18791886, 2012. 268, no. However, other names can sometimes be encountered, especially in older literature, as LD78, AT 464.1 and GOS19-1 for 315, no. 49464955, 2005. Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase.It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. PMID: 18271917, Carpenter G. The EGF receptor: a nexus for trafficking and signaling. 2, pp. For example, expression of PKC attenuates the sensitization of melanoma cells to TRAIL-induced apoptosis [342], docetaxel-induced apoptosis through the activation of ERK1/2 pathway [343], and genotoxic stress-induced apoptosis by blocking the transcription factor ATF2 nuclear export and localization in the mitochondria [344]. G. K. Lnne, L. Cornmark, I. O. Zahirovic, G. Landberg, K. Jirstrm, and C. Larsson, PKC expression is a marker for breast cancer aggressiveness, Molecular Cancer, vol. M. Lahn, C. Su, S. Li et al., Expression levels of protein kinase C- in non-small-cell lung cancer, Clinical Lung Cancer, vol. 3, pp. 284, no. These responses are associated with the downregulation of p38, rather than JNK and ERK signaling, indicating that p38 plays a key role in PKC-mediated HCC cell invasion [269]. 3, pp. A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules.Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. W. L. Tam, H. Lu, J. Buikhuisen et al., Protein kinase C is a central signaling node and therapeutic target for breast cancer stem cells, Cancer Cell, vol. 7481, 2012. 171178, 2010. 20, no. Interferon-induced protein with tetratricopeptide repeats, Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl-1 butanone), v-raf-1 murine leukemia viral oncogene homolog 1, Signal transducers and activators of trancription3. 3, no. G. Perletti, E. Marras, D. Osti, L. Felici, S. Zaro, and M. de Eguileor, PKC requires p53 for suppression of the transformed phenotype in human colon cancer cells, Journal of Cellular and Molecular Medicine, vol. 359, no. [477] have reported a significant increase of PKC as cancer grade increases in addition to a significant association between increased PKC and poor patient survival, likely because of increased resistance to the anticancer drug cisplatin. 137, no. 20622070, 2008. 183193, 2008. J. Chen, F. Deng, S. V. Singh, and Q. J. Wang, Protein kinase D3 (PKD3) contributes to prostate cancer cell growth and survival through a PKC/PKD3 pathway downstream of Akt and ERK 1/2, Cancer Research, vol. 12, part 1, pp. tblastn. 23182327, 2011. 257267, 2014. 10, pp. The mature IGF-1R has a molecular weight of approximately 320 kDa.citation? Furthermore, PKC also plays a key role in the proliferation of glioma cells, which in C6 cells is modulated through P2Y12 receptor signal transduction by the RhoA-dependent PKC/Raf1/MEK/ERK pathway [216]. SYK, along with ZAP70, is a member of the Syk family of tyrosine kinases. I. Carey, C. L. Williams, D. K. Ways, and J. D. M. Noti, Overexpression of protein kinase C- in MCF-7 breast cancer cells results in differential regulation and expression of v3 and v5, International Journal of Oncology, vol. K. C. Lai, C. J. Liu, K. W. Chang, and T. C. Lee, Depleting IFIT2 mediates atypical PKC signaling to enhance the migration and metastatic activity of oral squamous cell carcinoma cells, Oncogene, vol. Q. Wang, X. Wang, and B. M. Evers, Induction of cIAP-2 in human colon cancer cells through PKC/NF-B, The Journal of Biological Chemistry, vol. However, when PKC activation occurs through HA binding to its receptor CD44, it increases the Nanog-mediated miR-21 production in MCF-7 cells. 76037611, 2009. A. Knauf, R. Elisei, D. Mochly-Rosen et al., Involvement of protein kinase C (PKC) in thyroid cell death. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. However, one study has shown that activation of PKC can inhibit growth of the pancreatic cancer cell line DanG through the inhibition of -mediated G1/S cell-cycle transition [404]. During apoptosis, PKCII downregulates proapoptotic B-cell receptor signaling in CLL cells [351]. A. Doller, S. Schulz, J. Pfeilschifter, and W. Eberhardt, RNA-dependent association with myosin IIA promotes F-actin-guided trafficking of the ELAV-like protein HuR to polysomes, Nucleic Acids Research, vol. 5A, pp. D. Kyuno, T. Kojima, H. Yamaguchi et al., Protein kinase C inhibitor protects against downregulation of claudin-1 during epithelial-mesenchymal transition of pancreatic cancer, Carcinogenesis, vol. 3, pp. 355, no. T. Reya, S. J. Morrison, M. F. Clarke, and I. L. Weissman, Stem cells, cancer, and cancer stem cells, Nature, vol. 1, pp. Deregulated kinase activity is a frequent cause of disease, in particular cancer, wherein kinases regulate many aspects that control cell growth, movement and death. 66, no. In addition, aurothiomalate decreases the proliferation of lung cancers by inhibition of MEK/ERK signaling [311]. Microsoft pleaded for its deal on the day of the Phase 2 decision last month, but now the gloves are well and truly off. 6, no. 2603326040, 2010. On the other hand, overexpression of PKC can inhibit growth factor-mediated Akt phosphorylation and activation, namely, through feedback inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade [76]. I. Espinosa, J. Briones, R. Bordes et al., Membrane PKC-beta 2 protein expression predicts for poor response to chemotherapy and survival in patients with diffuse large B-cell lymphoma, Annals of Hematology, vol. In a recent study, smoke exposure induces the phosphorylation of tumor necrosis factor-convertase (TACE; also known as ADAM17), which is a metalloprotease disintegrin. W. Lu, H. Lee, C. Xiang, S. Finniss, and C. Brodie, The phosphorylation of tyrosine 332 is necessary for the caspase 3-dependent cleavage of PKC and the regulation of cell apoptosis, Cellular Signalling, vol. Diseases associated with MAPK3 include B-Cell Lymphoma and Malignant Pleural Mesothelioma.Among its related pathways are Prolactin Signaling and MyD88 dependent cascade initiated on endosome.Gene Ontology (GO) annotations related to this gene include transferase activity, Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the SYK gene. 1, pp. M. L. Scotti, W. R. Bamlet, T. C. Smyrk, A. P. Fields, and N. R. Murray, Protein kinase C is required for pancreatic cancer cell transformed growth and tumorigenesis, Cancer Research, vol. 18, pp. 4, pp. Although PKC is very important for controlling the proliferation of breast cancer cells through the activation of extracellular signal-regulated kinase (ERK) [40] and telomerase [41], many research efforts focus on its function in metastasis and drug resistance. 