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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The demonstration that RNA can be cleaved by cis or trans ribozymes (catalytic RNAs, RNA enzymes) has potentially important therapeutic implications. Since their discovery in the 1980s, the biochemistry and conserved sequences of ribozymes have been well characterized. Ribozymes are effective modulators of gene expression because of their simple structure, sitespecific cleavage activity, and catalytic potential. The targets of ribozyme-mediated gene modulation have ranged from cancer cells to foreign genes that cause infectious diseases. Additional target sites for ribozymes are in initial phases of development and design. Ribozymes have been targeted against a myriad of genes, including oncogenes (ras, BCR-ABL, c-fos) and drug resistance genes, as well as the human immunodeficiency virus-type I genome. These ribozymes have cleaved the target RNAs in vitro and altered the cellular pathology. Currently, the therapeutic application of ribozymes to human diseases is limited by gene transfer systems. It is anticipated that ribozymes ultimately will play an important role in human gene therapy.
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PMID:Therapeutic applications of ribozymes. 871 70

Wild-type p53 protein displays a spectrum of activities including the ability to suppress transformed cell growth to direct apoptotic cell death and to mediate G1 checkpoint in response to cellular DNA damage. Earlier work showed that a self-association defective p53 protein retained transformation suppressor activity in rat embryo fibroblast based assays, but that monomerisation of tumour mutant p53 proteins resulted in loss of dominant transforming activity. In order to acquire a more detailed understanding of the biological consequences attendant on disruption of p53:p53 association we have carried out a study of the wild-type-like activities that are retained by monomeric p53 proteins and which are associated with the suppression of transformation. Here we show that monomeric p53 proteins are G1 checkpoint defective. Although able to stimulate transcription via a p53 DNA binding motif from the p21waf1/cip1 gene promoter in episome based assays these p53 proteins are unable to transactive the chromosomal p21waf1/cip1 gene and are sensitive both to degeneracy of consensus binding site and to half site spacing. Monomeric p53 proteins fail to trigger apoptosis in a BRK cell line transformed with E7 and ras. However, they retain wild type transformation suppressor activity in BRK cell based transformation assays. Our results indicate that p21waf1/cip1 induction and all related p53 dependent G1 checkpoint activities are dispensable for the p53 directed suppression of transformed cell growth, and that such transformation suppression by monomeric p53 proteins may occur in the absence of an apoptotic response.
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PMID:Selective loss of endogenous p21waf1/cip1 induction underlies the G1 checkpoint defect of monomeric p53 proteins. 876 Mar

The peptide hormone prolactin (Prl) regulates proliferation of normal and malignant mammary cells. In the present study we demonstrate that two Prl responsive cell lines, NOG-8 and T47D, activate the JAK2-SHC-MAPK pathway in a rapid and transient manner. Within 1 min of Prl treatment there was an increase in association of JAK2 with SHC, followed by rapid phosphorylation of both the 52 kDa and 46 kDa SHC proteins. Grb2 and Sos associated with the SHC proteins within 1-3 min of Prl treatment in these mammary cells. Within 5 min of hormone treatment we observe an increase in ras-GTP suggesting activation of ras. We also showed a rapid and transient tyrosine phosphorylation of STAT5 in proliferating T47D cells which reached its peak after 30 min of Prl treatment. These results indicate that Prl receptors, after binding the ligand, activate several pathways for signal transduction leading to mitogenesis.
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PMID:Involvement of SHC, GRB2, SOS and RAS in prolactin signal transduction in mammary epithelial cells. 880 87

We have studied both the expression and the interactions of focal adhesion kinase (FAK) during brain development. We have discovered that during different periods of development, FAK apparently has different properties. During the early stage of neurogenesis, FAK is phosphorylated, shows multiple isoforms, and interacts with the proto-oncogenes, src, fyn, and lyn. At this stage, FAK also interacts with both the N- and C-terminal SH2 domains of GAP, a negative regulator of the ras pathway. During later embryonic development, none of these protein interactions are apparent even though FAK is still predominantly phosphorylated. By adulthood FAK is largely unphosphorylated and migrates as a single protein species on SDS--PAGE. We discuss these results in terms of the dynamic cell movements that occur during embryonic brain development.
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PMID:The regulation of the expression, phosphorylation, and protein associations of pp125FAK during rat brain development. 881 64

