Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elastin peptides (EPs) produced during cancer progression bind to the elastin binding protein (EBP) found at the surface of dermal fibroblasts, leading to the expression of collagenase-1 gene. The production of this enzyme involved in stromal reaction is caused by the sustained activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway via cAMP/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K). However, the mechanism of these signaling events remains unknown. We show that kappa-elastin (kappaE), a commonly used EP, induces maximum phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)1/2 and ERK1/2 after 30 min. The simultaneous inhibition of PKA and PI3K, by N-(2-(p-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide (H89) and 2-(4-morpholynil)-8-phenyl-4H-1-bemzopyran-4-one (LY294002), respectively, blocked MEK1/2 and ERK1/2 phosphorylation, as did lactose, an EBP antagonist. kappaE induced Raf-1 phosphorylation and activation in a PI3K-dependent manner. In our system, the PI3K p110gamma is expressed and activated by betagamma-derived subunits from a pertussis toxin-sensitive G protein after fibroblast stimulation. Pertussis toxin also blocks the Raf-1/MEK1/2/ERK1/2 phosphorylation cascade. In addition, we found that B-Raf is expressed in dermal fibroblasts and activated in a PKA-dependent manner after kappaE treatment, thereby integrating PKA signals to MEK1/2. It is noteworthy that Ras involvement was excluded because ERK1/2 activation by kappaE was not blocked in RasN17-transfected fibroblasts. Together, our results identify a novel Ras-independent ERK1/2 activation system in which p110gamma/Raf-1/MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. Thus, p110gamma and B-Raf seem to be important modulators of dermal fibroblasts physiology and should now qualify as therapeutic targets in strategies aiming at limiting elastin degradation contribution to cancer progression.
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PMID:Elastin peptides activate extracellular signal-regulated kinase 1/2 via a Ras-independent mechanism requiring both p110gamma/Raf-1 and protein kinase A/B-Raf signaling in human skin fibroblasts. 1565 54

Neoplastic transformation is a multistep process in which gene products of specific regulatory pathways are involved at each stage. Identification of these overexpressed or mutated gene products provides an unprecedented opportunity to address the immune system against defined antigens and eliminate transformed cells. Mice transgenic for these oncogenes (e.g. HER-2/neu, a prototype of deregulated oncogenic protein kinase membrane receptors) are ideal experimental models for assessing the potential of active immunization. The demonstration that vaccines can cure HER-2/neu transplantable tumors, prevent their onset and delay the progression of preneoplastic lesions in mice at risk suggests that efficient immunological inhibition of HER-2/neu carcinogenesis can be achieved by specific vaccination. To further explore this issue, halting of tumor progression in the mammary glands of BALB-neuT mice with two immunization protocols in two laboratories has been studied independently by DNA microarray analysis. Combination of the two sets of results revealed a clear correlation between them when the tumor mass was titrated by transcription profiling. It was also clear that both protocols induced a strong, polyclonal antibody response and halted tumor growth at a condition very similar to that at which the vaccination began. Differences in the expression profiles were mainly related to the expression levels of a few chemokines and T-cell-specific genes that may be in some way correlated with the efficacy of the vaccination. Last, combination of the expression data with the protection results indicated that chronic vaccination is needed to maintain an active IFN-gamma-mediated response in the mammary gland.
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PMID:Immune prevention of mammary carcinogenesis in HER-2/neu transgenic mice: a microarray scenario. 1569 Feb 7

beta2-Chimerin is a member of the "non-protein kinase C" intracellular receptors for the second messenger diacylglycerol and the phorbol esters that is yet poorly characterized, particularly in the context of signaling pathways involved in proliferation and cancer progression. beta2-Chimerin possesses a C-terminal Rac-GAP (GTPase-activating protein) domain that accelerates the hydrolysis of GTP from the Rac GTPase, leading to its inactivation. We found that beta2-chimerin messenger levels are significantly down-regulated in human breast cancer cell lines as well as in breast tumors. Adenoviral delivery of beta2-chimerin into MCF-7 breast cancer cells leads to inhibition of proliferation and G(1) cell cycle arrest. Mechanistic studies show that the effect involves the reduction in Rac-GTP levels, cyclin D1 expression, and retinoblastoma dephosphorylation. Studies using the mutated forms of beta2-chimerin revealed that these effects were entirely dependent on its C-terminal GAP domain and Rac-GAP activity. Moreover, MCF-7 cells stably expressing active Rac (V12Rac1) but not RhoA (V14RhoA) were insensitive to beta2-chimerin-induced inhibition of proliferation and cell cycle progression. The modulation of G(1)/S progression by beta2-chimerin not only implies an essential role for Rac in breast cancer cell proliferation but also raises the intriguing possibility that diacylglycerol-regulated non-protein kinase C pathways can negatively impact proliferation mechanisms controlled by Rho GTPases.
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PMID:Rac-GAP-dependent inhibition of breast cancer cell proliferation by {beta}2-chimerin. 1586 13

