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)

Lipoprotein-associated coagulation inhibitor (LACI) inhibits activated Factor X (Xa) directly and, in an Xa-dependent fashion, inhibits Factor VIIa-tissue factor (TF), presumably by forming a quaternary Xa-LACI-VIIa-TF complex. LACI isolated from the conditioned media of HepG2 cells grown in the presence of [32P]orthophosphate was observed to be covalently phosphorylated. Dephosphorylation of 32P-LACI with phosphatase resulted in an almost complete removal of the radiolabel. Phosphoamino acid analysis of the purified 32P-LACI established that the phosphorylation occurred on (a) serine residue(s). At its N-terminus, LACI contains a cluster of acidic residues C-terminal to the serine-2 residue. Such a site is characteristic of the sites phosphorylated by casein kinase II (CKII) in protein substrates. Edman degradation of endogenously labelled 32P-LACI revealed that the serine-2 residue was a major site of phosphorylation. Phosphorylation of purified LACI by bovine CKII was observed to occur in vitro; amino acid sequence analysis demonstrated that CKII phosphorylated LACI at the serine-2 residue. Recombinant LACI expressed from mouse C127 fibroblasts transfected using a bovine-papilloma-virus expression vector was found to be endogenously phosphorylated. By using site-directed mutagenesis, an altered form of LACI was produced in which the serine-2 residue had been changed to alanine. This altered LACI, although expressed in similar quantity to the wild-type LACI, was not detectably phosphorylated. Using the altered LACI in functional studies demonstrated that a serine residue at position 2, and thus the phosphorylation of this site, was not essential for LACI's inhibition of Xa and VIIa-TF activities.
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PMID:Endogenous phosphorylation of the lipoprotein-associated coagulation inhibitor at serine-2. 212 83

We have purified and characterized the 50 kd activator protein 2 (AP-2), another enhancer-binding protein interacting with the human metallothionein IIA (hMT-IIA) gene control region. Purified AP-2 activates transcription in vitro from a hybrid promoter containing hMT-IIA upstream sequences. AP-2 also recognizes control elements of the human growth hormone, c-myc, and H-2Kb genes, and the SV40 and bovine papilloma virus enhancers. Multiple synthetic copies of the hMT-IIA high-affinity AP-2 binding site can act as efficient, cell-type-specific enhancer elements; their activity increases after treatment of cells with phorbol ester or cAMP-elevating agents. In contrast, a synthetic enhancer recognized by factor AP-1 is activated only by phorbol ester. AP-2 appears to mediate transcriptional activation in response to two different signal-transduction pathways, one involving the phorbol-ester- and diacylglycerol-activated protein kinase C, the other involving cAMP-dependent protein kinase A.
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PMID:Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP. 282 55

In normal human diploid fibroblasts, cyclins of the A, B, and D classes each associate with cyclin-dependent kinases (CDKs), proliferating cell nuclear antigen (PCNA), and p21, thereby forming multiple independent quaternary complexes. Upon transformation of diploid fibroblasts with the DNA tumor virus SV40, or its transforming tumor antigen (T), the cyclin D/p21/CDK/PCNA complexes are disrupted. In transformed cells, CDK4 totally dissociates from cyclin D, PCNA, and p21 and, instead, associates exclusively with a polypeptide of 16 kD (p16). Quaternary complexes containing cyclins A or B1 and p21/CDK/PCNA also undergo subunit rearrangement in transformed cells. Both PCNA and p21 are no longer associated with CDC2-cyclin B1 binary complexes. Cyclin A complexes no longer contain p21, and a new 19-kD polypeptide (p19) is found in association with cyclin A. The pattern of subunit rearrangement of cyclin-CDK complexes in SV40-transformed cells is also shared in those containing adeno- or papilloma viral oncoproteins. Rearrangement also occurs in p53-deficient cells derived from Li-Fraumeni patients that carry no known DNA tumor virus. These findings suggest a mechanism by which oncogenic proteins alter the cell cycle of transformed cells.
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PMID:Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. 810 26

