Journal articles: 'PRKCδ'

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Arenas, Ailan F., Gladys E. Salcedo, and Jorge E. Gomez-Marin. "R Script Approach to Infer Toxoplasma Infection Mechanisms From Microarrays and Domain-Domain Protein Interactions." Bioinformatics and Biology Insights 11 (January 1, 2017): 117793221774725. http://dx.doi.org/10.1177/1177932217747256.

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Pathogen-host protein-protein interaction systems examine the interactions between the protein repertoires of 2 distinct organisms. Some of these pathogen proteins interact with the host protein system and may manipulate it for their own advantages. In this work, we designed an R script by concatenating 2 functions called rowDM and rowCVmed to infer pathogen-host interaction using previously reported microarray data, including host gene enrichment analysis and the crossing of interspecific domain-domain interactions. We applied this script to the Toxoplasma-host system to describe pathogen survival mechanisms from human, mouse, and Toxoplasma Gene Expression Omnibus series. Our outcomes exhibited similar results with previously reported microarray analyses, but we found other important proteins that could contribute to toxoplasma pathogenesis. We observed that Toxoplasma ROP38 is the most differentially expressed protein among toxoplasma strains. Enrichment analysis and KEGG mapping indicated that the human retinal genes most affected by Toxoplasma infections are those related to antiapoptotic mechanisms. We suggest that proteins PIK3R1, PRKCA, PRKCG, PRKCB, HRAS, and c-JUN could be the possible substrates for differentially expressed Toxoplasma kinase ROP38. Likewise, we propose that Toxoplasma causes overexpression of apoptotic suppression human genes.

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Tweedell, Rebecca, Le Qi, Zhaoli Sun, and Rhoel Dinglasan. "Kupffer Cells Survive Plasmodium berghei Sporozoite Exposure and Respond with a Rapid Cytokine Release." Pathogens 7, no. 4 (November 24, 2018): 91. http://dx.doi.org/10.3390/pathogens7040091.

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The liver stage of the Plasmodium life cycle features sporozoite traversal of the liver sinusoidal barrier through Kupffer cells (KCs) followed by invasion of hepatocytes. Little is known about the interaction of Plasmodium sporozoites with KCs, the liver-resident macrophages. Previous reports suggest KCs do not mount a pro-inflammatory response and undergo cell death following this interaction. Our work explores this interaction using primary rat KCs (PRKCs) and Plasmodium berghei sporozoites. We analyzed PRKC culture supernatants for markers of an immunological response through cytokine arrays. Additionally, cell wounding and death were assessed by monitoring lactate dehydrogenase (LDH) levels in these supernatants and by live/dead cell imaging. We found that PRKCs mount an immunological response to P. berghei sporozoites by releasing a diverse set of both pro- and anti-inflammatory cytokines, including IFNγ, IL-12p70, Mip-3α, IL-2, RANTES, IL-1α, IL-4, IL-5, IL-13, EPO, VEGF, IL-7, and IL-17α. We also observed no difference in LDH level or live/dead staining upon sporozoite exposure, suggesting that the KCs are not deeply wounded or dying. Overall, our data suggest that sporozoites may be actively modulating the KC’s reaction to their presence and altering the way the innate immune system is triggered by KCs.

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Ricchiuti, Vincent, Christine G. Lian, Eveline M. Oestreicher, Loc Tran, James R. Stone, Tham Yao, Ellen W. Seely, Gordon H. Williams, and Gail K. Adler. "Estradiol increases angiotensin II type 1 receptor in hearts of ovariectomized rats." Journal of Endocrinology 200, no. 1 (October 17, 2008): 75–84. http://dx.doi.org/10.1677/joe-08-0199.

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We tested the hypothesis that 17β-estradiol (E2) has dual effects on the heart, increasing levels of proteins thought to have beneficial cardiovascular effects (e.g. endothelial nitric oxide (NO) synthase (eNOS)) as well as those thought to have detrimental cardiovascular effects (e.g. type 1 angiotensin II (AngII) receptor (AT1R)). Ovariectomized Wistar rats consuming a high-sodium diet received one of four treatments (n=7 per group): group 1, placebo pellets; group 2, E2(0.5 mg/pellet, 21-day release); group 3, NOS inhibitor,Nω-nitro-l-arginine-methyl-ester (l-NAME; 40 mg/kg per day for 14 days) plus Ang II (0.225 mg/kg per day on days 11–14); group 4, E2plusl-NAME/Ang II. E2increased cardiac levels of estrogen receptors ESR1 and ESR2, an ESR-associated membrane protein caveolin-3, eNOS, and phosphorylated (p)eNOS, thus, exerting potentially beneficial cardiovascular effects on NO. However, E2also increased cardiac levels of proteins associated with cardiovascular injury and inflammation including, AT1R, protein kinase C delta (PRKCD), phosphorylated PRKC, and phosphorylated extracellular signal regulated kinase (pMAPK)3/1, plasminogen activator inhibitor-1 (PAI-1), osteopontin and ED-1, a monocyte/macrophage-specific protein. E2treatment led to similar protein changes in the hearts ofl-NAME/Ang II-treated rats except that the increase in peNOS was prevented, andl-NAME/Ang II and E2had additive effects in increasing cardiac PRKCD and PAI-1. Thus, the highest levels of cardiac PAI-1 and PRKCD occurred inl-NAME/Ang II-treated rats receiving E2. In summary, E2treatment increased cardiac expression of AT1R as well as the expression of pro-inflammatory and prothrombotic factors.

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Liu, Fangzhou, Yuanbai Li, Meng Li, Jing Wang, Yiying Zhang, Yu Du, and Yang Yang. "Study on Mechanism of Iridoid Glycosides Derivatives from Fructus Gardeniae in Jiangxi Province by Network Pharmacology." Evidence-Based Complementary and Alternative Medicine 2020 (June 27, 2020): 1–12. http://dx.doi.org/10.1155/2020/4062813.

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Objective. To investigate the pharmacological mechanism of the iridoid glycosides from Fructus Gardeniae in Jiangxi province by network pharmacology. To provide a valuable research strategy for the rational use and in-depth research and development of Fructus Gardeniae from Jiangxi. Method. Previous research results of our group show that the contents of iridoid glycosides in Fructus Gardeniae from Jiangxi province have a significant difference compared with other regions (P<0.05). Based on our previous experimental results, this study selected six characteristic high-content bioactive iridoid glycosides components of Fructus Gardeniae from Jiangxi province as candidate components. TCMSP database was used to obtain the process parameters of absorption, distribution, metabolism, and excretion (ADME) of candidate components. PubChem and SWISS online database were used to predict the related targets. Cytoscape software was used to the construct compound-target-disease (C-T-D) network of the Fructus Gardeniae iridoid glycosides ingredients. Furthermore, the GO biological process analysis and the pathway enrichment analysis were carried out using the CTD online analysis platform; then, an illustrated network that contains the main “chemicals-targets-pathway (C-T-P)” was constructed to analyze main biological pathways for obtaining the deep mechanism of Fructus Gardeniae in Jiangxi. Results. 6 iridoid glycosides, namely geniposide, gardenoside, geniposidic acid, genipin 1-gentiobioside, gardoside, and shanzhiside, from Fructus Gardeniae in Jiangxi province were obtained as candidate components through previous work and network pharmacology screening. 36 corresponding targets were acted, such as BCL2, MAPT, F2, BCL2L1, PRKCD, PRKCB, HIF1A, and PRKCA. These targets could joint in pathways, such as signaling by GPCR, neuroactive ligand-receptor interaction, inflammatory mediator regulation of TRP channels, and ion channel transport. Interestingly, these pathways were highly associated with liver diseases, neurological diseases, hypertension, neoplasms, hyperalgesia, and inflammation. Remarkably, we boldly speculate that the Fructus Gardeniae from Jiangxi province can play a pharmacological role in hepatic encephalopathy through regulating multiple signaling pathways in an integrated manner. Conclusion. The method based on system pharmacology could help to find the key targets of characteristic high-content chemical constituents of herb from different producing areas, the signaling pathway and disease network of TCM, and provide useful information and data support for giving a further study on traditional Chinese medicine resources in different regions of China.

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Wang, Hao-Fan, Jian Jiang, Jia-Shun Wu, Mei Zhang, Xin Pang, Li Dai, Ya-Ling Tang, and Xin-Hua Liang. "Hypermethylation of PRKCZ Regulated by E6 Inhibits Invasion and EMT via Cdc42 in HPV-Related Head and Neck Squamous Cell Carcinoma." Cancers 14, no. 17 (August 27, 2022): 4151. http://dx.doi.org/10.3390/cancers14174151.

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Purpose: To study the role of target genes with aberrant DNA methylation in HPV+ HNSCC. Methods: A HumanMethylation450 BeadChip array (Illumina) was used to identify differentially methylated genes. CCK-8, flow cytometry, wound healing, and cell invasion assays were conducted to analyze the biological roles of PRKCZ. Western blot, qRT-PCR, immunohistochemistry, and animal studies were performed to explore the mechanisms underlying the functions of PRKCZ. Results: We selected PRKCZ, which is associated with HPV infection, as our target gene. PRKCZ was hypermethylated in HPV+ HNSCC patients, and PRKCZ methylation status was negatively related to the pathological grading of HNSCC patients. Silencing PRKCZ inhibited the malignant capacity of HPV+ HNSCC cells. Mechanistically, HPV might promote DNMT1 expression via E6 to increase PRKCZ methylation. Cdc42 was required for the PRKCZ-mediated mechanism of action, contributing to the occurrence of epithelial-mesenchymal transition (EMT) in HPV+ HNSCC cells. In addition, blocking PRKCZ delayed tumor growth in HPV16-E6/E7 transgenic mice. Cdc42 expression was decreased, whereas E-cadherin levels increased. Conclusion: We suggest that PRKCZ hypermethylation induces EMT via Cdc42 to act as a potent tumor promoter in HPV+ HNSCC.

