Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O00750 (PI-3 kinase)
 667 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin-like growth factors (IGFs) are capable of blocking apoptosis in many cell lines in vitro. The IGF-I receptor (IGF-IR) is believed to mediate protective effects of the IGFs against apoptosis. To determine whether ceramide-mediated induction of apoptosis involved a decreased survival effect of the IGF-IR, apoptosis was induced in IGF-I receptor positive (R+) and negative (R-) murine fibroblasts by incubation with increasing doses of the sphingolipid analogue, C2 ceramide. Lower ceramide doses were required to induce death in receptor negative compared with receptor positive fibroblasts (P< 0.05 at ceramide doses of 2 microM or greater), not only corroborating evidence that the IGF-I receptor functions as a survival receptor, but also suggesting that ceramide is not inducing apoptosis by suppressing a survival effect of the IGF-IR. Ceramide has been reported to induce death through suppression of MAP kinase, and activation of JUN kinase signalling; since our initial data suggested that ceramide had not affected an anti-apoptotic signalling event of the IGF-IR, we monitored the activation of these enzymes. To our surprise, in the presence of ceramide, not only was JUN kinase activity increased, but so too was MAP kinase. Inhibition of MAP kinase, using the MEKK inhibitor, PD98059, significantly reduced ceramide-induced cell death (P< 0. 001). Ceramide also enhanced IGF-induced tyrosine phosphorylation of the IGF-I receptor and activated PI-3 kinase. The cumulative effects of these events resulted in increased progression to the G2 phase of the cell cycle, arrest without subsequent mitosis, and apoptosis. These results indicate that ceramide is capable of eliciting apparently contradictory events within a single cell type, and suggest that in the presence of an IGF-IR, survival is enhanced because ceramide can activate PI-3 kinase, believed to be an anti-apoptotic enzyme.
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PMID:Increased, not decreased activation of the insulin-like growth factor (IGF) receptor signalling pathway during ceramide-induced apoptosis. 1037 46

The TEL/PDGFR beta (T/P) fusion protein isolated from patients bearing a t(5;12) translocation is transforming when expressed in haematopoietic cells. To examine the signal transduction events activated by this protein, we measured the effect of T/P on activation of the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) in mouse bone marrow-derived Ba/F3 cells. Significant increase in the activity of JNK/SAPK1 was observed in transient transfection as well as in Ba/F3 cells stably expressing T/P. This activation was abrogated when the T/P-expressing cells were treated with a specific inhibitor of the PDGFR beta tyrosine kinase, indicating that the activity of the PDGFR beta part of the fusion protein was involved in JNK/SAPK activation. Expression of a dominant negative mutant of mitogen-activated protein kinase kinase 4 (MKK4), a direct activator of JNK/SAPK, prevented T/P-induced JNK/SAPK activation. In addition, inhibition of phosphoinositide-3 OH kinase (PI-3 kinase), a promoting survival factor, potentiated the effect of T/P on JNK/SAPK activation. Interestingly, expression of T/P was shown to initiate an apoptotic response that was enhanced by treatment of cells with the PI-3 kinase inhibitor LY294002, suggesting that T/P mediated cell death through activation of JNK/SAPK signalling pathway. Consistent with this hypothesis, expression of the dominant negative mutant of MKK4 decreased T/P-mediated apoptosis, while a dominant-negative mutant of PI-3 kinase enhances cell death. These findings indicate that activation of JNK/SAPK by T/P is related to apoptosis rather than cell proliferation and transformation.
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PMID:The oncogenic TEL/PDGFR beta fusion protein induces cell death through JNK/SAPK pathway. 1044 51

The HMGIC gene has been implicated in the control of cell proliferation and development. We show here that HMGIC has multiple mRNA isoforms that arise by transcription initiation from alternative tandem promoters. These transcripts are not only differentially expressed between cell lines, but they can also differ within an individual cell line, in response to particular stimuli. Whereas quiescent 3T3-L1 preadipocytes express low levels of HMGIC mRNA, stimulation by serum results in a dramatic upregulation with the characteristics of a delayed-early response gene. Characterization of involved signal transduction pathways showed that both FGF-1 and PDGF-BB are strong inducers of HMGIC expression mediated via both the PI-3 kinase and MAP kinase pathways. In order to characterize the regulatory elements, sequences upstream of the translation initiation site of HMGIC were assayed for promoter activity. The HMGIC 5' flanking sequences had constitutive promoter activity in all cell lines tested, suggesting that HMGIC is regulated by negative regulatory elements that were not present in the 5'-flanking regions analysed here.
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PMID:Regulation of HMGIC expression: an architectural transcription factor involved in growth control and development. 1049 Aug 44