By performing in vitro kinase assays we found in papilloma producing 308 mouse keratinocytes that okadaic acid elevated activities of extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinases (MAPKs). This okadaic acid mediated activation of MAP kinases correlated with increased AP-1 binding to a consensus TPA responsive element (TRE) and elevated TRE dependent transcription. To determine the role of p38 MAP kinases in these processes we employed the specific p38 MAP kinase inhibitor SB 203580. Using orthophosphate labeling we showed a decrease in phosphorylation of MAPK activated protein kinase-2 (MAPKAP-K2) indicating reduced activity of p38 MAPKs utilizing this kinase as substrate. In contrast, we found that SB 203580 raised activities of ERK-1/2 and JNKs. Electrophoretic mobility shift assays revealed an increase in TRE binding activity in response to SB 203580 most likely resulting from increased expression of the major TRE binding components JunD and FosB as indicated by Western blot analyses. Increased TRE DNA binding failed to lead to increased transactivation correlating with the inability of SB 203580 to increase phosphorylation of these AP-1 proteins. These data indicate that SB 203580 sensitive p38 MAP kinases are not involved in okadaic acid mediated increases in TRE DNA binding and transactivation.
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PMID:Inhibition of p38 MAP kinase increases okadaic acid mediated AP-1 expression and DNA binding but has no effect on TRE dependent transcription. 1038 Aug 84

To determine the role of protein kinase Cdelta in mouse skin carcinogenesis, we have developed transgenic FVB/N mouse lines expressing in the epidermis an epitope-tagged protein kinase Cdelta (T7-PKCdelta) regulated by the human keratin 14 promoter. The untreated T7-PKCdelta mice displayed excessive dryness in the skin of the tail with a variable penetrance over time. Histologically, the tail skin showed hyperplasia with evidence of hyperkeratosis. The epidermis of the rest of the T7-PKCdelta mouse was unremarkable. Despite this mild phenotype, the effects of PKCdelta overexpression on mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) were dramatic. Two independent lines of T7-PKCdelta mice (16 and 37) expressing the T7-PKCdelta transgene were examined for responsiveness to skin tumor promotion by 7,12-dimethylbenz[a]anthracene and TPA. By immunoblot analysis, the T7-PKCdelta-16 and T7-PKCdelta-37 mice showed an 8- and 2-fold increase of PKCdelta protein. The T7-PKCdelta-16 mice averaged 300% more T7-PKCdelta activity than the T7-PKCdelta-37 mice did. The T7-PKCdelta-37 mice did not manifest any difference in tumor burden or incidence. However, the reduction in papilloma burden at 25 weeks of promotion for the T7-PKCdelta-16 mice relative to wild-type mice averaged 72 and 74% for males and females, respectively. The T7-PKCdelta-16 mice reached 50% papilloma incidence between 12 and 13 weeks of promotion compared with 8 weeks for wild-type mice. Furthermore, the carcinoma incidence was also reduced in T7-PKCdelta-16 mice. Carcinoma incidence at 25 weeks of promotion treatment was: wild-type females, 78%; T7-PKCdelta16 females, 37%; wild-type males, 45%; and T7- PKCdelta-16 males, 7%. Thus, PKCdelta when expressed at sufficient levels can suppress skin tumor promotion by TPA.
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PMID:Transgenic mice overexpressing protein kinase Cdelta in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. 1058 89

We have evaluated the in vivo correlation between the expression of cell cycle markers and skin tumor development in SKH-1 hairless mice in a complete photocarcinogenesis protocol. Irradiated mice developed an average of 16 tumors per animal by week 23 with the average number of carcinomas per mouse being 2.1. The expression of p53 and cyclins A and D1 was confined initially to sporadic single cells and gradually developed into foci of patchy intense staining in the basal and granular layers of UVB-exposed epidermis. p53 was expressed in all the papilloma sections examined, whereas cyclins D1 and A were expressed in 68 and 71% of these lesions, respectively. In UVB-induced squamous cell carcinomas (SCC), p53 was expressed in >90% of the tumors, whereas cyclin D1 was detected in 55% of the lesions, and cyclin A staining was limited to 27%. These immunohistochemical observations were confirmed by Western blotting and protein kinase assays. We observed an early wave of cyclin A overexpression and cyclin A protein kinase activity preceding the appearance of detectable tumors. Cyclin D1 and p53 overexpression were coupled with the development of tumors, and these changes are likely to be relevant to the pathogenesis of these lesions.
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PMID:Stage-specific alterations of cyclin expression during UVB-induced murine skin tumor development. 1183 28