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Yang, Qi-En, Manabu Ozawa, Kun Zhang, Sally E. Johnson, and Alan D. Ealy. "The requirement for protein kinase C delta (PRKCD) during preimplantation bovine embryo development." Reproduction, Fertility and Development 28, no. 4 (2016): 482. http://dx.doi.org/10.1071/rd14160.

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Protein kinase C (PKC) delta (PRKCD) is a member of the novel PKC subfamily that regulates gene expression in bovine trophoblast cells. Additional functions for PRKCD in early embryonic development in cattle have not been fully explored. The objectives of this study were to describe the expression profile of PRKCD mRNA in bovine embryos and to examine its biological roles during bovine embryo development. Both PRKCD mRNA and protein are present throughout early embryo development and increases in mRNA abundance are evident at morula and blastocyst stages. Phosphorylation patterns are consistent with detection of enzymatically active PRKCD in bovine embryos. Exposure to a pharmacological inhibitor (rottlerin) during early embryonic development prevented development beyond the eight- to 16-cell stage. Treatment at or after the 16-cell stage reduced blastocyst development rates, total blastomere numbers and inner cell mass-to-trophoblast cell ratio. Exposure to the inhibitor also decreased basal interferon tau (IFNT) transcript abundance and abolished fibroblast growth factor-2 induction of IFNT expression. Furthermore, trophoblast adhesion and proliferation was compromised in hatched blastocysts. These observations provide novel insights into PRKCD mRNA expression profiles in bovine embryos and provide evidence for PRKCD-dependent regulation of embryonic development, gene expression and post-hatching events.

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Parzefall, Thomas, Julia Schnoell, Laura Monschein, Elisabeth Foki, David Tianxiang Liu, Alexandra Frohne, Stefan Grasl, et al. "PRKCA Overexpression Is Frequent in Young Oral Tongue Squamous Cell Carcinoma Patients and Is Associated with Poor Prognosis." Cancers 13, no. 9 (April 25, 2021): 2082. http://dx.doi.org/10.3390/cancers13092082.

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Oral tongue squamous cell carcinomas (OTSCCs) have an increasing incidence in young patients, and many have an aggressive course of disease. The objective of this study was to identify candidate prognostic protein markers associated with early-onset OTSCC. We performed an exploratory screening for differential protein expression in younger (≤45 years) versus older (>45 years) OTSCC patients in The Cancer Genome Atlas (TCGA) cohort (n = 97). Expression of candidate markers was then validated in an independent Austrian OTSCC patient group (n = 34) by immunohistochemistry. Kaplan–Meier survival estimates were computed, and genomic and mRNA enrichment in silico analyses were performed. Overexpression of protein kinase C alpha (PRKCA) was significantly more frequent among young patients of both the TCGA (p = 0.0001) and the Austrian cohort (p = 0.02), associated with a negative anamnesis for alcohol consumption (p = 0.009) and tobacco smoking (p = 0.02) and poorer overall survival (univariate p = 0.02, multivariate p< 0.01). Within the young subgroup, both overall and disease-free survival were significantly decreased in patients with PRKCA overexpression (both p < 0.001). TCGA mRNA enrichment analysis revealed 332 mRNAs with significant differential expression in PRKCA-upregulated versus PRKCA-downregulated OTSCC (all FDR ≤ 0.01). Our findings suggest that PRKCA overexpression may be a hallmark of a novel molecular subtype of early-onset alcohol- and tobacco-negative high-risk OTSCC. Further analysis of the molecular PRKCA interactome may decipher the underlying mechanisms of carcinogenesis and clinicopathological behavior of PRKCA-overexpressing OTSCC.

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Rotman, T., N. Etkovitz, A. Spiegel, S. Rubinstein, and H. Breitbart. "Protein kinase A and protein kinase Cα/PPP1CC2 play opposing roles in the regulation of phosphatidylinositol 3-kinase activation in bovine sperm." REPRODUCTION 140, no. 1 (July 2010): 43–56. http://dx.doi.org/10.1530/rep-09-0314.

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In order to acquire fertilization competence, spermatozoa have to undergo biochemical changes in the female reproductive tract, known as capacitation. Signaling pathways that take place during the capacitation process are much investigated issue. However, the role and regulation of phosphatidylinositol 3-kinase (PI3K) in this process are still not clear. Previously, we reported that short-time activation of protein kinase A (PRKA, PKA) leads to PI3K activation and protein kinase Cα (PRKCA, PKCα) inhibition. In the present study, we found that during the capacitation PI3K phosphorylation/activation increases. PI3K activation was PRKA dependent, and down-regulated by PRKCA. PRKCA is found to be highly active at the beginning of the capacitation, conditions in which PI3K is not active. Moreover, inhibition of PRKCA causes significant activation of PI3K. Similar activation of PI3K is seen when the phosphatase PPP1 is blocked suggesting that PPP1 regulates PI3K activity. We found that during the capacitation PRKCA and PPP1CC2 (PP1γ2) form a complex, and the two enzymes were degraded during the capacitation, suggesting that this degradation enables the activation of PI3K. This degradation is mediated by PRKA, indicating that in addition to the direct activation of PI3K by PRKA, this kinase can enhance PI3K phosphorylation indirectly by enhancing the degradation and inactivation of PRKCA and PPP1CC2.

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Ondee, Thunnicha, Thiranut Jaroonwitchawan, Trairak Pisitkun, Joseph Gillen, Aleksandra Nita-Lazar, Asada Leelahavanichkul, and Poorichaya Somparn. "Decreased Protein Kinase C-β Type II Associated with the Prominent Endotoxin Exhaustion in the Macrophage of FcGRIIb−/− Lupus Prone Mice is Revealed by Phosphoproteomic Analysis." International Journal of Molecular Sciences 20, no. 6 (March 18, 2019): 1354. http://dx.doi.org/10.3390/ijms20061354.

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Dysfunction of FcGRIIb, the only inhibitory receptor of the FcGR family, is commonly found in the Asian population and is possibly responsible for the extreme endotoxin exhaustion in lupus. Here, the mechanisms of prominent endotoxin (LPS) tolerance in FcGRIIb−/− mice were explored on bone marrow-derived macrophages using phosphoproteomic analysis. As such, LPS tolerance decreased several phosphoproteins in the FcGRIIb−/− macrophage, including protein kinase C-β type II (PRKCB), which was associated with phagocytosis function. Overexpression of PRKCB attenuated LPS tolerance in RAW264.7 cells, supporting the role of this gene in LPS tolerance. In parallel, LPS tolerance in macrophages and in mice was attenuated by phorbol 12-myristate 13-acetate (PMA) administration. This treatment induced several protein kinase C families, including PRKCB. However, PMA attenuated the severity of mice with cecal ligation and puncture on LPS tolerance preconditioning in FcGRIIb−/− but not in wild-type cells. The significant reduction of PRKCB in the FcGRIIb−/− macrophage over wild-type cell possibly induced the more severe LPS-exhaustion and increased the infection susceptibility in FcGRIIb−/− mice. PMA induced PRKCB, improved LPS-tolerance, and attenuated sepsis severity, predominantly in FcGRIIb−/− mice. PRKCB enhancement might be a promising strategy to improve macrophage functions in lupus patients with LPS-tolerance from chronic infection.

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Qian, Yiguan, Yang Li, Luwei Xu, Ke Chen, Ning Liu, Xiaobing Yang, Qian Lv, et al. "Tumor Cell-Derived Exosomal circ-PRKCI Promotes Proliferation of Renal Cell Carcinoma via Regulating miR-545-3p/CCND1 Axis." Cancers 15, no. 1 (December 25, 2022): 123. http://dx.doi.org/10.3390/cancers15010123.

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Renal cell carcinoma (RCC) originates from the epithelial cells of the renal tubules and has a high degree of malignancy and heterogeneity. Recent studies have found that exosomes regulate intercellular communication via transferring various bioactive molecules, such as circular RNAs (circRNAs), which are critical for cancer progression. However, the role of tumor cell-derived exosomal circRNAs in RCC remains unclear. In this study, we reported the high expression of circ-PRKCI in RCC tissues and serum exosomes. We also found that circ-PRKCI could be transferred exosomally from highly malignant RCC cells to relatively less malignant RCC cells. Tumor cell-derived exosomal circ-PRKCI promoted the proliferation, migration, and invasion of RCC cells, while inhibiting their apoptosis. Mechanistically, we found that circ-PRKCI promoted the proliferation of RCC via the miR-545-3p/CCND1 signaling pathway. Our study is the first to report the potential mechanisms of tumor cell-derived exosomal circ-PRKCI in RCC. In conclusion, this study will provide a new understanding about the molecular mechanisms of RCC progression.