Proto-oncogenes are genes coding for factors involved in cellular growth, reproduction, and differentiation. Cancer results through mutations of proto-oncogenes or through other mechanisms involving the products of proto-oncogenes. This study asks whether serum proteins immunologically related to the products of proto-oncogenes distinguish older men and women who manifest a new cancer during a 2-year follow-up. The authors conducted a nested case-control study that involved 248 men and women selected from a larger group of older (age > or = 65 years) healthy volunteers in a randomized clinical trial of preventive clinical services. Study subjects included 37 with a fatal cancer, 59 non-fatal breast, prostate, colon, or lung cancer, 58 hospitalized with at least one discharge diagnosis that coded to benign neoplasia (International Classification of Diseases, 9th Revision codes 210-239), and 94 randomly selected controls. Using seven monoclonal antibodies prepared against ras, erb-B, FES, myb, and SIS polypeptide sequences, immunoblots detected 17 proteins in serum collected from subjects before the clinical recognition of cancer. Five oncogene-related serum proteins appeared to distinguish older persons who manifested fatal (but not non-fatal) cancer over a brief (2-year) follow-up. Older persons hospitalized with benign neoplasia also had higher levels of these serum proteins. Relative to the 94 control subjects, a 52,000 dalton SIS-related protein (odd ratio (OR) = 5.9, 95% confidence interval (CI) 1.4-24.9) and a 35,000 dalton k-ras-related protein (OR = 11.3, 95% CI 1.2-104) were particularly common in serum from the 37 subjects who manifested a fatal cancer.
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PMID:Oncogene-related serum proteins and cancer risk: a nested case-control study. 885 20

The signal transduction of IL-2 in NK cells and T cells was compared. On 5 min incubation of these cells with IL-2, we observed tyrosine phosphorylation of 105-kD and 110-kD proteins in NK cells and of 95-kD and 110-kD proteins in T cells. The phosphorylation reached maximal levels in 15 min in both NK and T cells, but the levels were higher in NK cells, which showed superior killing against Daudi cells. With this phosphorylation, p52rhc was also tyrosine-phosphorylated and p21ras was activated by the short term (10 min) treatment of NK and T cells with IL-2. These signals were completely suppressed by anti-IL-2R beta MoAb, but only slightly suppressed by anti-IL-2R alpha MoAb, correlated with the suppression of the class-I-non-restricted cytotoxic activity of NK and T cells by these MoAbs. When tyrosine phosphorylation was inhibited by herbimycin A and genistein, the cytotoxic activities of NK and T cells were nearly completely suppressed. In addition, the tyrosine phosphorylation of JAK3 by IL-2 was more prominent in NK cells than in T cells, but JAK1, JAK2, STAT1 alpha, STAT2 and STAT3 were not phosphorylated. These results indicate that the IL-2 signal flows downstream via both ras-dependent and ras-independent pathways and that the superior killing activity of NK cells depends on their high susceptibility to protein tyrosine phosphorylation by IL-2.
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PMID:IL-2 signalling in T and natural killer (NK) cells associated with their class I-non-restricted killing activity. 887 Jul 17

A novel neuronal model (PC12EN cells), obtained by somatic hybridization of rat adrenal medullary pheochromocytoma (PC12) and bovine adrenal medullary endothelial (BAME) cells, was developed. PC12EN cells maintained numerous neuronal characteristics: they expressed neuronal glycolipid conjugates, synthesized and secreted catecholamines, and responded to differentiative agents with neurite outgrowth. PC12EN lacked receptors for EGF and both the p75 and trk NGF receptors, while FGF receptor expression was maintained. Staurosporine (5-50 nM), but not other members of the K252a family of protein kinase inhibitors, rapidly induced neurite outgrowth in PC12EN, as also found in the parental PC12 cells, but not in BAME cells. Similarly, both acidic and basic FGF (1-100 ng/ml) were neurotropic in PC12EN. In contrast to the mechanism by which FGF promoted neurite outgrowth in PC12EN, the neurotropic effect of staurosporine did not involve activation of established signalling pathways, such as tyrosine phosphorylation of erk (ras pathway) or SNT (a specific target of neuronal differentiation). In addition, staurosporine induced the tyrosine phosphorylation of the focal adhesion kinase p125FAK. However, since the latter effect was also observed with other protein kinase inhibitors of the K252a family, which induced PC12EN cells flattening but no neurite extension, we propose that FAK tyrosine phosphorylation may be related to ubiquitous changes in cell shape. We anticipate that PC12EN neuronal hybrids will become useful models in neuroscience research for evaluating unique cellular signalling mechanisms of novel neurotropic compounds.
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PMID:Staurosporine induces neurite outgrowth in neuronal hybrids (PC12EN) lacking NGF receptors. 887 7

