Inhibiting Tyrosine Phosphorylation of Protein Kinase Cδ (PKCδ) Protects the Salivary Gland from Radiation Damage

Wie, Sten M.; Adwan, Tariq S.; DeGregori, James; Anderson, Steven M.; Reyland, Mary E.

doi:10.1074/jbc.m114.551366

Cited by 29 publications

(42 citation statements)

References 48 publications

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“…Our studies support a model whereby nuclear translocation of PKCδ is initiated by tyrosine phosphorylation at Y155 and Y164 by Abl and Src tyrosine kinases, respectively, resulting in a conformational change that facilitates importin-α binding and nuclear import (see Fig. 2, arrows 4, 5, and 6) (Adwan et al, 2011; Wie, Adwan, DeGregori, Anderson, & Reyland, 2014). The sequential phosphorylation of PKCδ by Abl and Src is likely to be critical to cellular homeostasis as it assures that pro-apoptotic signaling by PKCδ is linked to activation of other cell death signals.…”

Section: Biological Functions Of Pkcδsupporting

confidence: 85%

“…We show that phosphorylation of PKCδ at Y64 and Y155, nuclear accumulation of PKCδ, and apoptosis can be specifically inhibited by pre-treatment with tyrosine kinase inhibitors such as dasatinib and imatinib (Wie et al, 2014). Importantly, suppression of apoptosis in mice treated with irradiation to the head and neck is coupled with protection of salivary function in vivo (Wie and Reyland, unpublished data).…”

Section: Targeting Pkcδmentioning

confidence: 93%

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Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Reyland

Jones

2016

Pharmacology & Therapeutics

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The serine–threonine protein kinase, protein kinase C-δ (PKCδ), is emerging as a bi-functional regulator of cell death and proliferation. Studies in PKCδ−/− mice have confirmed a pro-apoptotic role for this kinase in response to DNA damage and a tumor promoter role in some oncogenic contexts. In non-transformed cells, inhibition of PKCδ suppresses the release of cytochrome c and caspase activation, indicating a function upstream of apoptotic pathways. Data from PKCδ−/− mice demonstrate a role for PKCδ in the execution of DNA damage-induced and physiologic apoptosis. This has led to the important finding that inhibitors of PKCδ can be used therapeutically to reduce irradiation and chemotherapy-induced toxicity. By contrast, PKCδ is a tumor promoter in mouse models of mammary gland and lung cancer, and increased PKCδ expression is a negative prognostic indicator in Her2+ and other subtypes of human breast cancer. Understanding how these distinct functions of PKCδ are regulated is critical for the design of therapeutics to target this pathway. This review will discuss what is currently known about biological roles of PKCδ and prospects for targeting PKCδ in human disease.

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Section: Biological Functions Of Pkcδsupporting

confidence: 85%

Section: Targeting Pkcδmentioning

confidence: 93%

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Reyland

Jones

2016

Pharmacology & Therapeutics

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“…PKCδ is involved in numerous cellular functions, including apoptosis, cell survival, migration and proliferation (Wie et al, 2014). The unique capability of PKCδ to regulate numerous cellular functions is attributed, at least in part, to its differential subcellular localization, especially stimulus-dependent organelle translocation.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Gordon