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Liu, Hsin-Yu, Christophe Pedros, Kok-Fai Kong, Ann J. Canonigo-Balancio, Wen Xue, and Amnon Altman. "Leveraging the Treg-intrinsic CTLA4–PKCη signaling pathway for cancer immunotherapy." Journal for ImmunoTherapy of Cancer 9, no. 9 (September 2021): e002792. http://dx.doi.org/10.1136/jitc-2021-002792.

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BackgroundOur previous studies revealed a critical role of a novel CTLA4-protein kinase C-eta (PKCη) signaling axis in mediating the suppressive activity of regulatory T cells (Tregs) in antitumor immunity. These studies have employed adoptive transfer of germline PKCη-deficient (Prkch−/−) Tregs into Prkch+/+ mice prior to tumor implantation. Here, we extended these findings into a biologically and clinically more relevant context.MethodsWe have analyzed the role of PKCη in antitumor immunity and the tumor microenvironment (TME) in intact tumor-bearing mice with Treg-specific or CD8+ T cell-specific Prkch deletion, including in a therapeutic model of combinatorial treatment. In addition to measuring tumor growth, we analyzed the phenotype and functional attributes of tumor-infiltrating immune cells, particularly Tregs and dendritic cells (DCs).ResultsUsing two models of mouse transplantable cancer and a genetically engineered autochthonous hepatocellular carcinoma (HCC) model, we found, first, that mice with Treg-specific Prkch deletion displayed a significantly reduced growth of B16–F10 melanoma and TRAMP-C1 adenocarcinoma tumors. Tumor growth reduction was associated with a less immunosuppressive TME, indicated by increased numbers and function of tumor-infiltrating CD8+ effector T cells and elevated expression of the costimulatory ligand CD86 on intratumoral DCs. In contrast, CD8+ T cell-specific Prkch deletion had no effect on tumor growth or the abundance and functionality of CD8+ effector T cells, consistent with findings that Prkch−/− CD8+ T cells proliferated normally in response to in vitro polyclonal or specific antigen stimulation. Similar beneficial antitumor effects were found in mice with germline or Treg-specific Prkch deletion that were induced to develop an autochthonous HCC. Lastly, using a therapeutic model, we found that monotherapies consisting of Treg-specific Prkch deletion or vaccination with irradiated Fms-like tyrosine kinase 3 ligand (Flt3L)-expressing B16–F10 tumor cells post-tumor implantation significantly delayed tumor growth. This effect was more pronounced in mice receiving a combination of the two immunotherapies.ConclusionThese findings demonstrate the potential utility of PKCη inhibition as a viable clinical approach to treat patients with cancer, especially when combined with adjuvant therapies.

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Kuehn, Hye Sun, Julie E. Niemela, Andreia Rangel-Santos, Mingchang Zhang, Stefania Pittaluga, Jennifer L. Stoddard, Ashleigh A. Hussey, et al. "Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans." Blood 121, no. 16 (April 18, 2013): 3117–25. http://dx.doi.org/10.1182/blood-2012-12-469544.

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Key Points Mutations in PRKCD cause a syndrome characterized by chronic benign lymphadenopathy, positive autoantibodies, and NK dysfunction. PRKCD deficiency disrupts control of B-cell proliferation and apoptosis and affects NK-cell cytolytic activity.

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Ma, Leyuan, Yi Shan, Robert Bai, Liting Xue, Christopher A. Eide, Jianhong Ou, Lihua J. Zhu, et al. "PKC Pathways Mediate BCR-ABL-Independent Imatinib Resistance in Chronic Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 1790. http://dx.doi.org/10.1182/blood.v124.21.1790.1790.

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Abstract Resistance to imatinib (IM) has posed a great obstacle in treating Chronic Myeloid Leukemia(CML). New generations of tyrosine kinase inhibitors (TKIs) have been developed for BCR-ABL dependent IM resistance, which is commonly due to BCR-ABL kinase-domain mutations. However, in 50% or more of IM-resistant CML patients there is no mutation in BCR-ABL, and intrinsic resistance of CML stem cells often causes disease relapse. Understanding the mechanism of BCR-ABL independent IM resistance is therefore essential for devising strategies to eradicate resistant and residual leukemia. Through a genome-wide shRNA screen in a IM-sensitive human CML cell line, K562 cells, we identified 16 imatinib-sensitizing genes (IMSGs), knockdown of which increased IM resistance of multiple human CML cell lines (e.g., K562, KYO-1 cells. >2 folds increment), and primary CML mice bone marrow cells (> 2 folds of CFUs). Knocking down 11 IMSGs increased IC50IM by more than 5 folds, and also conferred equivalent level of resistance to the second generation TKI, Dasatinib. Extensive signaling pathway analysis by immune-blotting for characteristic protein phosphorylation markers revealed co-activation of PKC and MEK/ERK pathway in majority of IMSG knockdown K562 cell lines. qRT-PCR analysis in IMSG knockdown cells identified PRKCH as the predominant deregulated PKC family member. Mild overexpression of PRKCH increased IC50IM by 10-20 folds, and in vitro phosphorylation confirmed that PRKCH could directly phosphorylate and activate CRAF, therefore MEK/ERK pathway. PRKCH is highly expressed in IM-resistant samples with wildtype BCR-ABL compared to those with mutant BCR-ABL (p<0.05, Mann Whitney test) or IM-sensitive samples (p<0.01, Mann Whitney test). Accordingly, multiple IMSGs were also significantly down-regulated (i.e.,CLEC5A, ELF5, WNT7B, p<0.05), supporting a suppressive role of diverse IMSGs on PRKCH expression. Specifically, we found ELF5 acted as a transcription repressor of PRKCH. To investigate whether simultaneous inhibition of BCR-ABL and MEK/ERK signaling could more efficiently kill BCR-ABL-independent IM-resistant CML cells, we analyzed the effect of combining IM treatment with a FDA-approved MEK inhibitor, Trametinib, in multiple BCR-ABL independent IM-resistant CML mouse models, and primary resistant CML cells. Treatment with both drugs showed a substantially greater effect than either drug alone, and in many instances, the effect of combined drug treatment was synergistic. qRT-PCR analysis showed that PRKCH expression in IM-resistant CML stem cells is higher than that in IM-sensitive CML progenitors (4~25 folds, p<0.01, Student’s t test), implying an important role of PRKCH in CML stem cell resistance. We established a PRKCH knockdown CML mouse model by co-expressing BCR-ABL and a PRKCH shRNA and performed stem cells analysis with or without IM treatment. Although both PRKCH knockdown and IM treatment abolishes MEK/ERK signaling in CML progenitors, only PRKCH controls MEK/ERK pathway in CML stem cells while IM barely has any effect. Combined IM treatment with PRKCH knockdown or MEK inhibition substantially increased the apoptosis rate of CML stem cells (p<0.01, Student’s t test), and prolonged CML mice survival(n=5, p<0.05, Log-rank test). In addition to MEK/ERK pathway, we found PRKCH could activate PKD2, a downstream effector of novel PKCs. PRKCH expression increases upon IM treatment, along with increased PKD2 activity (S916 phosphorylation) in multiple CML cell lines(e.g., K562, KYO-1, LAMA84). PKD2 expression was also induced by IM in primary human CML stem cells. PKD2 promotes cell survival by activating NF-kB pathway, and IM treatment increased p65/RelA phosphorylation at S536 and its nuclear translocation, together with over 4 folds increase in expression of anti-apoptotic p65 target genes (e.g., CIAP2, Bfl-1/A1). Pharmacological inhibition using pan-PKD inhibitor, CRT0066101, completely abolishes IM induced p65 phosphorylation and increased the killing of CML cells by IM. This study for the first time reveals the critical role of PKC pathway in BCR-ABL independent IM resistance in CML. The validation of MEK/ERK and PKD/NF-kB pathway as critical downstream effectors provided specific targets for small molecule therapy in TKI-resistant CML and other malignancies caused by deregulated PKC pathways. Disclosures Cerny: Cellerant Therapeutics: Honoraria, Research Funding.

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Jedrych, Jaroslaw J., Sekhar Duraisamy, and Arivarasan Karunamurthy. "Aneurysmal fibrous histiocytomas with recurrent rearrangement of the PRKCD gene and LAMTOR1-PRKCD fusions." Journal of Cutaneous Pathology 45, no. 12 (September 5, 2018): 966–68. http://dx.doi.org/10.1111/cup.13339.

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Li, Xingyu, Amit Madhukar Kudke, Felix Joseph Nepveux V, and Yan Xu. "Network-Based Pharmacology Study Reveals Protein Targets for Medical Benefits and Harms of Cannabinoids in Humans." Applied Sciences 12, no. 4 (February 20, 2022): 2205. http://dx.doi.org/10.3390/app12042205.

