Protein Kinase C Signal Transduction Regulation in Physiological and Pathological Aging

Battaini, F.

doi:10.1196/annals.1356.011

Cited by 73 publications

(60 citation statements)

References 74 publications

(204 reference statements)

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“…Furthermore, PKC signaling represents a key element of the molecular changes associated with aging (98 -100). Although it appears that PKC isoform levels were not affected in rat cortex during brain aging (98,101,102), impaired activity of PKC␦ as well as other novel PKC isoforms has been reported (98,99). An age-associated increase in expression and activation of PKC␦ in the aged heart has been demonstrated in a number of studies (103,104).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Pro-apoptotic Protein Kinase Cδ

Jin

Kanthasamy

Anantharam

et al. 2011

Journal of Biological Chemistry

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We previously demonstrated that protein kinase C␦ (PKC␦; PKC delta) is an oxidative stress-sensitive kinase that plays a causal role in apoptotic cell death in neuronal cells. Although PKC␦ activation has been extensively studied, relatively little is known about the molecular mechanisms controlling PKC␦ expression. To characterize the regulation of PKC␦ expression, we cloned an ϳ2-kbp 5-promoter segment of the mouse Prkcd gene. Deletion analysis indicated that the noncoding exon 1 region contained multiple Sp sites, including four GC boxes and one CACCC box, which directed the highest levels of transcription in neuronal cells. In addition, an upstream regulatory region containing adjacent repressive and anti-repressive elements with opposing regulatory activities was identified within the region ؊712 to ؊560. PKC represents a large family of at least 12 serine/threonine kinases that participate in a wide variety of cellular events, including proliferation, cell cycle progression, differentiation, and apoptosis (1). Based on their structure and substrate requirements, PKC isoforms are divided into the following three groups: conventional PKCs (␣, ␤I, ␤II, and ␥), novel PKCs (␦, ⑀, , and ), and atypical PKCs ( and /). As a novel PKC, PKC␦ has been recognized as a key pro-apoptotic effector in various cell types (2, 3). The role of PKC␦ in nervous system function is beginning to emerge, and recent studies show that PKC␦ plays a role in regulation of receptor and channel activity, differentiation, migration, and apoptosis (4). In addition to lipid-mediated activation and phosphorylation activation, a new pathway of PKC␦ activation, proteolytic cleavage, was discovered recently. Previously, we showed that PKC␦ is an oxidative stress-sensitive kinase and that persistent activation of PKC␦ by caspase-3-mediated proteolytic cleavage is a key mediator in oxidative stress-induced dopaminergic neurodegeneration (5-9). Alternatively, pharmacological inhibition of PKC␦ and depletion of PKC␦ by siRNA are each sufficient to prevent dopaminergic neurodegeneration in cell culture and animal models of Parkinson disease (10 -12). We also showed that PKC␦ negatively regulates tyrosine hydroxylase activity and dopamine synthesis by enhancing protein phosphatase 2A activity in dopaminergic neurons (13). An elevated striatal dopamine level was observed in PKC␦ knock-out mice as compared with wild-type mice, further demonstrating a key role of the kinase in the nigrostriatal dopaminergic function (13). In addition, increased PKC␦ activity, caused by aberrant expression of PKC␦, has been implicated in disease conditions, such as ischemia/hypoxia (14 -17) and cancer (18 -28). Therefore, an understanding of the molecular mechanisms that control the amount and activity of PKC␦ is of physiological and pathophysiological interest.PKC␦ is ubiquitously expressed although the expression pattern is varied and complex (29 -32). Evidence suggests that diverse stimuli can induce PKC␦ expression (33)(34)(35)(37)(38)(39), but the detailed mechanisms...