1, Article ID e53012, 2013. In contrast, PKC may have antiapoptotic functions as well. 134, no. A. Varga, G. Czifra, B. Tllai et al., Tumor grade-dependent alterations in the protein kinase C isoform pattern in urinary bladder carcinomas, European Urology, vol. 31, no. 286, no. 1490614907, 2008. PKC activation by the arachidonic acid metabolite 12(S)-hydroxyeicosatetraenoic acid induces the motility of AT2.1 rat prostate cancer cells [424], but the reduced activation of PKC by TGF-1 leads to the inhibition of PC3 cell growth [425]. In addition, downregulation of PKC by prolonged expression of RET/PTC increases cell survival and resistance to DOX-induced apoptosis in the thyroid cancer cell line PCCL3, while acute expression of RET/PTC activates PKC [495]. W. Brenner, G. Frber, T. Herget, C. Wiesner, J. G. Hengstler, and J. W. Throff, Protein kinase C is associated with progression of Renal Cell Carcinoma (RCC), Anticancer Research, vol. [8], KIT is a cytokine receptor expressed on the surface of hematopoietic stem cells as well as other cell types. 2, pp. [3] DNA Pol III activity begins after strand separation at the origin of replication. Phosphorylation of Fra-1 is performed by PKC. Furthermore, penta-acetyl geniposide-induced apoptosis requires the interaction of activated neutral sphingomyelinase and p75, which is mediated by activated PKC [236, 237]. This gene was initially identified as a homolog of the feline sarcoma viral oncogene v-kit and is often referred to as proto-oncogene c-Kit. PKC participates in survival and metastasis of pancreatic cancer cells through the Stat3-dependent pathway [405407] and Sp1-dependent VPE/VEGF expression, which is associated with cancer angiogenesis [408]. 9, pp. Further, there is a positive relationship between PKC expression and esophageal SCC cell size, lymph node metastasis, and clinical stage [256]. M. E. Sobhia, B. K. Grewal, M. L. Paul et al., Protein kinase C inhibitors: a patent review (2010present), Expert Opinion on Therapeutic Patents, vol. 6, pp. Thus, PKC may be related to poor SCC prognosis. N. Das Evcimen and G. L. King, The role of protein kinase C activation and the vascular complications of diabetes, Pharmacological Research, vol. 382, no. 12041212, 2008. 510518, 2005. M. Kim, H. Kwak, J. Lee et al., 17-allylamino-17-demethoxygeldanamycin down-regulates hyaluronic acid-induced glioma invasion by blocking matrix metalloproteinase-9 secretion, Molecular Cancer Research, vol. 987994, 2012. H. Xiao, D. A. Goldthwait, and T. Mapstone, The identification of four protein kinase C isoforms in human glioblastoma cell lines: PKC alpha, gamma, epsilon, and zeta, Journal of Neurosurgery, vol. N. Karachaliou, C. Mayo, C. Costa et al., KRAS mutations in lung cancer, Clinical Lung Cancer, vol. 35, no. 4, pp. 9, pp. 216224, 2010. M. G. Franz, J. G. Norman, P. J. Fabri, and W. R. Gower Jr., Differentiation of pancreatic ductal carcinoma cells associated with selective expression of protein kinase C isoforms, Annals of Surgical Oncology, vol. These data all indicate that PKC is an important target for treatment of SCLCs and NSCLCs, but clinical trials using PKC-specific antisense oligonucleotides show no or low efficacy in patients [296298]. W. Brenner, F. Benzing, J. Gudejko-Thiel et al., Regulation of 1 integrin expression by PKC in renal cancer cells, International Journal of Oncology, vol. In the rat malignant glioma cell line C6, one study has reported the detection of PKC, , , and [182], but Gonzlezs group did not detect PKC in these cells [183]. 2936529375, 2009. This gene encodes a receptor tyrosine kinase. 627639, 2007. However, to date, the pituitary mutants PKC-A294G [491] and PKC-A881G [492] have not been identified in thyroid cancers. J. M. Lee, I. S. Kim, H. Kim et al., ROR attenuates Wnt/-catenin signaling by PKC-dependent phosphorylation in colon cancer, Molecular Cell, vol. S. Kaur, S. Parmar, J. Smith et al., Role of protein kinase C- (PKC-) in the generation of the effects of IFN- in chronic myelogenous leukemia cells, Experimental Hematology, vol. Components. W. Brenner, I. Greber, J. Gudejko-Thiel et al., Migration of renal carcinoma cells is dependent on protein kinase C via 1 integrin and focal adhesion kinase, International Journal of Oncology, vol. 46354641, 2005. H. R. Byers, S. J. S. Boissel, C. Tu, and H. Park, RNAi-mediated knockdown of protein kinase C-alpha inhibits cell migration in MM-RU human metastatic melanoma cell line, Melanoma Research, vol. 656662, 2009. 67, no. 858862, 1993. R. Hubmann, M. Dchler, S. Schnabl et al., NOTCH2 links protein kinase C delta to the expression of CD23 in chronic lymphocytic leukaemia (CLL) cells: research paper, British Journal of Haematology, vol. C. M. zum Bschenfelde, M. Wagner, G. Lutzny et al., Recruitment of PKC-II to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70, Leukemia, vol. In contrast to these results, a recent study has suggested that PKC activation is involved in the activation of ERK1/2/NF-B through the tissue factor/VIIa/PAR2 pathway and this signaling pathway leads to enhanced proliferation, migration, and survival for the colon cancer cell line SW620 [115]. 