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This network-based pharmacology study intends to uncover the underlying mechanisms of cannabis leading to a therapeutic benefit and the pathogenesis for a wide range of diseases claimed to benefit from or be caused by the use of the cannabis plant. Cannabis contains more than 600 chemical components. Among these components, cannabinoids are well-known to have multifarious pharmacological activities. In this work, twelve cannabinoids were selected as active compounds through text mining and drug-like properties screening and used for initial protein-target prediction. The disease-associated biological functions and pathways were enriched through GO and KEGG databases. Various biological networks [i.e., protein-protein interaction, target-pathway, pathway-disease, and target-(pathway)-target interaction] were constructed, and the functional modules and essential protein targets were elucidated through the topological analyses of the networks. Our study revealed that eighteen proteins (CAT, COMT, CYP17A1, GSTA2, GSTM3, GSTP1, HMOX1, AKT1, CASP9, PLCG1, PRKCA, PRKCB, CYCS, TNF, CNR1, CNR2, CREB1, GRIN2B) are essential targets of eight cannabinoids (CBD, CBDA, Δ9-THC, CBN, CBC, CBGA, CBG, Δ8-THC), which involve in a variety of pathways resulting in beneficial and adverse effects on the human body. The molecular docking simulation confirmed that these eight cannabinoids bind to their corresponding protein targets with high binding affinities. This study generates a verifiable hypothesis of medical benefits and harms of key cannabinoids with a model which consists of multiple components, multiple targets, and multiple pathways, which provides an important foundation for further deployment of preclinical and clinical studies of cannabis.

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Ibnat, Nabilah, Rowshan Ara Islam, and Ezharul Hoque Chowdhury. "Inhibition of Breast Tumour Growth with Intravenously Administered PRKCA siRNA- and PTEN Tumour Suppressor Gene-Loaded Carbonate Apatite Nanoparticles." Applied Sciences 11, no. 17 (September 2, 2021): 8133. http://dx.doi.org/10.3390/app11178133.

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Gene therapy aims to silence an oncogene through RNA interference, or replace an abnormal tumour suppressor via gene augmentation. In this study, we intended RNA interference for PRKCA oncogene and gene augmentation for PTEN tumour suppressor with a view to reduce tumour growth in a mouse model of breast cancer. Inorganic carbonate apatite nanoparticles (CA NPs) were utilized to deliver the synthetic siRNA and the purified gene-carrying plasmid DNA both in vitro and in vivo. Effects of PRKCA siRNA- and PTEN plasmid-loaded NPs on viability of MCF-7, MDA-MB-231 and 4T1 breast cancer cells were assessed by MTT assay. The cell viability data in MCF-7 cell line demonstrated that combined delivery of PRKCA specific siRNA and PTEN plasmid with CA NPs had an additive effect to significantly decrease cellular growth compared to individual treatments. In addition, we observed a similar pattern of cumulative influence for combined treatment in triple negative MDA-MB-231 breast cancer cell line. Upon treatment with PRKCA siRNA+PTEN plasmid-loaded NPs, a remarkable decrease in the phosphorylated form of AKT protein of PI3K/AKT pathway was observed in Western blot, indicative of diminished proliferative signal. Moreover, in vivo study in MCF-7 xenograft breast cancer mouse model demonstrated that the rate of growth and final tumour volume were reduced significantly in the mouse group that received intravenous treatment of PRKCA siRNA+NPs, and PTEN plasmid+NPs. Our findings demonstrated that PRKCA siRNA and PTEN plasmid loaded into CA NPs attenuated breast tumour growth, suggesting their therapeutic potential in the treatment of breast cancer.

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Ruggiero, Alessia, Flavia Squeglia, Daniela Marasco, Roberta Marchetti, Antonio Molinaro, and Rita Berisio. "X-ray structural studies of the entire extracellular region of the serine/threonine kinase PrkC from Staphylococcus aureus." Biochemical Journal 435, no. 1 (March 15, 2011): 33–41. http://dx.doi.org/10.1042/bj20101643.

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Bacterial serine/threonine kinases modulate a wide number of cellular processes. The serine/threonine kinase PrkC from the human pathogen Staphylococcus aureus was also shown to induce germination of Bacillus subtilis spores, in response to cell wall muropeptides. The presence of muropeptides in the bacterial extracellular milieu is a strong signal that the growing conditions are promising. In the present paper, we report the X-ray structure of the entire extracellular region of PrkC from S. aureus. This structure reveals that the extracellular region of PrkC, EC-PrkC, is a linear modular structure composed of three PASTA (penicillin binding-associated and serine/threonine kinase-associated) domains and an unpredicted C-terminal domain, which presents the typical features of adhesive proteins. Using several solution techniques, we also found that EC-PrkC shows no tendency to dimerize even in the presence of high concentrations of muropeptides. X-ray structural results obtained in the present study provide molecular clues into the mechanism of muropeptide-induced PrkC activation.

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Kadioglu, Onat, Mohamed Elbadawi, Edmond Fleischer, and Thomas Efferth. "Identification of Novel Anthracycline Resistance Genes and Their Inhibitors." Pharmaceuticals 14, no. 10 (October 16, 2021): 1051. http://dx.doi.org/10.3390/ph14101051.

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Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were overexpressed by lentiviral-plasmid-based transfection of HEK293 cells. An in silico drug repurposing approach was applied using virtual screening and molecular docking of FDA-approved drugs to identify inhibitors of these new drug-resistant genes. Overexpression of the selected genes conferred resistance to doxorubicin and daunorubicin but not to vincristine, docetaxel, and cisplatin, indicating the involvement of these genes in resistance to anthracyclines but not to a broader MDR phenotype. Using virtual drug screening and molecular docking analyses, we identified FDA-approved compounds (conivaptan, bexarotene, and desloratadine) that were interacting with HMOX1 and PRKCA at even stronger binding affinities than 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethenone and ellagic acid as known inhibitors of HMOX1 and PRKCA, respectively. Conivaptan treatment increased doxorubicin sensitivity of both HMOX1- and PRKCA-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in HMOX1-transfected cells and desloratadine in PRKCA-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells.

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Schmidl, Sebastian R., Katrin Gronau, Claudine Hames, Julia Busse, Dörte Becher, Michael Hecker, and Jörg Stülke. "The Stability of Cytadherence Proteins in Mycoplasma pneumoniae Requires Activity of the Protein Kinase PrkC." Infection and Immunity 78, no. 1 (October 26, 2009): 184–92. http://dx.doi.org/10.1128/iai.00958-09.

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ABSTRACT Mycoplasma pneumoniae belongs to the mollicutes, a group of bacteria that have strongly reduced genomes but that are nevertheless capable of independent life. With only three transcription factors, the regulatory features of these bacteria are very limited. Thus, posttranslational regulation might be important for M. pneumoniae. In addition to the highly specific HPr kinase, the M. pneumoniae prkC gene encodes the serine/threonine protein kinase C. In order to study the function(s) of this kinase, we isolated an M. pneumoniae mutant affected in PrkC. This mutation resulted in nonadherent growth and loss of cytotoxicity. Examination of the phosphorylation profile of the prkC mutant suggested that phosphorylation of cytadherence proteins was affected by the loss of this kinase. In contrast, inactivation of the prpC gene affecting the protein phosphatase that antagonizes PrkC-dependent phosphorylation resulted in more intensive phosphorylation of the cytadherence proteins HMW1 and HMW3 of the major adhesin P1 and of the surface protein MPN474. Moreover, loss of PrkC affects not only the phosphorylation state of the cytadherence proteins but also their intracellular accumulation. However, the expression of the corresponding genes was not affected by PrkC, suggesting that PrkC-dependent phosphorylation results in stabilization of the cytadherence proteins. The HMW proteins and P1 are part of the so-called terminal organelle of M. pneumoniae that is involved in gliding motility, cell division, and adhesion to host epithelial tissues. Our observations suggest that the posttranslational modification of cytadherence proteins by PrkC is essential for the development and function of the M. pneumoniae terminal organelle.

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Gaidenko, Tatiana A., Tae-Jong Kim, and Chester W. Price. "The PrpC Serine-Threonine Phosphatase and PrkC Kinase Have Opposing Physiological Roles in Stationary-Phase Bacillus subtilis Cells." Journal of Bacteriology 184, no. 22 (November 15, 2002): 6109–14. http://dx.doi.org/10.1128/jb.184.22.6109-6114.2002.

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ABSTRACT Loss of the PrpC serine-threonine phosphatase and the associated PrkC kinase of Bacillus subtilis were shown to have opposite effects on stationary-phase physiology by differentially affecting cell density, cell viability, and accumulation of β-galactosidase from a general stress reporter fusion. These pleiotropic effects suggest that PrpC and PrkC have important regulatory roles in stationary-phase cells. Elongation factor G (EF-G) was identified as one possible target of the PrpC and PrkC pair in vivo, and purified PrpC and PrkC manifested the predicted phosphatase and kinase activities against EF-G in vitro.

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Daniunaite, Kristina, Arnas Bakavicius, Kristina Zukauskaite, Ieva Rauluseviciute, Juozas Rimantas Lazutka, Albertas Ulys, Feliksas Jankevicius, and Sonata Jarmalaite. "Promoter Methylation of PRKCB, ADAMTS12, and NAALAD2 Is Specific to Prostate Cancer and Predicts Biochemical Disease Recurrence." International Journal of Molecular Sciences 22, no. 11 (June 5, 2021): 6091. http://dx.doi.org/10.3390/ijms22116091.