ARK5, AMP-activated protein kinase (AMPK)-related protein kinase mediating Akt signals, is closely involved in tumor progression, and its stage-associated expression was observed in colorectal cancer. In this study, we found ARK5 expression in multiple myeloma cell lines expressing c-MAF and MAFB. In addition, gene expression profiling of 351 clinical specimens revealed ARK5 expression in primary myelomas expressing c-MAF and MAFB, suggesting that ARK5 may be a transcriptional target of the Large-MAF family. Sequence analysis of the ARK5 gene promoter revealed that it contains two putative MAF-recognition element (MARE) sequences. In support of this hypothesis, ARK5 was induced when an MAFB or c-MAF expression vector was introduced into non-ARK5-expressing colon cancer cells. Furthermore, ARK5 promoter activity was dramatically decreased by mutation or deletion of MARE sequences. Chromatin immunoprecipitation assays revealed an interaction between the Large-MAF family proteins and MARE sequences in the ARK5 promoter. Moreover, in ARK5 mRNA-expressing multiple myeloma lines, but not in ARK5-negative lines, insulin-like growth factor (IGF)-1 increased invasion activity. IGF-1-induced invasion was reproduced when ARK5 was overexpressed in Burkitt's lymphoma and plasmacytoma lines. Based on results, we conclude that ARK5 is a transcriptional target of the Large-MAF family through MARE sequence and that ARK5 may in part mediate the aggressive phenotype associated with c-MAF- and MAFB-expressing myelomas.
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PMID:ARK5 is transcriptionally regulated by the Large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma. 1604 63

Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1-mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression.
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PMID:Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling. 1606 76

We recently reported that proteinase-activated receptors type I (PAR-1) are coupled to both negative and positive invasion pathways in colonic and kidney cancer cells cultured on collagen type I gels. Here, we found that treatments with the cell-permeant analog 8-Br-cGMP and the soluble guanylate cyclase activator BAY41-2272, and Rho kinase (ROK) inhibition by Y27632 or a dominant negative form of ROK lead to PAR-1-mediated invasion through differential Rac1 and Cdc42 signaling. Hypoxia or the counteradhesive matricellular protein SPARC/BM-40 (SPARC: secreted protein acidic rich in cysteine) overexpressed during cancer progression also commutated PAR-1 to cellular invasion through the cGMP/protein kinase G (PKG) cascade, RhoA inactivation, and Rac1-dependent or -independent signaling. Cultured primary cancer cells isolated from peritoneal and pleural effusions from patients with colon cancer or other malignant tumors harbored PAR-1, as shown by RT-PCR and FACS analyses. These malignant effusions also contained high levels of activated thrombin and fibrin, and induced a proinvasive response in HCT8/S11 human colorectal cancer cells. Our data underline the essential role of the tumor microenvironment and of several commutators targeting cGMP/PKG signaling and the RhoA-ROK axis in the control of PAR-1 proinvasive activity and metastatic potential of cancer cells in distant organs and peritoneal or pleural cavities. We also add new insights into the mechanisms linking the coagulation mediators thrombin and PAR-1 in the context of blood coagulation disorders and venous thrombosis often observed in cancer patients, as described in 1865 by Armand Trousseau.
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PMID:Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment. 1609 33

The IkappaB kinase (IKK)/NF-kappaB and phosphatidylinositol 3-OH-kinase/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt pathways regulate various cellular functions, especially cell survival. These two pathways are often activated in many tumors and are thought to be associated with tumor progression. However, the cross-talk between them remains unclear. Here we show that PDK1 can activate IKK/NF-kappaB signaling in addition to Akt signaling to promote cell survival. Screening kinases that could modulate NF-kappaB activity revealed that expression of an upstream Akt kinase PDK1 up-regulates NF-kappaB transcriptional activity. We found that PDK1 directly phosphorylates IKKbeta at the Ser(181) residue in the activation loop, leading to NF-kappaB nuclear translocation and NF-kappaB-dependent anti-apoptotic gene expression. IKKalpha is not required for PDK1-mediated NF-kappaB activation because NF-kappaB activation was observed in IKKalpha(-/-) mouse embryonic fibroblast (MEF) cells as in wild type MEF cells. Akt, which was previously reported to activate IKKalpha, did not participate in the PDK1-dependent IKKbeta or NF-kappaB activation. The siRNA-mediated PDK1 gene silencing attenuated NF-kappaB activity and increased TRAIL-mediated cytotoxicity. Moreover, expression of constitutively active IKKbeta overcame the PDK1 siRNA-mediated susceptibility to TRAIL. These results indicate that PDK1 is a critical regulator of cell survival by modulating the IKK/NF-kappaB pathway in addition to the Akt pathway.
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PMID:3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phosphorylation activates NF-kappaB signaling. 1620 22