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Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of Pro-apoptotic Protein Kinase Cδ

Jin

Kanthasamy

Anantharam

et al. 2011

Journal of Biological Chemistry

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“…Calcium-dependent (conventional) isoforms require both free calcium and diacylglycerol (DAG) for activation. Calcium-independent (novel) isoforms require DAG only, and atypical isoforms are activated independent of DAG and calcium [7,10]. Both calcium-dependent and calcium-independent PKC isoforms regulate the actin cytoskeleton [29] and overactivation of PKC results in spine loss and altered spine morphology in vitro [14] suggesting a role for PKC overactivation in structural deficits in the aged prefrontal cortex.…”

Section: Introductionmentioning

confidence: 99%

“…Although no studies have examined PKC activation within the aged prefrontal cortex, studies of the hippocampus [15,16] and the entire cortex [8][9][10] indicate that the cellular distribution and quantity of activated PKC is altered in the aged brain. Studies relating PKC and cognitive status in the aged have focused largely on the hippocampus.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C activity is associated with prefrontal cortical decline in aging

Brennan

Yuan

Dickstein

et al. 2009

Neurobiology of Aging

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Aging is associated with deficiencies in the prefrontal cortex, including working memory impairment, and compromised integrity of neuronal dendrites. Although protein kinase C (PKC) is implicated in structural plasticity, and overactivation of PKC results in working memory impairments in young animals, the role of PKC in prefrontal cortical impairments in the aged has not been examined. This study provides the first evidence that PKC activity is associated with prefrontal cortical dysfunction in aging. Pharmacological inhibition of PKC with chelerythrine rescued working memory impairments in aged rats and enhanced working memory in aged rhesus monkeys. Improvement correlated with age, with older monkeys demonstrating a greater degree of improvement following PKC inhibition. Furthermore, PKC activity within the prefrontal cortex was inversely correlated with the length of basal dendrites of prefrontal cortical neurons, as well as with working memory performance in aged rats. Together these findings indicate that PKC is dysregulated in aged animals and that PKC inhibitors may be useful in the treatment of cognitive deficits in the elderly.

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“…RACK1 is known to interact with a diverse array of proteins and functions to recruit and shuttle these proteins to their substrates or other binding partners [1,2]. Alterations in RACK1 expression and function are associated with a variety of disease states including Alzheimer's disease [5], bipolar disorder [6] and cancer including hepatocellular carcinoma, ovarian cancer and cancers of the prostate and breast [7][8][9][10][11]. The connection between RACK1 and cancer is complex, since RACK1 interacts with over 80 binding partners, either directly or indirectly in large complexes, thereby impacting on multiple signalling pathways.…”

Section: Introductionmentioning

confidence: 99%

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

Kiely

Adams

Hayes

et al. 2017

Cellular Signalling

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. (2017) RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells. Cellular Signalling, 35, pp. 290-300. (doi:10.1016Signalling, 35, pp. 290-300. (doi:10. /j.cellsig.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/128660/ RACK1/PP2A complex is required for cell adhesion, proliferation, migration, invasion.Potential role for the RACK1/PP2A complex in the progression of breast cancer. KeywordsBreast Cancer, RACK1, PP2A, Protein-Protein Interactions. ABSTRACTConflicting reports implicate the scaffolding protein RACK1 in the progression of breast cancer. RACK1 has been identified as a key regulator downstream of growth factor and adhesion signalling and as a direct binding partner of PP2A. Our objective was to further characterise the interaction between PP2A and RACK1 and to advance our understanding of this complex in breast cancer cells. We examined how the PP2A holoenzyme is assembled on the RACK1 scaffold in MCF-7 cells. We used immobilized peptide arrays representing the entire PP2A-catalytic subunit to identify candidate amino acids on the C subunit of PP2A that might be involved in binding of RACK1. We identified the RACK1 interaction sites on PP2A. Stable cell lines expressing PP2A with FR69/70AA, R214A and Y218F substitutions were generated and it was confirmed that the RACK1/PP2A interaction is essential to stabilize PP2A activity. We used Real-Time Cell Analysis and a series of assays to demonstrate that disruption of the RACK1/PP2A complex also reduces the adhesion, proliferation, migration and invasion of breast cancer cells and plays a role in maintenance of the cancer phenotype. This work has significantly advanced our understanding of the RACK1/PP2A complex and suggests a pro-carcinogenic role for the RACK1/PP2A interaction. This work suggests that approaches to target the RACK1/PP2A complex are a viable option to regulate PP2A activity and identifies a novel potential therapeutic target in the treatment of breast cancer.

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Protein Kinase C Signal Transduction Regulation in Physiological and Pathological Aging

Cited by 73 publications

References 74 publications

Transcriptional Regulation of Pro-apoptotic Protein Kinase Cδ

Transcriptional Regulation of Pro-apoptotic Protein Kinase Cδ

Protein kinase C activity is associated with prefrontal cortical decline in aging

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

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