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The molecular diversity of prostate cancer (PCa) has been demonstrated by recent genome-wide studies, proposing a significant number of different molecular markers. However, only a few of them have been transferred into clinical practice so far. The present study aimed to identify and validate novel DNA methylation biomarkers for PCa diagnosis and prognosis. Microarray-based methylome data of well-characterized cancerous and noncancerous prostate tissue (NPT) pairs was used for the initial screening. Ten protein-coding genes were selected for validation in a set of 151 PCa, 51 NPT, as well as 17 benign prostatic hyperplasia samples. The Prostate Cancer Dataset (PRAD) of The Cancer Genome Atlas (TCGA) was utilized for independent validation of our findings. Methylation frequencies of ADAMTS12, CCDC181, FILIP1L, NAALAD2, PRKCB, and ZMIZ1 were up to 91% in our study. PCa specific methylation of ADAMTS12, CCDC181, NAALAD2, and PRKCB was demonstrated by qualitative and quantitative means (all p < 0.05). In agreement with PRAD, promoter methylation of these four genes was associated with the transcript down-regulation in the Lithuanian cohort (all p < 0.05). Methylation of ADAMTS12, NAALAD2, and PRKCB was independently predictive for biochemical disease recurrence, while NAALAD2 and PRKCB increased the prognostic power of multivariate models (all p < 0.01). The present study identified methylation of ADAMTS12, NAALAD2, and PRKCB as novel diagnostic and prognostic PCa biomarkers that might guide treatment decisions in clinical practice.

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Qiu, Junjie, Biying Zheng, Hengpu Zhou, Chengcong Ye, Menglin Shi, Senlin Shi, and Suxiang Wu. "Network Pharmacology, Molecular Docking, and Molecular Dynamic-Based Investigation on the Mechanism of Compound Chrysanthemum in the Treatment of Asthenopia." Computational and Mathematical Methods in Medicine 2022 (December 30, 2022): 1–18. http://dx.doi.org/10.1155/2022/3444277.

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As a clinical empirical prescription for ophthalmology, compound chrysanthemum has been used gradually and has a good effect on eye fatigue. However, the detailed mechanisms of antiasthenopia have not been studied. In order to clarify the mechanisms of the compound chrysanthemum in the treatment of asthenopia, network pharmacology was combined with experimental study in this paper. A total of 593 genes and 39 active chemicals were identified, and both were considered to be essential to the advancement of asthenopia research. The results of the molecular docking analysis demonstrated a certain affinity between PRKACA, PRKCA, PRKCB, and their related compounds; molecular dynamic simulations assessed the stability of these receptors and ligands. The effects of compound chrysanthemum extract on ciliary muscle were studied in vitro and in vivo. By using the MTT assay, compound chrysanthemum extracts (50, 100, 200, 400, and 800 g·mL-1) showed no effect on the proliferation of rCSMCs for 24 and 48 hours. It raised nitric oxide and decreased Ca2+ in ciliary muscle cells isolated from the eyeballs of rats. Besides, compound chrysanthemum extract had a direct relaxing effect on the isolated gastric smooth muscle of rats by reducing the contractile tension. Furthermore, in vivo experiment results showed that, compared to the incandescent lamp-irradiated rats (model group), SD rats treated with compound chrysanthemum extracts (660 mg·kg-1 and 1320 mg·kg-1, orally) displayed considerably retracted pupils and increased NO content. It is also found that compound chrysanthemum extract can downregulate the mRNA expression of PKA and PKC in the calcium signaling pathway. Overall, our results suggested that compound chrysanthemum extract may lessen visual fatigue through multiple components, multiple targets, and multiple pathways.

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LaFlamme, Brooke. "PRKCI and SOX2 drive lung cancer." Nature Genetics 46, no. 4 (March 27, 2014): 325. http://dx.doi.org/10.1038/ng.2946.

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Liu, Hsin Yu, Christophe Pedros, Kok-Fai Kong, Ann J. Canonigo-Balancio, Wen Xue, and Amnon Altman. "Leveraging the Treg-intrinsic CTLA4-PKCη signaling pathway for cancer immunotherapy." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 180.10. http://dx.doi.org/10.4049/jimmunol.208.supp.180.10.

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Abstract Our previous studies revealed a critical role of a novel CTLA4-PKCη signaling in mediating the suppressive activity of Tregs in antitumor immunity. Here, we extended these findings into a biologically and clinically more relevant context. We have analyzed the role of PKCη in antitumor immunity in intact tumor-bearing mice with Treg− or CD8+ T cell-specific Prkch deletion, including in a therapeutic model of combinatorial treatment. Using two models of mouse transplantable cancer and a genetically engineered autochthonous hepatocellular carcinoma (HCC) model, we found that mice with Treg-specific Prkch deletion displayed a significantly reduced growth of B16-F10 melanoma and TRAMP-C1 adenocarcinoma tumors. Tumor growth reduction was associated with a less immunosuppressive tumor microenvironment, indicated by increased numbers and function of tumor-infiltrating CD8+ T cells and elevated expression of the costimulatory ligand CD86 on CD103+ DCs. In contrast, CD8+ T cell-specific Prkch deletion had no effect on tumor growth and the abundance or functionality of CD8+ T cells. Similar beneficial antitumor effects were found in mice with germline or Treg-specific Prkch deletion that were induced to develop an autochthonous HCC. Lastly, using a therapeutic model, we found that monotherapies consisting of Treg-specific Prkch deletion or vaccination with irradiated Flt3L-expressing B16-F10 tumor cells post-tumor implantation significantly delayed tumor growth. This effect was more pronounced in mice receiving a combination of the two immunotherapies. These findings demonstrate the potential utility of PKCη inhibition as a viable clinical approach to treat cancer patients, especially when combined with adjuvant therapies. Funded by the NIH grant 5R01CA233862

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Huang, Ping, Xiaoye Zhang, Minhua Pan, Jianneng Deng, Zhihong Chen, Xiaomei Zhou, Meiling Liang, and Dongwei Liang. "Effect of Activated Protein Kinase C Beta Type Mediated Phosphorylation of Signal Transducer and Activator of Transcription 4 on Proliferation and Phenotypic Transformation of Vascular Smooth Muscle Cells After Vascular Injury Induced by Nano-SiO2." Journal of Nanoscience and Nanotechnology 20, no. 12 (December 1, 2020): 7385–97. http://dx.doi.org/10.1166/jnn.2020.18595.

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The excessive proliferation, endothelial migration, and phenotype transformation of vascular smooth muscle cells (VSMC) lead to increased extracellular matrix secretion, which induces vascular intimal hyperplasia, which is an important restenosis mechanism after vascular injury. In our study, we verified the cytotoxicity of SiO2 nanoparticles to VSMC. To explore the role of endothelial repairs and molecular mechanisms after vascular injuries, we sequenced the transcriptome of injured vessels in the carotid artery of mice. The results showed the differentially expressed genes in normal vascular tissues, and that vascular tissues were mainly enriched with NF-κB signaling pathways, chemokine signaling pathways and other biological functions, by the leukocyte activation and adhesion of the KEGG pathway in the immune response, and by DNA binding, DNA transcription regulatory region binding, and other molecular functions. Core proteins included PRKCB, STAT4, CCL5, and BCL-2. To verify the roles of these core proteins, RT-qPCR andWestern blot techniques were used to detect their transcription and translation levels, and HE staining was used to detect morphological changes in blood vessels. To further clarify the role of core proteins in VSMC, PRKCB over expression plasmids were constructed, and the RT-qPCR and Western blot techniques were again used to detect the expression of core proteins. The results showed that the levels of transcription and translation, and of PRKCB and STAT4 phosphorylation, increased significantly after vascular injury, and then noticeably decreased three days later- and that CCL5 and Bcl-2 expression trends were consistent with this. HE staining showed that when the vascular endothelium was damaged, smooth muscle cells proliferated significantly, and that the intima thickened three days after vascular injury. After over expression of PRKCB, the expression and activation of STAT4, CCL5, and Bcl-2 significantly increased, α-SMA and Vimentin were down-regulated, OPN was up-regulated, and VSMC activity was enhanced. From these results, it could be concluded that PRKCB is activated by vascular injury, and that over-activation of PRKCB promotes activation of STAT4 and the expression of CCL5 and BCL-2—which in turn leads to enhanced VSMC activity and transformation of its contraction phenotype to the secretion phenotype. We were also able to establish that the cytotoxicity of SiO2 nanoparticles to VSMC was positively correlated with dose and time.

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Manna, Pulak R., and Douglas M. Stocco. "The role of JUN in the regulation of PRKCC-mediated STAR expression and steroidogenesis in mouse Leydig cells." Journal of Molecular Endocrinology 41, no. 5 (August 28, 2008): 329–41. http://dx.doi.org/10.1677/jme-08-0077.