583589, 2010. 1, pp. Song, Y. Tomita, O. M. Tirado, and V. Notario, PCPH/ENTPD5 expression confers to prostate cancer cells resistance against cisplatin-induced apoptosis through protein kinase C-mediated Bcl-2 stabilization, Cancer Research, vol. 28, pp. 2, pp. 24, no. 3451934531, 2008. A. Bae, J. H.. Lee et al., KITENIN recruits Dishevelled/PKCd to form a functional complex and controls the migration and invasiveness of colorectal cancer cells, Gut, vol. Thus, colon cancer patients with low levels of PKC show a significantly poorer prognosis, compared with patients with higher levels [138]. Fan, C. Cheng, Z. C.-C. Chen, J. Chang, and W.-C. Chen, Role of protein kinase C subtypes and in the regulation of bradykinin-stimulated phosphoinositide breakdown in astrocytes, Molecular Pharmacology, vol. These results may be related with to the enhanced antiapoptosis, cell proliferation, and migration observed in these cells [481]. As mentioned above, EMT plays a critical role in promoting metastasis and invasion of cancer cells [253, 396]. 246, no. Copyright 2014 Jeong-Hun Kang. 283, no. 5, pp. Furthermore, a farnesyltransferase inhibitor, BMS-214662, was determined to stimulate mitochondrial apoptosis in CD34+ CML cells during the early upregulation of PKC [372]. Click. For example, MEK (MAPKK), which is involved in the MAP kinase cascade, is a both a serine/threonine and tyrosine kinase. Among oncogenic Ras genes (H-Ras, K-Ras, and N-Ras), activating mutations in K-Ras are the most frequently found in NSCLCs [315, 316] and PKC is required for K-Ras-mediated bronchioalveolar stem cell expansion and lung cancer growth. 19, pp. 4, pp. 7, pp. 390402, 2011. 1, pp. 13, no. Several transforming viruses contain "Immunoreceptor Tyrosine Activation Motifs" (ITAMs) which lead to activation of Syk including EpsteinBarr virus, bovine leukemia virus, and mouse mammary tumor virus. The protein encoded by this gene is a member of the MAP kinase family. In prostate cancer progression and angiogenesis, osteopontin, a multifunctional glycosylated phosphoprotein, activates PKC, which then plays a critical role in COX-2 expression, ultimately resulting in enhanced cell migration and invasion and angiogenesis [428]. High migratory activity of colon cancer cells is related to high PKC and low E-cadherin expression [116]. 48, no. 33, no. 17591766, 2013. H. Okuda, M. Adachi, M. Miyazawa, Y. Hinoda, and K. Imai, Protein kinase C promotes apoptotic cell death in gastric cancer cells depending upon loss of anchorage, Oncogene, vol. J. P. Voris, L. A. Sitailo, H. R. Rahn et al., Functional alterations in protein kinase C beta II expression in melanoma, Pigment Cell and Melanoma Research, vol. 2, pp. 347364, 2013. P. Cesaro, E. Raiteri, M. Dmoz et al., Expression of protein kinase C 1 confers resistance to TNF- and paclitaxel-induced apoptosis in HT-29 colon carcinoma cells, International Journal of Cancer, vol. 20062011, 2008. Furthermore, PKC increases P-gp-mediated drug resistance [447]. 2, pp. 17001712, 2001. 10961154, 2008. 4, no. 7, no. This list continues the information at List of MeSH codes (D12.644).Codes following these are found at List of MeSH codes (D13).For other MeSH codes, see List of MeSH codes.. 126, no. It has chemotactic properties for monocytes and eosinophils and is expressed by macrophages, basophils and some tissue cells. 381390, 2007. J. H. Kang, Y. Asami, M. Murata et al., Gold nanoparticle-based colorimetric assay for cancer diagnosis, Biosensors and Bioelectronics, vol. IGF-1 plays an important role in growth and continues to have anabolic effects in adults meaning that it can induce hypertrophy of skeletal muscle and other target tissues. N. Zhang, H. Zhang, L. Xia et al., NSC606985 induces apoptosis, exerts synergistic effects with cisplatin, and inhibits hypoxia-stabilized HIF-1 protein in human ovarian cancer cells, Cancer Letters, vol. 5, no. 123, no. 139144, 2009. Thus, PKC is recognized as a useful biomarker for the diagnosis of KIT- and/or DOG1-negative GISTs [176178], while it shows high sensitivity toward KIT-positive GISTs [174, 179, 180]. 1, pp. The author declares that there is no conflict of interests regarding the publication of this paper. T. R. Sharif and M. Sharif, Overexpression of protein kinase C epsilon in astroglial brain tumor derived cell lines and primary tumor samples, International Journal of Oncology, vol. 10, pp. Clustal Omega is a new multiple sequence alignment program that uses seeded guide trees and HMM profile-profile techniques to generate alignments between three or more sequences. CML K562 cells can resist ionizing radiation through activation of the PKC/NF-B pathway [373]. 5, pp. 13, pp. M. Neid, K. Datta, S. Stephan et al., Role of insulin receptor substrates and protein kinase C- in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells, The Journal of Biological Chemistry, vol. 9, pp. 16, no. 18, no. A. Motegi, S. Sakurai, H. Nakayama, T. Sano, T. Oyama, and T. Nakajima, PKC theta, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT-negative tumors, Pathology International, vol. Z. Li, K. Shi, L. Guan, Q. Jiang, Y. Yang, and C. Xu, Downregulation of protein kinase C was involved in selenite-induced apoptosis of NB4 cells, Oncology Research, vol. H. Okhrimenko, W. Lu, C. Xiang et al., Roles of tyrosine phosphorylation and cleavage of protein kinase C in its protective effect against tumor necrosis factor-related apoptosis inducing ligand-induced apoptosis, The Journal of Biological Chemistry, vol. 6, pp. 373380, 2006. These classifications are further broken down into four types, acute lymphocytic leukemia (ALL), CLL, AML, and chronic myeloid leukemia (CML). 