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 expression of 10 protooncogenes has been quantitatively studied in liver of male rats L10 age of 1, 10.5, 22 and 37 months. It was shown that a number of specific mRNA transcripts and, therefore, the levels of expression of protooncogenes C-MYC, C-FOS, N-MYC, HA-RAS, KI-RAS, SIS, ABL, YES, MOS and MET in rat liver were constant during life span. These data are in accordance with resistance of the rat strain L10 to spontaneous hepatocarcinogenesis.
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PMID:[Proto-oncogene expression in the liver of male rats of different age]. 171 16

The expression and function of several proto-oncogenes were examined in a human acute T cell leukemia line, JURKAT, during phorbol ester-induced terminal differentiation. Treating JURKAT cells with the phorbol ester tetradecanoyl phorbol acetate (TPA) inhibited their proliferation and induced expression of the gene for the interleukin 2 receptor alpha chain (IL2R-alpha), consistent with previous reports. In unstimulated proliferating JURKAT cells, high levels of C-MYC, N-RAS, and BCL2 mRNAs were found that diminished rapidly following TPA-induced cessation of growth. In contrast, accumulation of mRNAs for the C-FOS, C-JUN, and EGR-1 genes increased markedly in TPA-treated cells and preceded the induction of IL2R-alpha mRNA. Expression of C-MYB, C-RAF-1, C-LCK, C-FYN, and C-FGR proto-oncogenes was relatively unchanged. To explore directly the function of two of these protooncogenes in regulating the growth of JURKAT T cells, we stably transferred C-MYC and BCL2 expression plasmids into these cells. Despite sustained expression of C-MYC, BCL2, or the combination of these protooncogenes, TPA continued to inhibit JURKAT cell growth and to induce IL2R expression. Thus, although C-MYC and BCL2 proto-oncogene expression correlated with proliferation in TPA-treated JURKAT cells, continuous over-expression of even the combination of these oncogenes was insufficient for abrogating the effects of TPA in these leukemic T cells. Because human lymphoid malignancies frequently contain chromosomal translocations that deregulate the expression of C-MYC and BCL2, our findings could have relevance for attempts to induce terminal differentiation of leukemic cells by in vitro exposure of patients' bone marrow cells to phorbol esters.
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PMID:Phorbol ester-mediated inhibition of growth and regulation of proto-oncogene expression in the human T cell leukemia line JURKAT. 201 1

We tested the hypothesis that wild-type p53 activity is required for c-Myc-dependent apoptosis in epithelial cells. Primary baby rat kidney epithelial cell lines were generated by immortalization through the concerted action of c-Myc and a temperature-sensitive (ts) dominant inhibitory mutant allele of p53 (BRK myc/p53ts cells). When shifted to the permissive temperature for wild-type p53 activity, the BRK myc/p53ts cells underwent growth arrest and apoptosis. However, apoptosis also could be induced by serum deprivation at the nonpermissive temperature, when p53 was in the mutant state. Bcl-2 suppressed both modes of cell death. Apoptosis induced by wild-type p53 but not by serum deprivation was accompanied by G1 cell cycle arrest and increased expression of the Bcl-2 antagonist Bax. We concluded that c-Myc could induce apoptosis in epithelial cells by at least two mechanisms that could be distinguished by their p53 requirement. Our results support the possibility that c-Myc-dependent cell death might be exploited for therapeutic ends during carcinoma development, without regard to p53 status of the target cell.
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PMID:c-Myc induces apoptosis in epithelial cells by both p53-dependent and p53-independent mechanisms. 857 Jan 93