Insulin-like growth factor (IGF)-I protects many cell types from apoptosis. As a result, it is possible that IGF-I-responsive cancer cells may be resistant to apoptosis-inducing chemotherapies. Therefore, we examined the effects of IGF-I on paclitaxel and doxorubicin-induced apoptosis in the IGF-I-responsive breast cancer cell line MCF-7. Both drugs caused DNA laddering in a dose-dependent fashion, and IGF-I reduced the formation of ladders. We next examined the effects of IGF-I and estradiol on cell survival following drug treatment in monolayer culture. IGF-I, but not estradiol, increased survival of MCF-7 cells in the presence of either drug. Cell cycle progression and counting of trypan-blue stained cells showed that IGF-I was inducing proliferation in paclitaxel-treated but not doxorubicin-treated cells. However, IGF-I decreased the fraction of apoptotic cells in doxorubicin- but not paclitaxel-treated cells. Recent work has shown that mitogen-activated protein kinase (MAPK) and phosphotidylinositol-3 (PI-3) kinase are activated by IGF-I in these cells. PI-3 kinase activation has been linked to anti-apoptotic functions while MAPK activation is associated with proliferation. We found that IGF-I rescue of doxorubicin-induced apoptosis required PI-3 kinase but not MAPK function, suggesting that IGF-I inhibited apoptosis. In contrast, IGF-I rescue of paclitaxel-induced apoptosis required both PI-3 kinase and MAPK, suggesting that IGF-I-mediated protection was due to enhancement of proliferation. Therefore, IGF-I attenuated the response of breast cancer cells to doxorubicin and paclitaxel by at least two mechanisms: induction of proliferation and inhibition of apoptosis. Thus, inhibition of IGF-I action could be a useful adjuvant to cytotoxic chemotherapy in breast cancer.
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PMID:Insulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death--proliferative and anti-apoptotic effects. 1051 38

Among the three major mitogen-activated protein kinase (MAPK) cascades--the extracellular signal regulated kinase (ERK) pathway, the c-JUN N-terminal/stress-activated protein kinase (JNK/SAPK) pathway, and the reactivating kinase (p38) pathway--retinoic acid selectively utilizes ERK but not JNK/SAPK or p38 when inducing myeloid differentiation of HL-60 human myeloblastic leukemia cells. Retinoic acid is known to activate ERK2. The present data show that the activation is selective for this MAPK pathway. JNK/SAPK or p38 are not activated by retinoic acid. Presumably because it activates relevant signaling pathways including MAPK, the polyoma middle T antigen, as well as certain transformation defective mutants thereof, is known to promote retinoic acid-induced differentiation, although the mechanism of action is not well understood. The present results show that consistent with the selective involvement of ERK2, ectopic expression of either the polyoma middle T antigen or its dl23 mutant, which is defective for PLCgamma and PI-3 kinase activation, or the delta205 mutant, which in addition is also weakened for activation of src-like kinases, caused no enhanced JNK/SAPK or p38 kinase activity that promoted the effects of retinoic acid. However, all three of these polyoma antigens are known to enhance ERK2 activation and promote differentiation induced by retinoic acid. Polyoma-activated MAPK signaling relevant to retinoic acid-induced differentiation is thus restricted to ERK2 and does not involve JNK/SAPK or p38. Taken together, the data indicate that among the three parallel MAPK pathways, retinoic acid-induced HL-60 myeloid differentiation selectively depends on activating ERK but not the other two MAPK pathways, JNK/SAPK or p38, with no apparent cross talk between pathways. Furthermore, the striking ability of polyoma middle T antigens to promote retinoic acid-induced differentiation appears to utilize ERK, but not JNK/SPK or p38 signaling.
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PMID:Retinoic acid selectively activates the ERK2 but not JNK/SAPK or p38 MAP kinases when inducing myeloid differentiation. 1054 34