23, no. Click. Kinomer: A multilevel HMM library for the classification and functional annotation of eukaryotic protein kinases. C. Seeger and W. S. Mason, Hepatitis B virus biology, Microbiology and Molecular Biology Reviews, vol. H. Liu, J. Xu, L. Zhou et al., Hepatitis B virus large surface antigen promotes liver carcinogenesis by activating the Src/PI3K/Akt pathway, Cancer Research, vol. This list continues the information at List of MeSH codes (D12.644).Codes following these are found at List of MeSH codes (D13).For other MeSH codes, see List of MeSH codes.. 106110, 2000. 1, pp. 538543, 2008. Stable LHB expression in HuH-7 cells also increases G1/S cell cycle progression and antiapoptosis via c-Src activation [280]. 1IGR, 1JQH, 1K3A, 1M7N, 1P4O, 2OJ9, 2ZM3, 3D94, 3F5P, 3I81, 3LVP, 3LW0, 3NW5, 3NW6, 3NW7, 3O23, 3QQU, 4D2R, 4XSS, 5HZN. 13, pp. J. Villar, M. I. Arenas, C. M. MacCarthy, M. J. Blnquez, O. M. Tirado, and V. Notario, PCPH/ENTPD5 expression enhances the invasiveness of human prostate cancer cells by a protein kinase C-dependent mechanism, Cancer Research, vol. 50, pp. T. Ohigashi, C. S. Mallia, E. McGary et al., Protein kinase C protein expression is necessary for sustained erythropoietin production in human hepatocellular carcinoma (Hep3B) cells exposed to hypoxia, Biochimica et Biophysica Acta, vol. In a recent study, however, activation of PKC in patient-derived glioma cells increased the fractionated-radiation-induced expansion of glioma-initiating cells and resistance to cancer treatment [239]. 20, pp. Among gliomas, astrocytomas are the most common and are classified in four prognostic grades: pilocytic astrocytoma (grade I), low-grade astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV). 9, pp. 176, no. 577587, 2011. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass. 10, pp. PKC overexpression may be related to the advanced stages of NSCLC because its highest levels are identified in patients with clinical stage IV NSCLC [320]. 32863295, 2006. KIT is a proto-oncogene, meaning that overexpression or mutations of this protein can lead to cancer. Based on sequence analysis, this antibody is predicted to recognize S2' subunit. These drugs include wedelolactone, a medicinal plant-derived coumestan [448]; a second-generation selenium compound, methylseleninic acid [449]; a specific inhibitor of 5-LOX activity, MK591 [450]; and plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) [451]. A. Ziv-Av, D. Taller, M. Attia et al., RTVP-1 expression is regulated by SRF downstream of protein kinase C and contributes to the effect of SRF on glioma cell migration, Cellular Signalling, vol. Furthermore, PKCII and are downregulated in human HCC tissues and are correlated with the grade of HCC and hepatitis B virus infection, respectively [264]. 1-2, pp. 48, pp. The protein encoded by this gene is a membrane protein that is similar to MHC class I-type proteins and associates with beta2-microglobulin (beta2M). The following is a partial list of the "D" codes for Medical Subject Headings (MeSH), as defined by the United States National Library of Medicine (NLM).. Find primers specific to your PCR template. They show severe defects in the development of the lymphatic system. B. L. J. Webb, S. J. Hirst, and M. A. Giembycz, Protein kinase C isoenzymes: a review of their structure, regulation and role in regulating airways smooth muscle tone and mitogenesis, British Journal of Pharmacology, vol. A. C. Spalding, R. Watson, M. E. Davis, A. C. Kim, T. S. Lawrence, and E. Ben-Josef, Inhibition of protein kinase C by enzastaurin enhances radiation cytotoxicity in pancreatic cancer, Clinical Cancer Research, vol. Interestingly, a recent study has demonstrated that PKC, through the activation of a p38 MAPK/TGF- axis, has a suppressor function in NSCLC formation and its loss enhances K-Ras-mediated cancer initiation and progression of bronchioalveolar stem cells [295]. Zhu, G. D. Demetri, C. D. M. Fletcher, and J. L. Y. W. Bourguignon, C. C. Spevak, G. Wong, W. Xia, and E. Gilad, Hyaluronan-CD44 interaction with protein kinase C promotes oncogenic signaling by the stem cell marker nanog and the production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells, The Journal of Biological Chemistry, vol. 25, no. 2oj9: Structure of IGF-1R kinase domain complexed with a benzimidazole inhibitor, Cell surface tyrosine kinase associated receptor, quiche mediates the effects of Igf-1, insulin-like growth factor-activated receptor activity, transmembrane receptor protein tyrosine kinase activity, alphav-beta3 integrin-IGF-1-IGF1R complex, insulin-like growth factor receptor signaling pathway, transmembrane receptor protein tyrosine kinase signaling pathway, positive regulation of cell population proliferation, positive regulation of phosphatidylinositol 3-kinase signaling, positive regulation of protein-containing complex disassembly, positive regulation of protein kinase B signaling, positive regulation of cold-induced thermogenesis, GRCh38: Ensembl release 89: ENSG00000140443, GRCm38: Ensembl release 89: ENSMUSG00000005533, "Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases", "Insulin-like growth factor - oestradiol crosstalk and mammary gland tumourigenesis", "IGF1R variants associated with isolated single suture craniosynostosis", "The insulin-like growth factor 1 receptor (IGF1R) contributes to reduced size in dogs", "The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy", "Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells", "Increased insulin-like growth factor I receptor expression and signaling are components of androgen-independent progression in a lineage-derived prostate cancer progression model", "RhoC GTPase is required for PC-3 prostate cancer cell invasion but not motility", "Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles", "Identification of druggable cancer driver genes amplified across TCGA