Disease relevance of Prkca

• When administered intraperitoneally in mice, the same oligodeoxynucleotide caused a dose-dependent, oligodeoxynucleotide sequence-dependent reduction of PKC-alpha mRNA in liver, with an IC50 value of 30-50 mg/kg of body weight [1].
• Characterization of conventional protein kinase C (PKC) isotype expression during F9 teratocarcinoma differentiation. Overexpression of PKC alpha alters the expression of some differentiation-dependent genes [2].
• These data demonstrate an irreversible decrease in and alteration of the subcellular distribution of PKC-alpha and beta 2 in DMBA-initiated/TPA-promoted papillomas [3].
• However, TPA-induced epidermal hyperplasia in T7-PKC epsilon mice was significantly increased (52%) compared with T7-PKC alpha, T7-PKC delta and wild-type mice [4].
• Cell type-specific expression of the genes for the protein kinase C family: down regulation of mRNAs for PKC alpha and nPKC epsilon upon in vitro differentiation of a mouse neuroblastoma cell line neuro 2a [5].

Psychiatry related information on Prkca

• Permissiveness to L. pneumophila was not the consequence of a general defect in the microbicidal capacities because killing of a temperature-sensitive mutant of Pseudomonas aeruginosa was normal in DN PKC-alpha-overexpressing RAW 264.7 clones [6].
• Protein kinase C (PKC) activity, Western blot analysis of PKC alpha, beta, gamma, epsilon and zeta with isozyme-specific antibodies, endogenous substrate protein phosphorylation, and Western blot analysis of neuromodulin, were studied in mouse brain after repeated electroconvulsive shock [7].

High impact information on Prkca

• The phosphorylation of the serine residue at position 121 of ATF-2 appears to be induced by protein kinase C alpha (PKC alpha) after treatment of cells with retinoic acid (RA) or induction with E1A [8].
• 12(S)-HETE induced a translocation of PKC-alpha to the plasma membrane and focal adhesion plaques, leading to enhanced adhesion of B16a cells to the matrix protein fibronectin [9].
• However, 13(S)-HODE inhibited these 12(S)-HETE effects on PKC-alpha [9].
• In this study, we investigated the regulation of PKC-alpha in murine B16 amelanotic melanoma (B16a) cells by the monohydroxy fatty acids 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] and 13(S)-hydroxyoctadecadienoic acid [13(S)-HODE] [9].
• In summary, our data provide evidence that regulation of PKC-alpha by 12(S)-HETE and 13(S)-HODE may be through a guanine nucleotide-binding protein-linked receptor-mediated hydrolysis of inositol phospholipids [9].

Chemical compound and disease context of Prkca

• The glucose-induced albuminuria seems to be mediated by PKC-alpha via downregulation of proteoglycans in the basement membrane and regulation of VEGF expression [10].
• We now used PKC-alpha(-/-) mice to test the hypothesis that this PKC isoform mediates streptozotocin-induced diabetic nephropathy [10].
• Differentiation of B16 mouse melanoma cells induced by retinoic acid (RA) is preceded by a large increase in protein kinase C alpha (PKC alpha) mRNA and protein [11].
• Apoptosis of murine melanoma B16-BL6 cells induced by quercetin targeting mitochondria, inhibiting expression of PKC-alpha and translocating PKC-delta [12].
• To determine whether alteration of PKC alpha expression would affect the metastatic potential of human melanoma cells, replicate cultures of C8161 cells were treated in vitro with a phosphorothioate antisense oligodeoxynucleotide (ODN) that specifically inhibits PKC alpha expression (ISIS-3521) [13].

Biological context of Prkca

• By radiation hybrid mapping, the Prkca gene was closely linked to sequence-tagged site marker D11Mit258 that locates 65.0 cM from the centromere of chromosome 11, and its transcription was towards the centromere [14].
• The Prkca gene was a unigene consisting of 17 exons and spanning at least 116 kb [14].
• The oligodeoxynucleotide exhibited an IC50 value of 100-200 nM and reduced PKC-alpha mRNA expression for up to 48 hr [1].
• These results provide evidence that the activation of PKC-alpha or PKC-epsilon in mouse fibroblasts can play an important role in enhancing cell cycle progression and cell proliferation [15].
• Deletion of the AP-1 enhancer element located at position -954 upstream from the initiation site abolished PKC-alpha-dependent activation of cyclin D1 expression [15].

