosen, Daria; Das, Kanad; Grimes, Kevin

doi:10.1038/nrd3871

Cited by 481 publications

(510 citation statements)

References 243 publications

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“…PKC is an attractive target to treat many diseases, including diabetes (7,67). Identification of RNA-binding proteins or specific splicing events as downstream effectors of PKC may provide us new tools to design safer and novel therapeutics such as the oligo-based therapy to correct these splicing defects.…”

Section: Discussionmentioning

confidence: 99%

Reactivation of Fetal Splicing Programs in Diabetic Hearts Is Mediated by Protein Kinase C Signaling

Verma

Deshmukh

Liu

et al. 2013

Journal of Biological Chemistry

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Background: Chronic PKC activation is the leading pathogenic component of diabetes in the heart. Results: PKC␣/␤ promotes fetal splicing patterns in adult diabetic hearts via phosphorylation of the RNA-binding proteins CELF1 and Rbfox2. Conclusion: PKC␣/␤ contributes to diabetes pathogenesis by manipulating developmentally regulated alternative splicing. Significance: Identifying downstream effectors of PKC can provide novel therapeutics for cardiac pathogenesis of diabetes.

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Section: Discussionmentioning

confidence: 99%

Reactivation of Fetal Splicing Programs in Diabetic Hearts Is Mediated by Protein Kinase C Signaling

Verma

Deshmukh

Liu

et al. 2013

Journal of Biological Chemistry

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“…Increased activity of select PKC isozymes has been observed in many disease states-for example, nonalcoholic fatty liver disease (Birkenfeld and Shulman, 2014), diabetes, cancers, ischemic heart disease, Parkinson's disease, and Alzheimer's disease [reviewed by Mochly-Rosen et al (2012)]. Modulation of PKC activity presents an attractive target for drug development (Mochly-Rosen et al, 2012;Sun and Alkon, 2012;SanchezBautista and Nicolas, 2013). Consequently, PKC activators and inhibitors have been developed for clinical trials for many diseases, either alone or in combination with other drugs (Mochly-Rosen et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Modulation of PKC activity presents an attractive target for drug development (Mochly-Rosen et al, 2012;Sun and Alkon, 2012;SanchezBautista and Nicolas, 2013). Consequently, PKC activators and inhibitors have been developed for clinical trials for many diseases, either alone or in combination with other drugs (Mochly-Rosen et al, 2012). The function of several human transport proteins is regulated by PKC activation.…”

Section: Introductionmentioning

confidence: 99%

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

et al. 2014

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The organic anion-transporting polypeptide (OATP) 1B3 is a membrane transport protein that mediates hepatic uptake of many drugs and endogenous compounds. Currently, determination of OATP-mediated drug-drug interactions in vitro is focused primarily on direct substrate inhibition. Indirect inhibition of OATP1B3 activity is under-appreciated. OATP1B3 has putative protein kinase C (PKC) phosphorylation sites. Studies were designed to determine the effect of PKC activation on OATP1B3-mediated transport in human hepatocytes using cholecystokinin-8 (CCK-8), a specific OATP1B3 substrate, as the probe. A PKC activator, phorbol-12-myristate-13-acetate (PMA), did not directly inhibit [ 3 H]CCK-8 accumulation in human sandwich-cultured hepatocytes (SCH). However, pretreatment with PMA for as little as 10 minutes rapidly decreased [ 3 H]CCK-8 accumulation. Treatment with a PKC inhibitor bisindolylmaleimide (BIM) I prior to PMA treatment blocked the inhibitory effect of PMA, indicating PKC activation is essential for downregulating OATP1B3 activity. PMA pretreatment did not affect OATP1B3 mRNA or total protein levels. To determine the mechanism(s) underlying the indirect inhibition of OATP1B3 activity upon PKC activation, adenoviral vectors expressing FLAG-Myc-tagged OATP1B3 (Ad-OATP1B3) were transduced into human hepatocytes; surface expression and phosphorylation of OATP1B3 were determined by biotinylation and by an anti-phosphor-Ser/Thr/Tyr antibody, respectively. PMA pretreatment markedly increased OATP1B3 phosphorylation without affecting surface or total OATP1B3 protein levels. In conclusion, PKC activation rapidly decreases OATP1B3 transport activity by posttranslational regulation of OATP1B3. These studies elucidate a novel indirect inhibitory mechanism affecting hepatic uptake mediated by OATP1B3, and provide new insights into predicting OATP-mediated drug interactions between OATP substrates and kinase modulator drugs/endogenous compounds.

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“…(71)). Besides these synthetic molecules short polypeptide sequence for different PKC isoforms exhibited promising results in animal models (71).…”

Section: Pkc Inhibitors In Cllmentioning

confidence: 99%

Protein kinase C (PKC) as a drug target in chronic lymphocytic leukemia

2013

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Protein kinase C (PKC) as a drug target in chronic lymphocytic leukemia.Uddin, Kazi; Kabir, Nuzhat N; Rönnstrand, Lars Link to publication Citation for published version (APA): Kazi, J. U., . Protein kinase C (PKC) as a drug target in chronic lymphocytic leukemia. Medical Oncology, 30(4), 757. DOI: 10.1007/s12032-013-0757-7General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

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Protein kinase C, an elusive therapeutic target?

Cited by 481 publications

References 243 publications

Reactivation of Fetal Splicing Programs in Diabetic Hearts Is Mediated by Protein Kinase C Signaling

Reactivation of Fetal Splicing Programs in Diabetic Hearts Is Mediated by Protein Kinase C Signaling

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

Protein kinase C (PKC) as a drug target in chronic lymphocytic leukemia

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