The product of the c-myc proto-oncogene has a central role in induction of apoptosis, a physiological form of cell death characterised in vitro by morphological rounding, detachment and nuclear disintegration. Induction of apoptosis by serum withdrawal from c-Myc-transformed chicken embryo fibroblasts (CEF) results in early proteolysis of focal adhesion kinase (ppl25FAK), a tyrosine kinase implicated in the conversion of integrin signals into their biological responses. Proteolysis of pp125 FAK occurs in adherent cells prior to commitment to death, suggesting that it contributes to c-Myc-induced apoptosis, rather than being a consequence of it. Furthermore, c-Myc-induced detachment, cell death and cleavage of pp125FAK are coordinately suppressed by treating with insulin or plating on the extracellular matrix components collagen and fibronectin. In addition, proteolysis of pp125FAK is suppressed by a beta1-specific integrin antibody, which promotes cell survival in the face of the oncoprotein-induced signal for apoptosis. These results provide compelling evidence that the c-Myc-induced cell death programme in CEF requires disruption of the integrin signalling pathways which normally function when cells are spread on ECM, and that maintaining cellular pp125FAK, which couples integrins to their downstream effectors, is closely linked to cell survival.
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PMID:Targeted proteolysis of the focal adhesion kinase pp125 FAK during c-MYC-induced apoptosis is suppressed by integrin signalling. 870 May 28

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

RIN1 was originally identified by its ability to physically bind to and interfere with activated Ras in yeast. Paradoxically, RIN1 potentiates the oncogenic activity of the BCR-ABL tyrosine kinase in hematopoietic cells and dramatically accelerates BCR-ABL-induced leukemias in mice. RIN1 rescues BCR-ABL mutants for transformation in a manner distinguishable from the cell cycle regulators c-Myc and cyclin D1 and the Ras connector Shc. These biological effects require tyrosine phosphorylation of RIN1 and binding of RIN1 to the Abl-SH2 and SH3 domains. RIN1 is tyrosine phosphorylated and is associated with BCR-ABL in human and murine leukemic cells. RIN1 exemplifies a new class of effector molecules dependent on the concerted action of the SH3, SH2, and catalytic domains of a cytoplasmic tyrosine kinase.
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PMID:Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RIN1. 920 49

The proliferative capacity of T cells infiltrating human tumors is known to be impaired, possibly through their interaction with tumor. Here we demonstrate that soluble products derived from renal cell carcinoma (RCC-S) explants but not normal kidney can inhibit an IL-2-dependent signaling pathway that is critical to T cell proliferation. A major target of the immunosuppression was the IL-2R-associated protein tyrosine kinase, Janus kinase 3 (Jak3). RCC-S suppressed basal expression of Jak3 and its increase following stimulation with anti-CD3/IL-2. Jak3 was most sensitive to suppression by RCC-S; however, reduction in expression of p56(lck), p59(fyn), and ZAP-70 was observed in some experiments. Expression of other signaling elements linked to the IL-2R (Jak1) and the TCR (TCR-zeta, CD3-epsilon, and phospholipase C-gamma) were minimally affected. In naive T cells, RCC-S also partially blocked induction of IL-2R alpha-, beta- and gamma-chain expression when stimulating via the TCR/CD3 complex with anti-CD3 Ab. To determine whether RCC-S suppressed IL-2-dependent signaling, primed T cells were employed since RCC-S had no effect on IL-2R expression but did down-regulate Jak3 expression and, to a lesser degree, p56(lck) and p59(fyn). Reduction in Jak3 correlated with impaired IL-2-dependent proliferation and signal transduction. This included loss of Jak1 kinase tyrosine phosphorylation and no induction of the proto-oncogene, c-Myc. These findings suggest that soluble products from tumors may suppress T cell proliferation through a mechanism that involves down-regulation of Jak3 expression and inhibition of IL-2-dependent signaling pathways.
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PMID:Tumor-induced suppression of T lymphocyte proliferation coincides with inhibition of Jak3 expression and IL-2 receptor signaling: role of soluble products from human renal cell carcinomas. 930 Jul 31