Death-associated protein kinase (DAPK) is frequently inactivated by promotor hypermethylation in various human cancers. At present, little is known about the significance of DAPK inactivation in colorectal carcinogenesis. We therefore, investigated macrodissected samples of 22 formalin-fixed and paraffin-embedded T1-carcinomas showing normal colon mucosa, intraepithelial neoplasia and carcinoma tissue on the same slice. Dissected carcinoma areas showed a higher frequency of DAPK promotor methylation (81.2%) compared to intraepithelial neoplasia (68.2%). Colon mucosa adjacent to intraepithelial neoplasia or carcinoma showed DAPK promotor methylation in only two of eight cases (25%). We suggest that DAPK promotor hypermethylation may play an important role in the early steps of tumor progression in colorectal carcinoma.
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PMID:DAPK promotor methylation is an early event in colorectal carcinogenesis. 1624 86

A better understanding of the molecular basis of tumor progression and invasion is needed to improve therapy for malignant tumors. Recently, we established a mouse metastatic MK16 model by transduction of secondary kidney cells with human papillomavirus type 16 (HPV16) E6 and E7 oncogenes and human H-ras activated by G12V mutation. In this study, we extended the model to MK16 cell lines derived from lung metastases and compared the oncogenicity of seven cell lines successively isolated from primary tumors or metastases. By observing the formation and growth of subcutaneous tumors and generation of lung metastasis, we showed a gradual increase in oncogenicity of MK16 cell lines. Interestingly, we demonstrated metastatic potential of MK16/A cells with low oncogenic potential in primary tumor development. To detect changes in gene expression associated with increasing oncogenicity of MK16 cell lines, we performed transcriptional profiling with the Atlas Plastic Mouse 5K microarray. We found that a substantial proportion of up-regulated genes encoded ribosomal proteins. Among the down-regulated genes, the highest number (n=10) belonged to a group coding for transcription factors. Expression of two of these, Pou3f2 and Gtl3, was reduced both in cells derived from primary tumors and those isolated from metastases. Furthermore, microarray hybridization suggested that the down-regulation of cyclin-dependent kinase inhibitors p16(Ink4a) and p57(Kip2) and up-regulation of A6 and A10 members of the S100 protein family might play a role in the increase of MK16 oncogenicity.
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PMID:Analysis of tumor progression by transcriptional profiling of mouse MK16 cell lines transformed with human papillomavirus type 16 E6 and E7 oncogenes and activated H-ras. 1627 73

Cyclooxygenase-2 (COX-2) is well established to play an important role in the tumorigenesis of a variety of human cancers; however, the function of COX-2 in the development of esophageal squamous cell carcinoma (ESCC) remains less clear. Here, we determined, first, the pattern of COX-2 expression in normal esophageal mucosa, dysplasia, carcinoma in situ (CIS) and invasive SCC. Immunohistochemical analysis showed that, while COX-2 was weakly expressed, if at all, in normal squamous epithelium, strong COX-2 expression was detected as early as the stage of dysplasia and frequently in 20 of 26 (77%) CIS and 86 of 111 (77%) invasive SCC. Upregulation of COX-2 in ESCC was found to be significantly associated with tumor progression (R = 0.493, P < 0.01). Further, treatment of human ESCC cell lines (KYSE450 and KYSE510) with NS-398, a COX-2 specific chemical inhibitor, suppressed the production of prostaglandin E2 (PGE2) and induced cell growth inhibition, cell cycle arrest at the G1-S checkpoint, and the expression of cyclin-dependent kinase inhibitors p21waf1/cip1 and p27kip1. Finally, knockdown expression of COX-2 in KYSE450 cells by a specific COX-2 siRNA dramatically inhibited PGE2 production, cell growth and, more importantly, colony formation and tumorigenesis in nude mice. Together, this study suggested that COX-2 may be involved in an early stage of squamous cell carcinogenesis of the esophagus and has a non-redundant role in the regulation of cellular proliferation and tumorigenesis of esophageal epithelial cells.
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PMID:Significance of COX-2 expression in human esophageal squamous cell carcinoma. 1635 17


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