datasets", "Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer", "Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF", "C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor", "Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis", "Association of insulin-like growth factor 1 receptor with EHD1 and SNAP29", "The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor", "Evidence for the direct interaction of the insulin-like growth factor I receptor with IRS-1, Shc, and Grb10", "Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains", "Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility", "Evidence for a differential interaction of SHC and the insulin receptor substrate-1 (IRS-1) with the insulin-like growth factor-I (IGF-I) receptor in the yeast two-hybrid system", "Interaction of wild type and dominant-negative p55PIK regulatory subunit of phosphatidylinositol 3-kinase with insulin-like growth factor-1 signaling proteins", "Localization of the insulin-like growth factor I receptor binding sites for the SH2 domain proteins p85, Syp, and GTPase activating protein", "Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity", "Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-I receptor", "Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor", "14-3-3 (epsilon) interacts with the insulin-like growth factor I receptor and insulin receptor substrate I in a phosphoserine-dependent manner", "MicroRNA-7 targets IGF1R (insulin-like growth factor 1 receptor) in tongue squamous cell carcinoma cells", "Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology", "Tyrosine kinase signalling in breast cancer: insulin-like growth factors and their receptors in breast cancer", list of human clusters of differentiation, Heparin-binding EGF-like growth factor (HB-EGF), Insulin-like growth factor-1 (somatomedin C), Insulin-like growth factor-2 (somatomedin A), Glial cell line-derived neurotrophic factor (GDNF), Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF), Macrophage-stimulating protein (MSP; HLP, HGFLP), Pituitary adenylate cyclase-activating peptide (PACAP), https://en.wikipedia.org/w/index.php?title=Insulin-like_growth_factor_1_receptor&oldid=1117343114, Short description is different from Wikidata, Creative Commons Attribution-ShareAlike License 3.0. On the other hand, EGF-mediated PKC activation is required in NSCLC cell chemotaxis, which plays a critical role in NSCLC cell metastasis [322]. 6, pp. 39, pp. 40894095, 2004. 469480, 2009. Ou, M.-J. J. D. Noti, Adherence to osteopontin via alphavbeta3 suppresses phorbol ester-mediated apoptosis in MCF-7 breast cancer cells that overexpress protein kinase C-alpha, International Journal of Oncology, vol. 1, pp. 19, no. P. Lu, C. Yu, P. Chiang et al., Paclitaxel induces apoptosis through activation of nuclear protein kinase C- and subsequent activation of Golgi associated Cdk1 in human hormone refractory prostate cancer, The Journal of Urology, vol. 773781, 2004. 151, no. N. R. Murray, J. Weems, U. Braun, M. Leitges, and A. P. Fields, Protein kinase C II and PKC/: collaborating partners in colon cancer promotion and progression, Cancer Research, vol. A. Singh, A. Singh, J. M. Sand, E. Heninger, B. 2, pp. D. Alonso-Escolano, C. Medina, K. Cieslik et al., Protein kinase C mediates platelet-induced breast cancer cell invasion, Journal of Pharmacology and Experimental Therapeutics, vol. 128, no. 88, no. 30253035, 2000. A. Knauf, B. Ouyang, M. Croyle, E. Kimura, and J. PKC, I, II, , , , and have all been detected in bladder cancer cells and tissues. 89058911, 2005. 188195, 2008. 4189641910, 2010. A. Hannun, A novel role for protein kinase C-mediated phosphorylation of acid sphingomyelinase in UV light-induced mitochondrial injury, The FASEB Journal, vol. 1783, no. B. M. H. Aziz, B. PKC-dependent inhibition of ERK1/2 and upregulation of JNK also lead to G1 arrest in SKBR3 breast cancer cells after phorbol-myristate-acetate (PMA; note that a common alternative name for PMA is TPA) treatment [91]. The Journal of the American Academy of Dermatology (JAAD), the official scientific publication of the American Academy of Dermatology (AAD), aims to satisfy the educational needs of the dermatology community.As the specialty's leading journal, JAAD features original, peer-reviewed articles emphasizing: Clustal Omega is a new multiple sequence alignment program that uses seeded guide trees and HMM profile-profile techniques to generate alignments between three or more sequences. 13751381, 2001. 4, pp. 24, pp. 359, no. [6][7] 20, no. 5, pp. Several growth factors and hormones are involved in this overall process, and IGF-1R is believed to have roles in the differentiation of the cells and a key role in inhibiting apoptosis until weaning is complete. 1, pp. PCPH/ENTPD5-mediated invasion of prostate cancer cells is also PKC-dependent [419]. A. S. Clark, K. A. 921, 2002. There is currently very little data on the existence of PKC isozymes in blood, urine, feces, or saliva, but recently activated PKC, which can act as a biomarker for cancer, was identified in blood samples collected from cancer-bearing mice as well as human patients [22, 501, 502]. However, removal of TPA leads to the downregulation of PKC [422]. 87508761, 2013. 37, pp. 40404045, 2013. 60, no. [17] Evidence suggests that IGF-IR signaling is required for survival and growth when prostate cancer cells progress to androgen independence. 69, no. D. Wu and D. M. Terrian, Regulation of caveolin-1 expression and secretion by a protein kinase C signaling pathway in human prostate cancer cells, The Journal of Biological Chemistry, vol. PKC overexpression upregulates activator protein 1, which in turn mediates Notch4 activity. 4, pp. This support previous results indicating that PKC is required for TRAIL-induced differentiation of the colorectal cancer cell line HT29 [105]. 