Survival signalling by ligand-activated tyrosine kinase receptors plays a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains and pathways involved in survival signalling, the nerve growth factor receptor TrkA was expressed in Rat-1/MycER fibroblasts. We demonstrate that wt-TrkA receptor delays c-Myc-, U.V.- and Cycloheximide-induced apoptosis and activates targets such as the mitogen-activated protein kinase (MAPK) Erk2 and the serine/threonine kinase Akt/PKB, both of which have been implicated in survival signalling. TrkA mutated within its SHC binding site (Y490F) delays c-Myc-induced apoptosis without activating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant receptor does not delay U.V.-induced apoptosis whilst TrkA mutated at its PLC-gamma binding site (Y785F) is capable of protecting from apoptosis induced by c-Myc or U.V. treatment. The double mutant TrkA YY490/785FF fails to block either of these two apoptotic stimuli. While P13-kinase inhibitors LY294002 and Wortmannin completely block survival signalling following U.V. treatment, neither drug affects the ability of TrkA to block c-Myc-induced apoptosis. We show that the Akt/PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V.-induced apoptosis, but that apoptosis induced by c-Myc is also blocked by a novel, Akt/PKB-independent, pathway. These observations suggest that TrkA can activate different survival signalling pathways, which can interfere with specific apoptotic pathways.
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PMID:Specific TrkA survival signals interfere with different apoptotic pathways. 948 73

The decision between survival and death is an important aspect of cellular regulation during development and malignancy. Central to this regulation is the process of apoptosis, which is conserved in multicellular organisms [1]. A variety of signalling cascades have been implicated in modulation of apoptosis, including the phosphatidylinositol (Pl) 3-kinase pathway. Activation of Pl 3-kinase is protective, and inhibition of this lipid kinase enhances cell death under several conditions including deregulated expression of c-Myc, neurotrophin withdrawal and anoikis [2-7]. Recently, the protective effects of Pl 3-kinase have been linked to its activation of the pleckstrin homology (PH)-domain-containing protein kinase B (PKB or AKT) [8]. PKB/AKT was identified from an oncogene, v-akt, found in a rodent T-cell lymphoma [9]. To initiate a genetic analysis of PKB, we have isolated and characterized a Drosophila PKB/AKT mutant (termed Dakt1) that exhibits ectopic apoptosis during embryogenesis as judged by induction of membrane blebbing, DNA fragmentation and macrophage infiltration. Apoptosis caused by loss of Dakt function is rescued by caspase suppression but is distinct from the previously described reaper/grim/hid functions. These data implicate Dakt1 as a cell survival gene in Drosophila, consistent with cell protection studies in mammals.
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PMID:Genetic analysis of protein kinase B (AKT) in Drosophila. 960 46

The mechanism by which early lymphoid cells are selectively transformed by v-Abl is currently unknown. Previous studies have shown constitutive activation of IL-4 and IL-7 signaling pathways, as measured by activation of Janus protein kinase (JAK)1, JAK3, STAT5, and STAT6, in pre-B cells transformed by v-Abl. To determine whether activation of these cytokine signaling pathways by v-Abl is important in the cellular events induced by the Abelson murine leukemia virus, the effects of IL-4 and IL-7 on pre-B cells transformed with a temperature-sensitive v-Abl mutant were examined. Whereas IL-4 had little or no effect, IL-7 delayed both the apoptosis and cell cycle arrest that occur upon v-Abl kinase inactivation. IL-7 also delayed the decreases in the levels of c-Myc, Bcl-2, and Bcl-xL that occur upon loss of v-Abl kinase activity. IL-7 did not maintain v-Abl-mediated differentiation arrest of the pre-B cells, as activation of NF-kappaB and RAG gene transcription was unaffected by IL-7. These results identify a potential role for IL-7 signaling pathways in transformation by v-Abl while demonstrating that a combination of IL-4 and IL-7 signaling cannot substitute for an active v-Abl kinase in transformed pre-B cells.
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PMID:IL-7 reconstitutes multiple aspects of v-Abl-mediated signaling. 979 89


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