Anatomical context of Prkca

• In animals in which lymphocytes were irradiated ex vivo, the expression of the Prkca isozyme was found to be maximum at 3 Gy, while in vivo irradiation did not increase the expression beyond that of 1 Gy [16].
• In mouse C127 mammary epithelial cells, the reduction in PKC-alpha mRNA expression was both dose and time dependent [1].
• To this end, we have stably overexpressed a dominant-negative (DN) version of PKC-alpha (DN PKC-alpha) in the murine macrophage cell line RAW 264 [17].
• We have found that three isoforms of protein kinase C (PKC alpha, -beta, and -gamma) were expressed in undifferentiated stem cells [2].
• The loss of the basement membrane proteoglycan perlecan and the podocyte protein nephrin in the diabetic state was not prevented in the PKC-beta(-/-) mice as previously demonstrated in the nonalbuminuric diabetic PKC-alpha(-/-) mice [18].

Associations of Prkca with chemical compounds

• A 20-mer phosphorothioate oligodeoxynucleotide designed to hybridize to the AUG translation initiation codon of mRNA encoding murine protein kinase C-alpha (PKC-alpha) inhibits the expression of PKC-alpha both in vitro and in vivo [1].
• Urinary osmolality was reduced to similar hypotonic levels in PKC-alpha -/- and +/+ mice during acute oral water loading or application of the vasopressin V(2)-receptor antagonist SR-121463 [19].
• We have previously shown that overexpression of a dominant-negative (DN) mutant of protein kinase C-alpha (PKC-alpha) in RAW 264.7 macrophages inhibited lipopolysaccharide (LPS)-induced IL-1alpha, inducible nitric oxide synthase and cyclooxygenase-2 expression [20].
• Clearance experiments under inactin/ketamine anesthesia revealed a modestly reduced glomerular filtration rate and showed a reduced absolute and fractional renal fluid reabsorption in PKC-alpha -/- mice [19].
• Additional treatment with dibutyryl cyclic AMP (dbcAMP), required for terminal differentiation into parietal endoderm, further increased PKC alpha expression and total PKC activity [21].

Regulatory relationships of Prkca

• In contrast, LPS-induced DNA-binding and transcriptional activities of NF-IL6 were inhibited in DN PKC-alpha-overexpressing RAW 264.7 cells and correlated with an impairment of NF-IL6 nuclear translocation [20].
• T7-PKC alpha transgenic mice (line 115) express 8-fold more PKC alpha protein than wild-type mice [4].
• These results suggest that PKC-alpha may play a role in regulating PLD expression [22].
• Considering that PKC-beta I and -beta II are coexpressed with PKC-alpha in mouse medullary collecting duct, the present results indicate that conventional PKC isoenzymes cannot fully compensate for each other [19].
• Over-expression of PKC alpha down-regulated GnRH promoter activity, indicating that PKC activation was sufficient to inhibit GnRH gene expression [23].

Other interactions of Prkca

• In wild-type mice, diabetes increased the translocation of PKC-alpha and -beta1 to the membrane, whereas only PKC-alpha was elevated in PKC-beta(-/-) mice [24].
• At the functional level, DN PKC-alpha overexpression strongly inhibited LPS-induced interleukin-1alpha mRNA accumulation, and to a lesser extent inducible nitric oxide synthase and tumor necrosis factor-alpha expression [17].
• This inhibition was not related to defective NF-kappaB nuclear translocation, suggesting that PKC-alpha might be involved in the modulation of other LPS-inducible transcription factors [20].
• In the present study, we have investigated the impact of PKC-alpha on the activation of AP-1 and NF-IL6 in LPS-treated RAW 264.7 macrophages [20].
• In a mouse neuroblast cell line, Neuro 2a, down modulation of mRNAs for both PKC alpha and nPKC epsilon was observed in association with in vitro differentiation [5].

Analytical, diagnostic and therapeutic context of Prkca

• The sodium-restricting response to a low-sodium diet was unaffected in PKC-alpha -/- mice [19].
• Electrophoretic mobility shift assays and luciferase reporter constructs revealed that LPS-induced AP-1 transcriptional activity was normal in DN PKC-alpha-overexpressing RAW 264.7 cells [20].
• In the present study, we examined the expression of PKC-alpha and PKC-delta at protein and mRNA level in mouse testis by Western blotting and RT-PCR [25].
• By immunoblotting with specific antibodies, the cells were found to express PKC-alpha, -gamma,-delta, -epsilon and -zeta [26].
• Immunofluorescence and confocal microscopy studies demonstrate that in mitogene-stimulated TTA-treated cells, the translocation of phosphorylated ERK1/2, protein kinase C alpha (PKC alpha), and PKC beta(1) from the cytoplasm into the nucleus is considerably decreased and delayed [27].

References