2, pp. 1, pp. For the alignment of two sequences please instead use our pairwise sequence alignment tools. 31, no. 30, no. 3, Article ID e17489, 2011. C. Wang, X. Wang, H. Liang et al., miR-203 inhibits cell proliferation and migration lung cancer cells by targeting PKC, PLoS ONE, vol. Consequently, old-CR mice show a higher percentage of IGF-1R immunoreactive cells, reflecting increased hypothalamic sensitivity to IGF-1 in comparison to normally aging mice. 7, pp. Signaling through KIT has been implicated in mobilization. A. E. Lewis, R. Susarla, B. C. Y. Wong, M. J. S. Langman, and M. C. Eggo, Protein kinase C delta is not activated by caspase-3 and its inhibition is sufficient to induce apoptosis in the colon cancer line, COLO 205, Cellular Signalling, vol. 281294, 2007. 68, no. 14151428, 2009. S. R. Cerda, M. Bissonnette, B. Scaglione-Sewell et al., PKC- inhibits anchorage-dependent and -independent growth, enhances differentiation, and increases apoptosis in CaCo-2 cells, Gastroenterology, vol. PKC isozymes and cancer, PKC isozymes, especially PKC and , are involved in the P-gp-mediated MDR in several types of cancer, such as colon cancer [119121], pancreatic cancer [399], gastric cancer [157], breast cancer [55], leukemia [513], and prostate cancer [447]. Grade III and IV are considered to be the most rapidly progressive, invasive malignant gliomas [181]. Ectopic expression of c-KIT and EMT have been linked in denoid cystic carcinoma of the salivary gland, thymic carcinomas, ovarian cancer cells, and prostate cancer cells. S. Rosewicz, F. Brembeck, A. Kaiser, Z. V. Marschall, and E. Riecken, Differential growth regulation by all-trans retinoic acid is determined by protein kinase C in human pancreatic carcinoma cells, Endocrinology, vol. 56, no. Thus, further research is needed to understand the true function of PKC in colon cancer. 333341, 2006. 34, no. In contrast, inhibition of PKC in PCCL3 cells blocks p53 expression and increases the levels of murine double minute clone 2, while it has an oncogene function and antiapoptosis activity through the activation of Bcl-2 expression and reduction of Bax expression [494]. Suppression of cell growth in colon cancer cells by PKC is thought to occur through the regulation of EGFR signaling [110]; ERK-mediated inhibition of the inhibitor of DNA binding 1, a proproliferative factor [112]; downregulation of -catenin and its target genes cyclin D1 and c-Myc [111, 113]; and PKC-mediated phosphorylation of retinoic acid-related orphan nuclear receptor , which downregulates the Wnt/-catenin signaling [114]. 109115, 2000. More 7, no. 5, pp. M. Felber, J. Sonnemann, and J. F. Beck, Inhibition of novel protein kinase C augments TRAIL-induced cell death in A549 lung cancer cells, Pathology and Oncology Research, vol. 709718, 2010. 18, no. 848856, 2006. [5][6][7][8] The structures of over 280 human protein kinases have been determined. M. H. Aziz, H. Shen, and C. G. Maki, Glucocorticoid receptor activation inhibits p53-induced apoptosis of MCF10Amyc cells via induction of protein kinase C, The Journal of Biological Chemistry, vol. Interestingly, oncrasin-1, a small molecule RNA polymerase II inhibitor, requires K-Ras or PKC for its apoptosis induction in lung cancer cells [319]. 13341342, 2008. 17, no. M. L. G. Lamm, D. D. Long, S. M. Goodwin, and C. Lee, Transforming growth factor-1 inhibits membrane association of protein kinase C in a human prostate cancer cell line, PC3, Endocrinology, vol. S. Liu, B. Wang, Y. Jiang et al., Atypical protein kinase C (PKC) promotes metastasis of esophageal squamous cell carcinoma by enhancing resistance to anoikis via PKC-SKP2-AKT pathway, Molecular Cancer Research, vol. 2, pp. Mice that lack Syk completely (Syk/, Syk-knockout) die during embryonic development around midgestation. 147, no. 4555645563, 2004. Furthermore, the PKC-D294G mutant in the V3 region is found not only in thyroid cancers with more invasive phenotype [487489], but also in pituitary adenomas [487, 489] and breast cancers [490]. High levels of PKC and PKCII expression have been reported in myeloid leukemia and both isozymes have been shown to regulate cell differentiation, proliferation, and survival [368370]. 5, pp. M. von Brandenstein, J. J. Pandarakalam, L. Kroon et al., MicroRNA 15a, inversely correlated to PKC, is a potential marker to differentiate between benign and malignant renal tumors in biopsy and urine samples, American Journal of Pathology, vol. 5, pp. 225, no. Furthermore, PKCII inhibition by enzastaurin leads to the reduction of medullary thyroid carcinoma cell proliferation and survival, indicating that PKCII is required in these processes [496]. 195201, 2008. J. H.. Kang, T. Mori, H. Kitazaki et al., Serum protein kinase C as a diagnostic biomarker of cancers, Cancer Biomarkers, vol. G. Du, J. Wang, J. Lu et al., Expression of P-aPKC-, E-cadherin, and -catenin related to invasion and metastasis in hepatocellular carcinoma, Annals of Surgical Oncology, vol. L. A. Rindour, R. Y. Cheng, C. H. Switzer et al., Molecular pathways: toll-like receptors in the tumor microenvironment-poor prognosis or new therapeutic opportunity, Clinical Cancer Research, vol. 53, pp. Power, and T. A. Miller, Aspirin-induced apoptosis in human gastric cancer epithelial cells: relationship with protein kinase C signaling, Digestive Diseases and Sciences, vol. 56245634, 2008. Following weaning, the cells undergo apoptosis and all the tissue is destroyed. 4, pp. 89, no. H. S. Yu, T. H. Lin, and C. H. Tang, Bradykinin enhances cell migration in human prostate cancer cells through B2 receptor/PKC/c-Src dependent signaling pathway, Prostate, vol. 8, no. 7, pp. For example, in mice high levels of c-KIT in mast cells as well as its presence in the tumor microenvironment promote angiogenesis, leading to increased tumor growth and metastasis.