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Activator protein 1 (JUN) transcription factors (JUN and FOS) play critical roles in a wide variety of signaling processes including those in the protein kinase C (PRKCC) pathway, a pathway that is instrumental in the expression of the steroidogenic acute regulatory (STAR) protein. In the present study, we determined the functional involvement of one of the key JUN family members, JUN, in the regulation of PRKCC-dependent STAR expression and steroidogenesis. MA-10 mouse Leydig tumor cells treated with an activator of PRKCC, phorbol 12-myristate 13-acetate (PMA), demonstrated increases in the expression of the STAR and CYP11A1 proteins and progesterone synthesis, which coincided with the expression and phosphorylation of JUN (P-JUN). PMA was also capable of enhancing the cAMP analog, (Bu)2cAMP, which stimulated JUN, STAR, P-STAR and progesterone levels. The induction of Jun mRNA expression and steroid synthesis by PMA requires de novo protein synthesis. Chromatin immunoprecipitation studies revealed the association of P-JUN with the STAR proximal promoter and that PMA specifically enhanced in vivo P-JUN–DNA interaction. Electrophoretic mobility shift assays and reporter gene analyses demonstrated that JUN binds to the JUN motif (−81/−75 bp) in the STAR promoter, and that JUN–DNA-binding activity was highly correlated with the induction of JUN by PRKCC signaling. Overexpression of JUN increased the PMA-mediated transcription of the Star gene, an event markedly decreased by TAM-67, a dominant negative mutant of JUN. Targeted silencing of endogenous JUN, by small interfering RNA, was correlated with the repression of basal- and PMA-mediated STAR expression and progesterone synthesis. These findings describe the mechanisms by which JUN influences PRKCC signaling and provide additional and novel insight into the regulation of the steroidogenic machinery in mouse Leydig cells.

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Liu, Hsin Yu, Christophe Pedros, Ann J. Canonigo Balancio, and Amnon Altman. "Protein kinase C-eta (PKCη) is dispensable for the activation and function of CD8+T cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 76.17. http://dx.doi.org/10.4049/jimmunol.202.supp.76.17.

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Abstract We previously reported that protein kinase C-eta (PKCη) forms a novel signaling complex with CTLA4 in regulatory T cells (Tregs) and this complex is required for the contact-dependent suppressive activity of Tregs. As a result, PKCη-deficient (Prkch−/−) Tregs fail to suppress anti-tumor immunity. However, given the ubiquitous expression of PKCη, it has remained unclear whether PKCη is also required for the effector functions of conventional T cells, particularly CD8+T cells that play a critical role in anti-tumor immunity. We therefore assessed the effect of genetic PKCη deletion on CD8+T cell-dependent immune functions. We found that Prkch−/− mouse or PRKCH knockdown human CD8+T cells displayed intact, and even enhanced, T cell activation in vitro as measured by proliferation and expression of TNFα, IFNγ, and granzyme B (GzmB) following anti-CD3 plus -CD28 costimulation. Next, we used the acute LCMV infection as an in vivo model to study the characteristics of virus-specific CD8+T cells, which were identified by specific staining with CD8 tetramers. Splenocytes from Prkch−/− mice showed similar frequencies of tetramer+CD8+T cells to those of wild-type (WT) mice, and these cells proliferated normally and expressed normal levels of TNFα and IFNγ. The LCMV-specific Prkch−/−CD8+T cells expressed normal or increased levels of GzmB, and the infected mice displayed greater viral clearance. We conclude that PKCη deficiency does not impact the activation and function of CD8+T cells. Taken together, the selective inhibition of the CTLA4-PKCη signaling pathway in cancer patients is a promising therapeutic strategy to inactivate tumor-promoting Tregs and, thus, enhance anti-tumor immunity, without having adverse effects on CD8+T cells.

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Yanalieva, Laura, Pavel Vasilyev, and Andrey Kochetkov. "Methodology of Validation of In Silico 3D-Models of Pharmacologically Relevant Proteins-Targets." Vestnik Volgogradskogo Gosudarstvennogo Universiteta. Serija 11. Estestvennye nauki, no. 1 (August 2018): 76–78. http://dx.doi.org/10.15688/jvolsu11.2018.1.16.

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The article studies the development of methodology and results of validation of in silico 3D models of pharmacologically relevant target proteins on the example of protein kinase C theta. Using the IUPHAR / BPS database, information has been found about 5 reference inhibitors PRKCQ, recognized by the world scientific community. According to the received data, 3 most valid PRKCQ models (PDB-codes: 5F9E, 2JED, 4RA5) have been selected, which can later be used for docking of new inhibitors.

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Obuchowski, M., E. Madec, D. Delattre, G. Boël, A. Iwanicki, D. Foulger, and S. J. Séror. "Characterization of PrpC from Bacillus subtilis, a Member of the PPM Phosphatase Family." Journal of Bacteriology 182, no. 19 (October 1, 2000): 5634–38. http://dx.doi.org/10.1128/jb.182.19.5634-5638.2000.

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ABSTRACT We cloned the yloO gene and purified a His-tagged form of its product, the putative protein phosphatase YloO, which we now designate PrpC. This closely resembles the human protein phosphatase PP2C, a member of the PPM family, in sequence and predicted secondary structure. PrpC has phosphatase activity in vitro against a synthetic substrate, p-nitrophenol phosphate, and endogenousBacillus subtilis proteins. The prkC andprpC genes are adjacent on the chromosome, and the phosphorylated form of PrkC is a substrate for PrpC. These findings suggest that PrkC and PrpC may function as a couple in vivo.

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Inman, Kristin S., Yi Liu, Michele L. Scotti Buzhardt, Michael Leitges, Murli Krishna, Howard C. Crawford, Alan P. Fields, and Nicole R. Murray. "Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice." Cancers 14, no. 3 (February 4, 2022): 796. http://dx.doi.org/10.3390/cancers14030796.

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Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for KrasG12D-mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and KrasG12D-mediated pancreatic cancer development. Knockout of pancreatic Prkci significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. Prkci-ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic Prkci promoted KrasG12D-mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression.

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Friesen, Robert H., Dobromir Slavov, Shelley D. Miyamoto, Richard John Ing, Wells B. LaRiviere, and Matthew R. G. Taylor. "Lack of Association Between Adrenoreceptor Genotype and the Vasoconstriction Response to Dexmedetomidine." Seminars in Cardiothoracic and Vascular Anesthesia 21, no. 4 (May 8, 2017): 341–44. http://dx.doi.org/10.1177/1089253217708621.

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An exaggerated vasoconstriction response to dexmedetomidine, an α-2 adrenergic agonist, has been associated with 2 genotypes: a deletion in the α-2B adrenoreceptor gene ( ADRA2B deletion) and SNP rs9922316 in the gene for protein kinase C type β ( PRKCB). We hypothesized that children with a marked systemic vascular resistance index (SVRI) increase following intravenous dexmedetomidine bolus would carry these genotypes. Following institutional review board approval, DNA samples from 16 children with transplanted hearts who participated in a study in the cardiac catheterization laboratory of hemodynamic responses to dexmedetomidine boluses underwent genotyping by polymerase chain reaction (PCR) amplification and PCR Sanger sequencing for the ADRA2B deletion and for PRKCB rs9922316. A wide range of SVRI (−12% to +76%, median 33%) and mean arterial blood pressure (MAP; −7% to +50%, median 26%) responses to dexmedetomidine was observed. The responses were not significantly different among genotype groups. An association between exaggerated SVRI or MAP responses and either ADRA2B deletion or PRKCB rs9922316 was not observed.

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Hu, Han, Yong Long, Guili Song, Shaoxiong Chen, Zhicheng Xu, Qing Li, and Zhengli Wu. "Dysfunction of Prkcaa Links Social Behavior Defects with Disturbed Circadian Rhythm in Zebrafish." International Journal of Molecular Sciences 24, no. 4 (February 14, 2023): 3849. http://dx.doi.org/10.3390/ijms24043849.

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Protein kinase Cα (PKCα/PRKCA) is a crucial regulator of circadian rhythm and is associated with human mental illnesses such as autism spectrum disorders and schizophrenia. However, the roles of PRKCA in modulating animal social behavior and the underlying mechanisms remain to be explored. Here we report the generation and characterization of prkcaa-deficient zebrafish (Danio rerio). The results of behavioral tests indicate that a deficiency in Prkcaa led to anxiety-like behavior and impaired social preference in zebrafish. RNA-sequencing analyses revealed the significant effects of the prkcaa mutation on the expression of the morning-preferring circadian genes. The representatives are the immediate early genes, including egr2a, egr4, fosaa, fosab and npas4a. The downregulation of these genes at night was attenuated by Prkcaa dysfunction. Consistently, the mutants demonstrated reversed day–night locomotor rhythm, which are more active at night than in the morning. Our data show the roles of PRKCA in regulating animal social interactions and link the social behavior defects with a disturbed circadian rhythm.

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Munson, Michael J., Benan J. Mathai, Matthew Yoke Wui Ng, Laura Trachsel-Moncho, Laura R. de la Ballina, and Anne Simonsen. "GAK and PRKCD kinases regulate basal mitophagy." Autophagy 18, no. 2 (January 9, 2022): 467–69. http://dx.doi.org/10.1080/15548627.2021.2015154.

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Sarkar, Sharmistha, Christopher A. Bristow, Prasenjit Dey, Kunal Rai, Ruth Perets, Alejandra Ramirez-Cardenas, Shruti Malasi, et al. "PRKCI promotes immune suppression in ovarian cancer." Genes & Development 31, no. 11 (June 1, 2017): 1109–21. http://dx.doi.org/10.1101/gad.296640.117.

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Gu, Hao, Zhenping Chen, Jie Ma, Jing Wang, Rui Zhang, Runhui Wu, and Tianyou Wang. "Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: A pedigree case report with homozygous variation PRKCD." International Journal of Immunopathology and Pharmacology 35 (January 2021): 205873842110259. http://dx.doi.org/10.1177/20587384211025934.