The Gab1 protein is tyrosine phosphorylated in response to various growth factors and serves as a docking protein that recruits a number of downstream signaling proteins, including phosphatidylinositol 3-kinase (PI-3 kinase). To determine the role of Gab1 in signaling via the epidermal growth factor (EGF) receptor (EGFR) we tested the ability of Gab1 to associate with and modulate signaling by this receptor. We show that Gab1 associates with the EGFR in vivo and in vitro via pTyr sites 1068 and 1086 in the carboxy-terminal tail of the receptor and that overexpression of Gab1 potentiates EGF-induced activation of the mitogen-activated protein kinase and Jun kinase signaling pathways. A mutant of Gab1 unable to bind the p85 subunit of PI-3 kinase is defective in potentiating EGFR signaling, confirming a role for PI-3 kinase as a downstream effector of Gab1. Inhibition of PI-3 kinase by a dominant-interfering mutant of p85 or by Wortmannin treatment similarly impairs Gab1-induced enhancement of signaling via the EGFR. The PH domain of Gab1 was shown to bind specifically to phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], a product of PI-3 kinase, and is required for activation of Gab1-mediated enhancement of EGFR signaling. Moreover, the PH domain mediates Gab1 translocation to the plasma membrane in response to EGF and is required for efficient tyrosine phosphorylation of Gab1 upon EGF stimulation. In addition, overexpression of Gab1 PH domain blocks Gab1 potentiation of EGFR signaling. Finally, expression of the gene for the lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4, 5)P3, inhibits EGF signaling and translocation of Gab1 to the plasma membrane. These results reveal a novel positive feedback loop, modulated by PTEN, in which PI-3 kinase functions as both an upstream regulator and a downstream effector of Gab1 in signaling via the EGFR.
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PMID:A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling. 1064 29

Growth hormone acts through binding to membrane receptors that belong to the cytokine receptor superfamily. Ligand binding induces receptor dimerization and activation of the receptor-associated kinase: JAK2; this results in phosphorylation of the kinase itself, of the receptor, and of many cellular proteins. Among these are the Stat proteins as well as adaptors leading to the activation of the Ras/MAP kinase pathway and of the PI-3 kinase pathway. Activation by growth hormone is very transient and several mechanisms are involved in this downregulation: internalization and degradation of the receptor and recruitment of phosphatases or of specific inhibitors of the JAK/Stat pathway, the SOCS proteins.
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PMID:Regulators of growth hormone signaling. 1071 37

Interleukin (IL)-6-related cytokines share gp130 as the signal-transducing protein. Cardiac myocytes produce various kinds of cytokines including IL-6 and cardiotrophin-1. Activation of gp130 transduces hypertrophic and cytoprotective signals in cardiac myocytes via JAK/STAT, MAP kinase and PI-3 kinase pathways. Besides various well-established mechanisms by which cardiac growth and myocardial remodeling are regulated, gp130 signalling may be a newly discovered mechanism that regulates these events in association with cytoprotective effect in myocardial diseases.
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PMID:Cytokines and their receptors in cardiovascular diseases--role of gp130 signalling pathway in cardiac myocyte growth and maintenance. 1071 60

The molecular basis for the modulatory properties of CD99 is not well understood. Treatment of human Jurkat T lymphocytes with anti-CD99 antibody led to activation of three mitogen-activated protein kinase (MAPK) members, ERK, JNK, and p38 MAPK, along with homotypic aggregation. While phosphorylation of ERK and JNK was inhibited by the pretreatment of a PKC inhibitor, bisindolylmaleimide I, activation of p38 MAPK was upregulated by the same pretreatment. The signaling pathways to MAPKs by CD99 engagement were independent of PI-3 kinase, distinguishing from those by CD3 engagement. Among MAPKs, ERK pathway was essential for homotypic aggregation together with intracytoplasmic Ca(2+).
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PMID:Differential activation of MAP kinase family members triggered by CD99 engagement. 1074 95

Mammary epithelial cells in primary cell culture require both growth factors and specific extracellular matrix (ECM)-attachment for survival. Here we demonstrate for the first time that inhibition of the ECM-induced Erk 1/Erk 2 (p42/44 MAPK) pathway, by PD 98059, leads to apoptosis in these cells. Associated with this cell death is a possible compensatory signalling through the p38 MAP kinase pathway the inhibition of which, by SB 203580, leads to a more rapid onset of apoptosis. This provides evidence for a hitherto undescribed Erk 1/Erk 2 to p38 MAP kinase pathway 'cross-talk' that is essential for the survival of these cells. The cell death associated with inhibition of these two MAP kinase pathways however, occurred in the presence of insulin that activates the classical PI-3 kinase-dependent Akt/PKB survival signals and Akt phosphorylation. Cell death induced by inhibition of the MAP kinase pathways did not affect Akt phosphorylation and may, thus, be independent of PI-3 kinase signalling.
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PMID:MAP kinase pathway signalling is essential for extracellular matrix determined mammary epithelial cell survival. 1074 75


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