This study reports in vivo therapeutic efficacy of silymarin against skin tumors with mechanistic rationale. 7,12-Dimethylbenz[a]anthracene-12-O-tetradecanoyl-phorbol-13-acetate (DMBA-TPA)-induced established skin papilloma (tumor)-bearing SENCAR mice were fed with 0.5% silymarin in AIN-93M-purified diet (w/w), and both tumor growth and regression were monitored during 5 weeks of feeding regimen. Silymarin feeding significantly inhibited (74%, P < 0.01) tumor growth and also caused regression (43%, P < 0.01) of established tumors. Proliferating cell nuclear antigen and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling immunohistochemical staining of tumors showed that silymarin decreases proliferation index by 48% (P < 0.001) and increases apoptotic index by 2.5-fold (P < 0.001), respectively. Skin tumor growth inhibition and regression by silymarin were also accompanied by a strong decrease (P < 0.001) in phospho-ERK1/2 levels in tumors from silymarin-fed mice compared with controls. In the studies evaluating bioavailability and physiologically achievable level of silymarin (as silibinin) in plasma, skin tumor, skin, liver, lung, mammary gland and spleen, we found 10, 6.5, 3.1, 13.7, 7.7, 5.9 and 4.4 microg silibinin/ml plasma or per gram tissue, respectively. In an attempt to translate these findings to human skin cancer and to establish biological significance of physiologically achievable level, effect of plasma concentration of silibinin was next examined in human epidermoid carcinoma A431 cells. Silibinin treatment of cells in culture at 12.5, 25 (plasma level) and 50 microM doses resulted in 30-74% (P < 0.01-0.001) growth inhibition and 7-42% death of A431 cells in a dose- and time-dependent manner; apoptosis was identified as a cell death response by silibinin. Similar silibinin treatments also resulted in a significant decrease in phospho-mitogen-activated protein kinase/extracellular signal-regulated protein kinase 1/2 (MAPK/ERK1/2) levels, but an up-regulation of stress-activated protein kinase/jun NH(2)-terminal kinase (SAPK/JNK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) activation in A431 cells. The use of MEK1 inhibitor, PD98059, showed that inhibition of ERK1/2 signaling, in part, contributes to silibinin-caused cell growth inhibition. Together, the data suggest that an inhibition of ERK1/2 activation and an increased activation of JNK1/2 and p38 by silibinin could be possible underlying molecular events involved in inhibition of proliferation and induction of apoptosis in A431 cells. These data suggest that silymarin and/or its major active constituent silibinin could be an effective agent for both prevention and intervention of human skin cancer.
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PMID:Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis. 1189 66

In Drosophila and Caenorhabditis elegans, kinase suppressor of ras (KSR) positively modulates Ras/Raf-mitogen-activated protein kinase (MAPK) signaling. The precise signaling mechanism of mammalian KSR1 and its role in Ras-mediated transformation, however, remain uncertain. To gain insight into KSR1 function in vivo, we generated mice homozygous null for KSR1. ksr1-/- mice are viable and without major developmental defects. However, an unusual disorganized hair follicle phenotype manifest in epidermal growth factor receptor knockout mice is recapitulated in ksr1-/- mice, providing genetic support for the notion that epidermal growth factor receptor, Ras, and KSR1 are on the same signaling pathway in mammals. Furthermore, ksr1-/- mice allow for the definition of KSR1-dependent and -independent mechanisms of c-Raf-1 activation. In embryonic fibroblasts, epidermal growth factor and 12-O-tetradecanoylphorbol-13-acetate activated the MAPK cascade to a similar extent, yet only c-Raf-1 activation by epidermal growth factor depended on KSR1. Moreover, whereas the genesis of polyomavirus middle T antigen (MT)-driven mammary cancer appears independent of KSR1, KSR1 is obligate for v-Ha-ras-mediated skin tumor formation. The growth of MT-driven mammary tumor was moderately slowed in ksr1-/- mice, however, consistent with a decreased rate of proliferation of ksr1-/- cells (T cells and embryonic fibroblasts). Nonetheless, all ksr1-/- animals succumbed to mammary cancer. In contrast, papilloma formation in Tg.AC mice, resulting from skin-specific v-Ha-ras expression, was completely abrogated in the ksr1-/- background. Hence, MT-driven mammary tumor genesis, which is signaled through src and phosphatidylinositol 3'-kinase, appears KSR1 independent, whereas v-Ha-ras-mediated skin cancer, signaled through the Raf-1/MAPK cascade, requires KSR1. These results suggest KSR1 may represent a therapeutic target for Ras/MAPK signaling of human tumorigenesis.
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PMID:Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. 1287 31