Singh

Lawana

et al. 2016

Neurobiology of Disease

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Chronic microglial activation has been linked to the progressive degeneration of the nigrostriatal dopaminergic neurons evidenced in Parkinson's disease (PD) pathogenesis. The exact etiology of PD remains poorly understood. Although both oxidative stress and neuroinflammation are identified as co-contributors in PD pathogenesis, signaling mechanisms underlying neurodegenerative processes have yet to be defined. Indeed, we recently identified that protein kinase C delta (PKCδ) activation is critical for induction of dopaminergic neuronal loss in response to neurotoxic stressors. However, it remains to be defined whether PKCδ activation contributes to immune signaling events driving microglial neurotoxicity. In the present study, we systematically investigated whether PKCδ contributes to the heightened microglial activation response following exposure to major proinflammatory stressors, including α-synuclein, tumor necrosis factor α (TNFα), and lipopolysaccharide (LPS). We report that exposure to the aforementioned inflammatory stressors dramatically upregulated PKCδ with a concomitant increase in its kinase activity and nuclear translocation in both BV-2 microglial cells and primary microglia. Importantly, we also observed a marked upregulation of PKCδ in the microglia of the ventral midbrain region of PD patients when compared to age-matched controls, suggesting a role for microglial PKCδ in neurodegenerative processes. Further, shRNA-mediated knockdown and genetic ablation of PKCδ in primary microglia blunted the microglial proinflammatory response elicited by the inflammogens, including ROS generation, nitric oxide production, and proinflammatory cytokine and chemokine release. Importantly, we found that PKCδ activated NFκB, a key mediator of inflammatory signaling events, after challenge with inflammatory stressors, and that transactivation of NFκB led to translocation of the p65 subunit to the nucleus, IκBα degradation and phosphorylation of p65 at Ser536. Furthermore, both genetic ablation and siRNA-mediated knockdown of PKCδ attenuated NFκB activation, suggesting that PKCδ regulates NFκB activation subsequent to microglial exposure to inflammatory stimuli. To further investigate the pivotal role of PKCδ in microglial activation in vivo, we utilized pre-clinical models of PD. We found that PKCδ deficiency attenuated the proinflammatory response in the mouse substantia nigra, reduced locomotor deficits and recovered mice from sickness behavior in an LPS-induced neuroinflammation model of PD. Likewise, we found that PKCδ knockout mice treated with MPTP displayed a dampened microglial inflammatory response. Moreover, PKCδ knockout mice exhibited reduced susceptibility to the neurotoxin-induced dopaminergic neurodegeneration and associated motor impairments. Taken together, our studies propose a pivotal role for PKCδ in PD pathology, whereby sustained PKCδ activation drives sustained microglial inflammatory responses and concomitant dopaminergic neurotoxicity consequently leading to neurobehavioral deficits. We...

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“…6), suggesting that beneficial effects of the peptide are related to biochemical inhibition of this PKCd activation mechanism. Nuclear translocation of PKCd is critical for the initiation of cytotoxic or proapoptotic signaling (Humphries et al, 2008;Pabla et al, 2011), and inhibition of PKCd nuclear translocation was reported to be cytoprotective following ischemia-reperfusion (Kostyak et al, 2006), focal cerebral ischemia (Shimohata et al, 2007), and radiation damage (Wie et al, 2014). Nuclear translocation is required for cleavage of PKCd, which may increase PKCd activity by removal of the regulatory domain (Okhrimenko et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury

Mondrinos

Knight

Kennedy

et al. 2015

J Pharmacol Exp Ther

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Sepsis and sepsis-induced lung injury remain a leading cause of death in intensive care units. We identified protein kinase C-d (PKCd) as a critical regulator of the acute inflammatory response and demonstrated that PKCd inhibition was lung-protective in a rodent sepsis model, suggesting that targeting PKCd is a potential strategy for preserving pulmonary function in the setting of indirect lung injury. In this study, whole-body organ biodistribution and pulmonary cellular distribution of a transactivator of transcription (TAT)-conjugated PKCd inhibitory peptide (PKCd-TAT) was determined following intratracheal (IT) delivery in control and septic [cecal ligation and puncture (CLP)] rats to ascertain the impact of disease pathology on biodistribution and efficacy. There was negligible lung uptake of radiolabeled peptide upon intravenous delivery [,1% initial dose (ID)], whereas IT administration resulted in lung retention of .65% ID with minimal uptake in liver or kidney (,2% ID). IT delivery of a fluorescent-tagged (tetramethylrhodamine-PKCd-TAT) peptide demonstrated uniform spatial distribution and cellular uptake throughout the peripheral lung. IT delivery of PKCd-TAT at the time of CLP surgery significantly reduced PKCd activation (tyrosine phosphorylation, nuclear translocation and cleavage) and acute lung inflammation, resulting in improved lung function and gas exchange. Importantly, peptide efficacy was similar when delivered at 4 hours post-CLP, demonstrating therapeutic relevance. Conversely, spatial lung distribution and efficacy were significantly impaired at 8 hours post-CLP, which corresponded to marked histopathological progression of lung injury. These studies establish a functional connection between peptide spatial distribution, inflammatory histopathology in the lung, and efficacy of this anti-inflammatory peptide.

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Inhibiting Tyrosine Phosphorylation of Protein Kinase Cδ (PKCδ) Protects the Salivary Gland from Radiation Damage

Cited by 29 publications

References 48 publications

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease

Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury

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