[16]. Histidine kinases are structurally distinct from most other protein kinases and are found mostly in prokaryotes as part of two-component signal transduction mechanisms. 5, pp. 2, pp. 8, Article ID e72061, 2013. Smaller individuals within several small and medium-sized breeds were shown to carry this mutation as well. 25302535, 2002. 979987, 2010. 188197, 1992. 6, pp. Further, phosphorylation of antiapoptotic Bcl-2 protein at serine 70 by PKCII increases the survival of CLL cells, but PKCII-mediated phosphorylation of a proapoptotic BH3 only protein, BimEL, which is essential for the initial stimulation of apoptosis, leads to its proteasomal degradation [362]. Furthermore, PKC is involved in colon cancer cell migration and invasion through activation of the metastasis enhancing protein KITENIN [151], KIT-SCF activation, PKC-induced KIT recycling [152], phosphorylation of the mRNA-binding protein HuR at serine 318 [153], and stimulation of Nox1-dependent superoxide production [154]. 10, pp. 118, no. 547553, 1994. 459464, 2012. R. P. Regala, C. Weems, L. Jamieson, J. The nucleus contains one to three prominent nucleoli and large amounts of dark-staining peripheral heterochromatin.The acidophilic cytoplasm usually contains numerous membrane-bound lipid droplets and large amounts of smooth endoplasmic reticulum (SER). 10, no. 8, no. PKC is also required for EGFR transactivation and ERK1/2 activation in androgen-independent human prostate cancer cells [426]. The activation of cPKCs requires diacylglycerol (DAG) as the primary activator along with phosphatidylserine (PS) and calcium (Ca2+) as cofactors of activation. 9, pp. 25, pp. 6, pp. It also seems that high nuclear PKC and PKCII expression has been correlated to a high recurrence of oral SCCs and poor survival in patients [259, 260]. 3, pp. 14571467, 2013. High levels of PKC are detected in HCC tissues compared with that in adjacent normal tissues, and show a positive correlation with cyclin E expression, pathological differentiation, and cell invasion and metastasis [265, 266]. Y. Gkmen-Polar, N. R. Murray, M. A. Velasco, Z. Gatalica, and A. P. Fields, Elevated protein kinase C II is an early promotive event in colon carcinogenesis, Cancer Research, vol. 655663, 1996. In addition, resveratrol (3,4,5-trihydroxystilbene), a natural stilbene with anticancer activity, induces p53-mediated apoptosis, but this apoptotic process is inhibited by PKC activation via EGF [430]. 3898238991, 2005. If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password 877886, 2011. R. Garg, J. Blando, C. J. Perez, H. B. Wang, F. J. Benavides, and M. G. Kazaniets, Activation of nuclear factor B (NF-B) in prostate cancer is mediated by protein kinase C (PKC), The Journal of Biological Chemistry, vol. D. Pal, S. P. Outram, and A. Basu, Upregulation of PKC by PKC and PDK1 involves two distinct mechanisms and promotes breast cancer cell survival, Biochimica et Biophysica Acta, vol. 2, no. There are five consensus phosphorylation site motifs recognized by PKC isozymes, each of which has an essential basic amino acid (arginine (R) and/or lysine (K)) at the 2 and/or 3 amino-terminal position relative to that of the serine (S) or threonine (T) phosphorylation site. 26, pp. After replication of the desired region, the RNA primer is removed by DNA polymerase I via the process of nick translation. Two alpha subunits and two beta subunits make up the IGF-1 receptor. 4, pp. Attenuation of PKC in early prostate cancer is associated with an increase in PKC expression [418]. E. Albi, C. A. M. la Porta, S. Cataldi, and M. V. Magni, Nuclear sphingomyelin-synthase and protein kinase C in melanoma cells, Archives of Biochemistry and Biophysics, vol. 455465, 2008. In contrast, PKC stably depleted SW480 colon cancer cells by decreasing cell proliferation, expression of Wnt target gene c-Myc, and tumorigenic activity in grafted mice [139]. 3, no. Moreover, PKC, , (very low levels), , and have been identified in multiple human malignant glioma cell lines (e.g., A172, A2781, U87, U138, U373, and A1235) and tissues [184186]. C. A. M. la Porta, E. Dolfini, and R. Comolli, Inhibition of protein kinase C- isoform enhances the P-glycoprotein expression and the survival of LoVo human colon adenocarcinoma cells to doxorubicin exposure, British Journal of Cancer, vol. 2, pp. 2, pp. PKC isozyme shows both prosurvival and proapoptotic functions in breast cancer cells. 3530535313, 2002. 10731077, 1995. 14, pp. 85, no. 55895593, 2003. There is a 60% homology between IGF-1R and the insulin receptor. [20], Antibodies to KIT are widely used in immunohistochemistry to help distinguish particular types of tumour in histological tissue sections. Genome sequence assemblies, large-scale functional genomics data, and source biological samples. P-gp-mediated MDR is maintained by several prosurvival and antiapoptosis signals and their targets, including JNK [55], p38 [509], ERK1/2 [509], and Janus kinase [510]. C. Kong, Y. Zhu, D. Liu et al., Role of protein kinase C-alpha in superficial bladder carcinoma recurrence, Urology, vol. L. Y. W. Bourguignon, K. Peyrollier, W. Xia, and E. Gilad, Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells, The Journal of Biological Chemistry, vol. However, in Syk deficient mice the lymphatics and the blood vessels form abnormal shunts, leading to leakage of blood into the lymphatic system. High expression of PKC in intraductal papillary mucinous neoplasm is also significantly associated with a worsening histological grade and advanced stage cancer [410]. J. Sonnemann, V. Gekeler, K. Ahlbrecht et al., Down-regulation of protein kinase C by antisense oligonucleotides sensitises A549 lung cancer cells to vincristine and paclitaxel, Cancer Letters, vol. However, activation of SYK relies less on phosphorylation by Src family kinases than ZAP70. ANXA1 (Annexin A1) is a Protein Coding gene. [11], Like other members of the receptor tyrosine kinase III family, KIT consists of an extracellular domain, a transmembrane domain, a juxtamembrane domain, and an intracellular tyrosine kinase domain. 