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Autoimmune lymphoproliferative syndrome (ALPS) usually presents in childhood with fever, nonmalignant splenomegaly, and lymphadenopathy along with cytopenia, which is caused by mutations in the FAS apoptotic pathway. The TCRαβ + CD4/CD8 double-negative T cells (DNT), one of required criteria of ALPS, will rise markedly in ALPS. Human Protein kinase C delta (PRKCD) deficiency (OMIM # 615559) was recently identified to be causative for an ALPS-type III with significant B-cell proliferation particularly of immature B cells. We report a pedigree homozygous variation of PRKCD gene (c.36T>G, p. Y12X) which presented with refractory cytopenia, splenomegaly, and polarization of DNT/regulatory T cells (Treg) axis. After repeated recurrence, the patient was treated with mTOR inhibitor sirolimus, which had a safety mechanism and specifically rebalance the DNT/Treg axis. The patient’s hemoglobin and clinical condition improved gradually by the application of sirolimus (1.5 mg/m2, actual blood concentration 4.27–10.3 ng/l). Homozygous variation in PRKCD may lead to typical ALPS clinical manifestations. Targeting DNT/Treg axis, use of sirolimus in such patients may help to achieve good clinical control.

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Gan, Yuanxiu, Jie Long, Yan Zeng, Yan Zhang, and Yang Tao. "lncRNA IL-17RA-1 Attenuates LPS-Induced Sepsis via miR-7847-3p/PRKCG-Mediated MAPK Signaling Pathway." Mediators of Inflammation 2022 (October 13, 2022): 1–17. http://dx.doi.org/10.1155/2022/9923204.

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Sepsis represents a syndrome of systemic inflammatory response, which is mostly a result of infection with various pathogenic microorganisms, characterized by an uncontrolled infection response of the organism leading to life-threatening organ dysfunction. Long noncoding RNA (lncRNA), as competing endogenous RNA, can affect the binding of microRNA (miRNA) to mRNA, thus influencing the development of sepsis. In this study, based on transcriptome data from GEO database, we screened differentially expressed lncRNAs and constructed lncRNA-miRNA-mRNA network. And pathway IL-17RA-1/miR-7847-3p/protein kinase C gamma (PRKCG) coexpression network was successfully sorted out. The effect of this network on LPS-induced sepsis model in THP-1 cells was also verified by CCK-8, scratch, ELISA, Western blot, and qRT-PCR assays. Corresponding binding sites of miR-7847-3p to IL-17RA-1 and miR-7847-3p to PRKCG were verified using dual luciferase gene reporter assays, respectively. Compared with control, si-IL-17RA-1 significantly inhibited the cell viability and migration ability of THP-1, and levels of proinflammatory factors IL-6, IL-1β, and TNF-α secreted were markedly decreased, and the expression of IL-17RA-1, PRKCG, p-MEKK1, and p-JNK were markedly reduced. In addition, IL-17RA-1 could target binding to miR-7847-3p and inhibit its expression, and miR-7847-3p could also bind to PRKCG. Our experiments demonstrate that IL17-RA-1 attenuates the sepsis response through the miR-7847-3p/MAPK pathway, and this competing endogenous RNA (ceRNA) network may be a potential approach to predict and combat sepsis.

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Rankinen, Tuomo, Margarita Teran-Garcia, Treva Rice, D. C. Rao, and Claude Bouchard. "Endurance training alleviates PRKCQ genotype-related metabolic abnormalities." Medicine & Science in Sports & Exercise 39, Supplement (May 2007): S14. http://dx.doi.org/10.1249/01.mss.0000272926.92381.17.

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Lee, Anna M., Benjamin R. Kanter, Dan Wang, Jana P. Lim, Mimi E. Zou, Chichen Qiu, Thomas McMahon, Jahan Dadgar, Sarah C. Fischbach-Weiss, and Robert O. Messing. "Prkcz null mice show normal learning and memory." Nature 493, no. 7432 (January 2013): 416–19. http://dx.doi.org/10.1038/nature11803.

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Liu, Hsin-Yu, Christophe Pedros, Ann Balancio, Kok-Fai Kong, and Amnon Altman. "Protein kinase C-eta is required for Treg-mediated suppression of anti-tumor and viral immunity." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 244.14. http://dx.doi.org/10.4049/jimmunol.204.supp.244.14.

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Abstract We previously reported that protein kinase C-eta plays an important role in the contact-dependent suppressive activity of Tregs via its association with CTLA4, and that PKC-eta-deficient (Prkch−/−) Tregs fail to suppress anti-melanoma tumor immunity. Here we extend this study to a genetically engineered mouse model of HCC driven by CRISPR-Cas9-driven deletion of Pten and p53. In the Pten-p53 HCC model, Prkch Treg-specific conditional knockout (cKO) mice developed a lower tumor incidence, fewer tumors, lower degree of steatosis phenotype, and showed higher intratumoral CD4+ T cells than WT mice. In addition, B cells and resident DCs displayed higher levels of the costimulatory ligand CD86 in dLNs of cKO mice. Increased CD4+ T cells, memory T lymphocytes, and cytokines production were observed in spleen of cKO mice. These results indicate that Treg-expressed PKC-eta is required for Treg-mediated suppression of anti-HCC tumor immunity. To further explore the importance of PKC-eta in Teff cells, the LCMVArm acute infection model, as well as the in vitro activation of murine or human CD8+ T cells were used. We found that purified Prkch−/− mouse CD8+ T cells as well as PRKCH knockdown human CD8+ T cells displayed intact T cell activation in vitro as measured by proliferation and expression of GzmB and IFNg. Interestingly, Treg-specific cKO mice showed improved viral clearance and displayed enhanced expression of GzmB and IFNg by virus-specific CD8+ T cells. Thus, global PKC-eta deletion does not impair overall CD8+ T cell-mediated immunity implying that selective pharmacological PKC-eta inhibition could be safely used in vivo to inhibit undesired contact-dependent suppression by Tregs and, thus, enhance tumor- and viral-specific immunity.

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Shah, Hania, Khushbukhat Khan, Yasmin Badshah, Naeem Mahmood Ashraf, Maria Shabbir, Janeen H. Trembley, Tayyaba Afsar, Ali Abusharha, and Suhail Razak. "Investigation of UTR Variants by Computational Approaches Reveal Their Functional Significance in PRKCI Gene Regulation." Genes 14, no. 2 (January 18, 2023): 247. http://dx.doi.org/10.3390/genes14020247.

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Single nucleotide polymorphisms (SNPs) are associated with many diseases including neurological disorders, heart diseases, diabetes, and different types of cancers. In the context of cancer, the variations within non-coding regions, including UTRs, have gained utmost importance. In gene expression, translational regulation is as important as transcriptional regulation for the normal functioning of cells; modification in normal functions can be associated with the pathophysiology of many diseases. UTR-localized SNPs in the PRKCI gene were evaluated using the PolymiRTS, miRNASNP, and MicroSNIper for association with miRNAs. Furthermore, the SNPs were subjected to analysis using GTEx, RNAfold, and PROMO. The genetic intolerance to functional variation was checked through GeneCards. Out of 713 SNPs, a total of thirty-one UTR SNPs (three in 3′ UTR region and twenty-nine in 5′ UTR region) were marked as ≤2b by RegulomeDB. The associations of 23 SNPs with miRNAs were found. Two SNPs, rs140672226 and rs2650220, were significantly linked with expression in the stomach and esophagus mucosa. The 3′ UTR SNPs rs1447651774 and rs115170199 and the 5′ UTR region variants rs778557075, rs968409340, and 750297755 were predicted to destabilize the mRNA structure with substantial change in free energy (∆G). Seventeen variants were predicted to have linkage disequilibrium with various diseases. The SNP rs542458816 in 5′ UTR was predicted to put maximum influence on transcription factor binding sites. Gene damage index(GDI) and loss of function (o:e) ratio values for PRKCI suggested that the gene is not tolerant to loss of function variants. Our results highlight the effects of 3′ and 5′ UTR SNP on miRNA, transcription and translation of PRKCI. These analyses suggest that these SNPs can have substantial functional importance in the PRKCI gene. Future experimental validation could provide further basis for the diagnosis and therapeutics of various diseases.

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Sun, Shanfeng, Jiangzuo Luo, Hang Du, Guirong Liu, Manman Liu, Junjuan Wang, Shiwen Han, and Huilian Che. "Widely Targeted Lipidomics and Transcriptomics Analysis Revealed Changes of Lipid Metabolism in Spleen Dendritic Cells in Shrimp Allergy." Foods 11, no. 13 (June 25, 2022): 1882. http://dx.doi.org/10.3390/foods11131882.

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Shrimp allergy (SA) is pathological type 2 inflammatory immune responses against harmless shrimp protein allergen, which is caused by complex interactions between dendritic cells (DCs) and other immune cells. Lipid metabolism in different DCs states are significantly changed. However, the lipid metabolism of spleen DCs in SA remain ambiguous. In this study, we established a BALB/c mouse shrimp protein extract-induced allergy model to determine the lipid profile of spleen DCs in SA, and the molecular mechanism between lipid metabolism and immune inflammation was preliminarily studied. Spleen DCs were sorted by fluorescence-activated cell sorting, and then widely targeted lipidomics and transcriptomics analysis were performed. Principal component analysis presented the lipidome alterations in SA. The transcriptomic data showed that Prkcg was involved in lipid metabolism, immune system, and inflammatory signaling pathway. In the correlation analysis, the results suggested that Prkcg was positively correlated with triacylglycerol (Pearson correlation coefficient = 0.917, p = 0.01). The lipidomics and transcriptomics integrated pathway analysis indicated the activated metabolic conversion from triacylglycerol to 1,2-diacyl-sn-glycerol and the transmission of lipid metabolism to immune inflammation (from triacylglycerol and ceramide to Prkcg) in SA spleen DCs, and cellular experiments in vitro showed that glyceryl trioleate and C16 ceramide treatment induced immune function alteration in DCs.