JAK2, a member of the Janus kinase superfamily was found to interact functionally with Raf-1, a central component of the ras/mitogen-activated protein kinase signal transduction pathway. Interferon-gamma and several other cytokines that are known to activate JAK2 kinase were also found to stimulate Raf-1 kinase activity toward MEK-1 in mammalian cells. In the baculovirus coexpression system, Raf-1 was activated by JAK2 in the presence of p21ras. Under these conditions, a ternary complex of p21ras, JAK2, and Raf-1 was observed. In contrast, in the absence of p21ras, coexpression of JAK2 and Raf-1 resulted in an overall decrease in the Raf-1 kinase activity. In addition, JAK2 phosphorylated Raf-1 at sites different from those phosphorylated by pp60v-src. In mammalian cells treated with either erythropoietin or interferon-gamma, a small fraction of Raf-1 coimmunoprecipitated with JAK2 in lysates of cells in which JAK2 was activated as judged by its state of tyrosine phosphorylation. Taken together, these data suggest that JAK2 and p21ras cooperate to activate Raf-1.
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PMID:The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner. 887 96

Hypo-osmotic stimulation of human Intestine 407 cells rapidly activated compensatory CL- and K+ conductances that limited excessive cell swelling and, finally, restored the original cell volume. Osmotic cell swelling was accompanied by a rapid and transient reorganization of the F-actin cytoskeleton, affecting both stress fibers as well as apical ruffles. In addition, an increase in total cellular F-actin was observed. Pretreatment of the cells with recombinant Clostridium botulinum C3 exoenzyme, but not with mutant enzyme (C3-E173Q) devoid of ADP-ribosyltransferase activity, greatly reduced the activation of the osmo-sensitive anion efflux, suggesting a role for the ras-related GTPase p21rho. In contrast, introducing dominant negative N17-p21rac into the cells did not affect the volume-sensitive efflux. Cell swelling-induced reorganization of F-actin coincided with a transient, C3 exoenzyme-sensitive tyrosine phosphorylation of p125 focal adhesion kinase (p125FAK) as well as with an increase in phosphatidylinositol-3-kinase (PtdIns-3-kinase) activity. Pretreatment of the cells with wortmannin, a specific inhibitor of PtdIns-3-kinase, largely inhibited the volume-sensitive ion efflux. Taken together, our results indicate the involvement of a p21rho signaling cascade and actin filaments in the activation of volume-sensitive chloride channels.
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PMID:Activation of the osmo-sensitive chloride conductance involves P21rho and is accompanied by a transient reorganization of the F-actin cytoskeleton. 888 36

The viability of vertebrate cells depends on survival factors which activate signal transduction pathways that suppress apoptosis. Defects in anti-apoptotic signalling pathways are implicated in many pathologies including cancer, in which apoptosis induced by deregulated oncogenes must be forestalled for a tumour to become established. Phosphatidylinositol-3-kinase (PI(3)K) is involved in the intracellular signal transduction of many receptors and has been implicated in the transduction of survival signals in neuronal cells. We therefore examined the role of PI(3)K, its upstream effector Ras, and its putative downstream protein kinase effectors PKB/Akt and p70S6K (ref. 5) in the modulation of apoptosis induced in fibroblasts by the oncoprotein c-Myc. Here we show that Ras activation of PI(3)K suppresses c-Myc-induced apoptosis through the activation of PKB/Akt but not p70S6K. However, we also found that Ras is an effective promoter of apoptosis, through the Raf pathway. Thus Ras activates contradictory intracellular pathways that modulate cell viability. Induction of apoptosis by Ras may be an important factor in limiting the expansion of somatic cells that sustain oncogenic ras mutations.
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PMID:Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. 902 Mar 62


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