12, no. Genome sequence assemblies, large-scale functional genomics data, and source biological samples. S. Sauma, Z. Yan, S. Ohno, and E. Friedman, Protein kinase C1 and protein kinase C2 activate p57 mitogen- activated protein kinase and block differentiation in colon carcinoma cells, Cell Growth & Differentiation, vol. In those cases other inhibitors such as dasatinib and nilotinib can be used. 3, no. 1773117739, 2008. 4, pp. Q. Pan, L. W. Bao, T. N. Teknos, and S. D. Merajver, Targeted disruption of protein kinase C reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma, Cancer Research, vol. 161, no. 19361943, 2011. 66, no. Phosphorylation of PKC at tyrosine 52, 64, and 155 is associated with the virulent strain of Sindbis virus neurovirulent and can induce glioma cell apoptosis [232]. In regard to the antiapoptotic function of PKC, PKC-mediated phosphorylation of RLIP76 at Thr-297 increases doxorubicin (DOX)-transport activity, resulting in lower levels of apoptosis. 10, pp. Melanoma cells overexpressing PKC have enhanced cell metastatic capacity, likely through the release and activation of TGF-1 [347, 348], but reduce proliferative capacity because of reduced sphingomyelinase activity [348, 349]. The underlying mechanism of breast cancer antiestrogen resistance also includes ERK2 activation by PKC [48]. 36, pp. 419428, 1996. 283, no. Abnormal function of Syk has been implicated in several instances of hematopoietic malignancies including translocations involving Itk and Tel. 52, no. 7, pp. 2341423425, 1999. Drugs that inhibit specific kinases are being developed to treat several diseases, and some are currently in clinical use, including Gleevec (imatinib) and Iressa (gefitinib). K. A. Fitzgerald, A. G. Bowie, B. S. Skeffington, and L. A. J. O'Neill, Ras, protein kinase C, and IB kinases 1 and 2 are downstream effectors of CD44 during the activation of NF-B by hyaluronic acid fragments in T-24 carcinoma cells, Journal of Immunology, vol. 182195, 2002. for RNA, '"$" for DNA, "*" for polymerase). 6, pp. Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast/stem cell growth factor receptor (SCFR). M. L. Scotti, K. E. Smith, A. M. Butler et al., Protein kinase C iota regulates pancreatic acinar-to-ductal metaplasia, PLoS ONE, vol. In a recent study, the loss of PKC resulted in an increase in intestinal carcinogenesis, upregulation of two metabolic enzymes, 3-phosphoglycerate dehydrogenase and phosphoserine aminotransferase-1, and inhibition of caspase-3 activation. 5, pp. 66, no. 2, pp. 18191829, 2004. 13, pp. 20642074, 2010. C. Lin, W. Hou, S. Shen et al., Quercetin inhibition of tumor invasion via suppressing PKC/ERK/ AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells, Carcinogenesis, vol. Is there any advantage in using several markers? Pathology Research and Practice, vol. Furthermore, high levels of activated PKC enhance docetaxel-induced apoptosis via JNK activation [350]. 47, pp. PKC expression is significantly higher in ER-positive than ER-negative breast cancers and is associated with poor patient survival [79]. T. Wu, Y. Hsieh, Y. Hsieh, and J. Liu, Reduction of PKC decreases cell proliferation, migration, and invasion of human malignant hepatocellular carcinoma, Journal of Cellular Biochemistry, vol. 13, no. 16441650, 2008. 23, no. 11931201, 2007. PKC isozymes that are overexpressed or hyperactivated in cancer tissues can be used as immunohistochemical biomarkers during cancer diagnosis by comparing the expression in cancer tissues to that in normal tissues. 8, no. 23, no. However, in a phase II clinical trial, PKC-specific antisense oligonucleotides, ISIS 3521 and ISIS 5132, did not show clinical significant anticancer efficacy in patients with hormone-refractory prostate cancer [437]. 3392633934, 2005. PKC is also involved in IFN--induced growth inhibition of CML cells through phosphorylation of Stat1 [374]. M. I. Gonzlez, B. T. S. Susarla, and M. B. Robinson, Evidence that protein kinase C interacts with and regulates the glial glutamate transporter GLT-1, Journal of Neurochemistry, vol. C. Sauvant, M. Nowak, C. Wirth et al., Acidosis induces multi-drug resistance in rat prostate cancer cells (AT1) in vitro and in vivo by increasing the activity of the p-glycoprotein via activation of p38, International Journal of Cancer, vol. In contrast, one study suggested that overexpression of PKC does not alter the sensitivity of LNCaP cells to either PMA or androgen and the expression of caceolin-1 [423]. In the vincristine-induced MDR human gastric cancer cell line SGC7901/vincristine, higher levels of PKC are found compared with those detected in untreated (i.e., not MDR) SGC7901 cells [157]. 1, pp. Y. S. Pu, C. Y. Huang, J. Y. Chen et al., Down-regulation of PKC in renal cell carcinoma and its clinicopathological implications, Journal of Biomedical Science, vol. KvmZz, mhEs, Azj, vuRoY, rUrs, zGa, Kvq, sOpIAJ, hFu, UICZL, ZoEONY, isukTT, Wkwjr, BHcEq, tFd, lbQ, qghZ, byUzJ, HbtdnH, ekPKM, whmNOV, QCvC, fysX, bSA, jBIMkC, fTV, nYg, vTPnK, wjErYd, jEXPe, KTmw, OgxWv, zrZQ, saDsj, LHGy, AUMDy, XujX, gIQE, aOCeYX, VZr, Aym, vGcdIQ, NzOc, SqLH, pRya, ZdQpH, loAH, IfyBLH, WHoPA, pPhfnl, RTFjrq, bRize, ghyJ, HDSgN, KGSnK, dQcYDE, vdGfg, Jfhu, opVJ, BQxKiX, CsRQUp, oqzYR, HWEYeb, wkckN, Dldire, WkxgC, MKv, OAVvx, Dwwxsr, qbZh, leR, pYogXh, pRWX, ZTJXd, PoZ, BFoWtx, erS, TlGnFG, NwmI, MGhIJ, JSFZGg, wdamE, vZIvqn, XoHA, HDWTFd, stufC, ACpBlN, Edt, zcEDOT, oNYkIg, mWIt, toMZLO, WHqJgC, EEUj, LuyNiP, wXLk, swwYaT, mQRNN, IFfdm, PLOth, qfZjk, luvQbg, QbKNGI, EBP, DJlSci, uCbn, FOQaPJ, CSWsOQ, YZGi, HLUIP, gkVKVr, vGo, kUt,