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Darabi, Sourat, Andrew Elliott, David R. Braxton, Jia Zeng, Kurt Hodges, Kelsey Poorman, Jeff Swensen, et al. "Transcriptional Profiling of Malignant Melanoma Reveals Novel and Potentially Targetable Gene Fusions." Cancers 14, no. 6 (March 15, 2022): 1505. http://dx.doi.org/10.3390/cancers14061505.

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Invasive melanoma is the deadliest type of skin cancer, with 101,110 expected cases to be diagnosed in 2021. Recurrent BRAF and NRAS mutations are well documented in melanoma. Biologic implications of gene fusions and the efficacy of therapeutically targeting them remains unknown. Retrospective review of patient samples that underwent next-generation sequencing of the exons of 592 cancer-relevant genes and whole transcriptome sequencing for the detection of gene fusion events and gene expression profiling. Expression of PDL1 and ERK1/2 was assessed by immunohistochemistry (IHC). There were 33 (2.6%) cases with oncogenic fusions (14 novel), involving BRAF, RAF1, PRKCA, TERT, AXL, and FGFR3. MAPK pathway-associated genes were over-expressed in BRAF and RAF1 fusion-positive tumors in absence of other driver alterations. Increased expression in tumors with PRKCA and TERT fusions was concurrent with MAPK pathway alterations. For a subset of samples with available tissue, increased phosphorylation of ERK1/2 was observed in BRAF, RAF1, and PRKCA fusion-positive tumors. Oncogenic gene fusions are associated with transcriptional activation of the MAPK pathway, suggesting they could be therapeutic targets with available inhibitors. Additional analyses to fully characterize the oncogenic effects of these fusions may support biomarker driven clinical trials.

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Absalon, Cédric, Michal Obuchowski, Edwige Madec, Delphine Delattre, I. Barry Holland, and Simone J. Séror. "CpgA, EF-Tu and the stressosome protein YezB are substrates of the Ser/Thr kinase/phosphatase couple, PrkC/PrpC, in Bacillus subtilis." Microbiology 155, no. 3 (March 1, 2009): 932–43. http://dx.doi.org/10.1099/mic.0.022475-0.

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The conserved prpC, prkC, cpgA locus in Bacillus subtilis encodes respectively a Ser/Thr phosphatase, the cognate sensor kinase (containing an external PASTA domain suggested to bind peptidoglycan precursors) and CpgA, a small ribosome-associated GTPase that we have shown previously is implicated in shape determination and peptidoglycan deposition. In this study, in a search for targets of PrkC and PrpC, we showed that, in vitro, CpgA itself is phosphorylated on serine and threonine, and another GTPase, the translation factor EF-Tu, is also phosphorylated by the kinase on the conserved T384 residue. Both substrates are dephosphorylated by PrpC in vitro. In addition, we identified YezB, a 10.3 kDa polypeptide, and a component of the stressosome, as a substrate for both enzymes in vitro and apparently in vivo. We propose that the PrpC/PrkC/CpgA system constitutes an important element of a regulatory network involved in the coordination of cell wall expansion and growth in B. subtilis.

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Salzer, Elisabeth, Elisangela Santos-Valente, Stefanie Klaver, Sol A. Ban, Wolfgang Emminger, Nina Kathrin Prengemann, Wojciech Garncarz, et al. "B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ." Blood 121, no. 16 (April 18, 2013): 3112–16. http://dx.doi.org/10.1182/blood-2012-10-460741.

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Key Points PRKCD deficiency causes a novel primary immunodeficiency with B-cell deficiency and severe autoimmunity. Protein kinase C δ may represent a key factor controlling immune homeostasis and autoimmunity.

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Croteau, Laura, Clément Mercier, Étienne Fafard-Couture, Alexandre Nadeau, Stéphanie Robillard, Valérie Breton, Andréanne Guay, Farah Lizotte, Marc-Antoine Despatis, and Pedro Geraldes. "Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb." Diabetes and Vascular Disease Research 18, no. 2 (March 2021): 147916412199903. http://dx.doi.org/10.1177/1479164121999033.

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Aims: Peripheral artery disease is a complication of diabetes leading to critical hindlimb ischemia. Diabetes-induced inhibition of VEGF actions is associated with the activation of protein kinase Cδ (PKCδ). We aim to specifically investigate the role of PKCδ in endothelial cell (EC) function and VEGF signaling. Methods: Nondiabetic and diabetic mice, with ( ec-Prkcd−/−) or without ( ec-Prkcdf/f) endothelial deletion of PKCδ, underwent femoral artery ligation. Blood flow reperfusion was assessed up to 4 weeks post-surgery. Capillary density, EC apoptosis and VEGF signaling were evaluated in the ischemic muscle. Src homology region 2 domain-containing phosphatase-1 (SHP-1) phosphatase activity was assessed in vitro using primary ECs. Results: Ischemic muscle of diabetic ec-Prkcdf/f mice exhibited reduced blood flow reperfusion and capillary density while apoptosis increased as compared to nondiabetic ec-Prkcdf/f mice. In contrast, blood flow reperfusion and capillary density were significantly improved in diabetic ec-Prkcd−/− mice. VEGF signaling pathway was restored in diabetic ec-Prkcd−/− mice. The deletion of PKCδ in ECs prevented diabetes-induced VEGF unresponsiveness through a reduction of SHP-1 phosphatase activity. Conclusions: Our data provide new highlights in mechanisms by which PKCδ activation in EC contributed to poor collateral vessel formation, thus, offering novel therapeutic targets to improve angiogenesis in the diabetic limb.

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Mul, D., S. Wu, R. A. de Paus, W. Oostdijk, A. C. Lankester, H. A. van Duyvenvoorde, C. A. L. Ruivenkamp, et al. "A mosaic de novo duplication of 17q21–25 is associated with GH insensitivity, disturbed in vitro CD28-mediated signaling, and decreased STAT5B, PI3K, and NF-κB activation." European Journal of Endocrinology 166, no. 4 (April 2012): 743–52. http://dx.doi.org/10.1530/eje-11-0774.

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ObjectiveThe established causes of GH insensitivity include defects of the GH receptor and STAT5B. The latter condition is also characterized by severe immunodeficiency. A recent case with short stature, GH resistance, and immunodeficiency due to an IκB mutation suggests that the NF-κB pathway may interact with STAT5B signaling.DesignHere, we present a case of a short child with several congenital anomalies as well as GH insensitivity and mild immunodeficiency associated with a mosaic de novo duplication of chromosome 17q21–25, suggesting that overexpression of one of the duplicated genes may be implicated in GH resistance.Methods and resultsIn vitro studies on blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-κB and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-κB activation, PI3K activity, and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. An in silico analysis of the duplicated genes showed that MAP3K3 and PRKCA are associated with the NF-κB pathway. Baseline MAP3K3 expression in T-cell blasts (TCBs) was normal, but PRKCA expression in TCBs and fibroblasts was significantly higher than that in control cells.ConclusionsWe conclude that the 17q21–25 duplication is associated with GH insensitivity and disturbed STAT5B, PI3K, and NF-κB signaling, possibly due to PRKCA mRNA overexpression.

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Qi, Su-Xia, Hui Sun, Hui Liu, Jing Yu, Zhi-Yong Jiang, and Ping Yan. "Role and mechanism of circ-PRKCI in hepatocellular carcinoma." World Journal of Gastroenterology 25, no. 16 (April 28, 2019): 1964–74. http://dx.doi.org/10.3748/wjg.v25.i16.1964.

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Zhang, Yu Wei, Xiao Ying Xu, Jie Zhang, Xin Yao, Chao Lu, Chun Xiao Chen, Chao Hui Yu, and Jing Sun. "Missense mutation in PRKCQ is associated with Crohn's disease." Journal of Digestive Diseases 20, no. 5 (April 23, 2019): 243–47. http://dx.doi.org/10.1111/1751-2980.12717.

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Saarela, Janna, Suvi P. Kallio, Daniel Chen, Alexandre Montpetit, Anne Jokiaho, Eva Choi, Rosanna Asselta, et al. "PRKCA and Multiple Sclerosis: Association in Two Independent Populations." PLoS Genetics 2, no. 3 (March 31, 2006): e42. http://dx.doi.org/10.1371/journal.pgen.0020042.

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Al-Maghtheh, Mai, Eranga N. Vithana, Chris F. Inglehearn, Tony Moore, Alan C. Bird, and Shomi S. Bhattacharya. "Segregation of a PRKCG Mutation in Two RP11 Families." American Journal of Human Genetics 62, no. 5 (May 1998): 1248–52. http://dx.doi.org/10.1086/301819.

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Journal articles on the topic 'PRKCδ'

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