To investigate changes in cellular gene expression associated with malignant progression, we identified differentially expressed genes in a cottontail rabbit papillomavirus (CRPV) squamous carcinoma model employing New Zealand White rabbits. The technique of suppression subtractive cDNA hybridization was applied to pairs of mRNA isolates from CRPV-induced benign papillomas and carcinomas, with each pair derived from the same individual rabbit. The differential expression of 23 subtracted cDNAs was further confirmed by quantitative reverse transcription-PCR (RT-PCR) with additional biopsies. Eight papilloma-carcinoma pairs examined showed a constant upregulation of the transcripts for the multifunctional adaptor protein 14-3-3 zeta and the Y-box binding transcription factor YB-1, whereas transcripts for m-type calpain 2 and NB thymosin beta, which are involved in cell motility and tissue invasion, as well as casein kinase 1 alpha, chaperonin, and annexin I, were found to be upregulated in the majority of the cases. RNA-RNA in situ hybridization and laser capture microdissection in combination with quantitative RT-PCR analysis verified the deregulated expression of the transcripts in the tumor cells. In contrast, CRPV E7 transcript levels remained rather constant indicating no requirement for a further upregulation of E7 expression following tumor induction. Small interfering RNA-mediated interference with expression of genes encoding YB-1, m-type calpain 2, or NB thymosin beta in a CRPV-positive cell line established from New Zealand White rabbit keratinocytes resulted in decreased cell invasion in matrigel chamber assays.
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PMID:Gene profiling of cottontail rabbit papillomavirus-induced carcinomas identifies upregulated genes directly Involved in stroma invasion as shown by small interfering RNA-mediated gene silencing. 1522 Apr 21

Epidermal growth factor receptor (EGFR) signaling regulates a variety of cellular functions, including proliferation, gene expression, and differentiation. Infection of laryngeal epithelial cells by human papillomaviruses causes recurrent respiratory papillomas, benign tumors characterized by an altered pattern of differentiation. Papilloma cells overexpress the EGFR and have constitutively active extracellular signal-regulated kinase (ERK) and enhanced phosphatidylinositol 3-kinase (PI3K) activity, but overexpression of the lipid phosphatase PTEN (Phosphatase and Tensin Homolog) reduces activation of Akt by PI3K. We hypothesized that the altered differentiation of papillomas reflects these changes in signaling from the EGFR-ERK and PI3K-Akt pathways and that one or both of these pathways is required for the normal differentiation process in mucosal epithelium. Inhibiting either the enzymatic activity or the synthesis of PI3K in uninfected laryngeal cells blocked expression of keratin-13 (K13), a protein induced during normal differentiation. In contrast, inhibiting activation of ERK had minimal effect. Using ribonucleic acid interference to reduce protein levels of integrin-linked kinase 1 or phosphoinositide-dependent protein kinase 1, intermediates in the activation of Akt by PI3K, or reducing levels of Akt-1 itself did not inhibit K13 expression by normal laryngeal keratinocytes. We conclude that PI3K activation is an important regulator of expression of K13, a marker for the normal differentiation process in human mucosal keratinocytes, that this function does not require activation of Akt-1, and that the failure to express K13 in papilloma cells is not because of reduction in activated Akt.
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PMID:Phosphatidylinositol 3-kinase regulates early differentiation in human laryngeal keratinocytes. 1602 72


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