Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CBP protein (cAMP response element binding protein (CREB) binding protein) is a co-activator for several transcription factors with a wide range of important biological functions, such as sterol regulatory element binding proteins (SREBPs), CCAAT/enhancer-binding proteins (C/EBPs), nuclear receptors (including peroxisome proliferator-activated receptors, PPARs), and signal transducers and activators of transcription (STATs). In contrast to these individual transcription factors, the biological roles of CBP are poorly understood. CBP enhances transcriptional activities via histone acetylation and the recruitment of additional co-activators such as SRC (steroid coactivator)-1 (ref. 9). To identify its physiological functions using a loss-of-function mutant, we analyzed CBP-deficient mice. As Crebbp null mice (Crebbp-/-) died during embryogenesis, we used Crebbp+/- mice. Unexpectedly, Crebbp+/- mice showed markedly reduced weight of white adipose tissue (WAT) but not of other tissues. Despite this lipodystrophy, Crebbp+/- mice showed increased insulin sensitivity and glucose tolerance and were completely protected from body weight gain induced by a high-fat (HF) diet. We observed increased leptin sensitivity and increased serum adiponectin levels in Crebbp+/- mice. These increased effects of insulin-sensitizing hormones secreted from WAT may explain, at least in part, the phenotypes of Crebbp+/- mice. This study demonstrates that CBP may function as a 'master-switch' between energy storage and expenditure.
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PMID:Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. 1181 64

Nuclear hormone receptors are ligand-dependent transcription factors that require coactivators to regulate target gene expression. The steroid receptor coactivator-3 (SRC-3), also known as p/CIP, RAC3, AIB1, ACTR and TRAM-1, is a cancer-amplified coactivator in the SRC gene family that also contains SRC-1 and TIF2/GRIP1. SRC-3 interacts with nuclear receptors and certain other transcription factors, recruits histone acetyltransferases and methyltransferases for chromatin remodeling and facilitates target gene transcription. Accumulated results from both ex vivo and animal model studies indicate that SRC-3 plays important roles in many biological processes involving cell proliferation, cell migration, cell differentiation, somatic growth, sexual maturation, female reproductive function, vasoprotection and breast cancer. This article summarizes our current knowledge about SRC-3 under the following topics: molecular cloning and characterization; molecular structure and functional mechanisms; SRC-3 as a molecular target of growth factors and cytokines; organization and expression of the SRC-3 gene; generation and characterization of SRC-3 knockout mice; role of SRC-3 in the vasoprotective effects of estrogen; role of SRC-3 in cell migration, proliferation and cancers.
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PMID:Molecular structure and biological function of the cancer-amplified nuclear receptor coactivator SRC-3/AIB1. 1265 Jun 96

Transcriptional activation from chromatin by nuclear receptors (NRs) requires multiple cofactors including CBP/p300, SWI/SNF and Mediator. How NRs recruit these multiple cofactors is not clear. Here we show that activation by androgen receptor and thyroid hormone receptor is associated with the promoter targeting of SRC family members, p300, SWI/SNF and the Mediator complex. We show that recruitment of SWI/SNF leads to chromatin remodeling with altered DNA topology, and that both SWI/SNF and p300 histone acetylase activity are required for hormone-dependent activation. Importantly, we show that both the SWI/SNF and Mediator complexes can be targeted to chromatin by p300, which itself is recruited through interaction with SRC coactivators. Furthermore, histone acetylation by CBP/p300 facilitates the recruitment of SWI/SNF and Mediator. Thus, our data indicate that multiple cofactors required for activation are not all recruited through their direct interactions with NRs and underscore a role of cofactor-cofactor interaction and histone modification in coordinating the recruitment of multiple cofactors.
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PMID:A role for cofactor-cofactor and cofactor-histone interactions in targeting p300, SWI/SNF and Mediator for transcription. 1272 81

It is well established that steroid receptor function requires interaction with coactivators. However, the mechanisms through which steroid receptors elicit precise assembly of coactivator complexes and the way the steroid activation signal is transduced remain elusive. Using a T47D cell line stably integrated with a mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) reporter, we demonstrate that specific steroid receptors exhibit preferential recruitment of SRC-1 family coactivators, which determines the subsequent recruitment of specific downstream coregulator molecules. Upon ligand treatment, progesterone receptor (PR) interacted preferentially with SRC-1, which recruited CBP and significantly enhanced acetylation at K5 of histone H4. In contrast, activated glucocorticoid receptor (GR) preferentially associated with SRC-2 (TIF-2/GRIP-1), which subsequently recruited pCAF and led to specific modification of histone H3, suggesting that specific coactivators recruit distinct histone acetyltransferases to modulate the transcription of steroid-responsive genes. Loss-of-function experiments further support the predicted roles of SRC-1 and SRC-2 in, respectively, PR- and GR-mediated transcription on the MMTV promoter. This study indicates that differential recruitment of coactivators by nuclear receptors determines the assembly of coactivator complexes on target promoters to mediate specific transcription signals.
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PMID:Progesterone and glucocorticoid receptors recruit distinct coactivator complexes and promote distinct patterns of local chromatin modification. 1274 80

Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase essential for signaling via cytokine receptors that comprise the common gamma-chain (gammac), i.e., the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Jak3 is preferentially expressed in hemopoietic cells and is up-regulated upon cell differentiation and activation. Despite the importance of Jak3 in lymphoid development and immune function, the mechanisms that govern its expression have not been defined. To gain insight into this issue, we set out to characterize the Jak3 promoter. The 5'-untranslated region of the Jak3 gene is interrupted by a 3515-bp intron. Upstream of this intron and the transcription initiation site, we identified an approximately 1-kb segment that exhibited lymphoid-specific promoter activity and was responsive to TCR signals. Truncation of this fragment revealed that core promoter activity resided in a 267-bp fragment that contains putative Sp-1, AP-1, Ets, Stat, and other binding sites. Mutation of the AP-1 sites significantly diminished, whereas mutation of the Ets sites abolished, the inducibility of the promoter construct. Chromatin immunoprecipitation assays showed that histone acetylation correlates with mRNA expression and that Ets-1/2 binds this region. Thus, transcription factors that bind these sites, especially Ets family members, are likely to be important regulators of Jak3 expression.
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PMID:Characterization and analysis of the proximal Janus kinase 3 promoter. 1279 34

The development of autoimmunity is correlated with heightened sensitivity of B cells to B cell Ag receptor (BCR) cross-linking. BCR signals are down-regulated by Lyn, which phosphorylates inhibitory receptors. lyn(-/-) mice have reduced BCR signaling thresholds and develop autoantibodies, glomerulonephritis, splenomegaly due to myeloid hyperplasia, and increased B-1 cell numbers. Bruton's tyrosine kinase (Btk), a critical component of BCR signaling pathways, is required for autoantibody production in lyn(-/-) mice. It is unclear whether Btk mediates autoimmunity at the level of BCR signal transduction or B cell development, given that lyn(-/-)Btk(-/-) mice have a severe reduction in conventional B and B-1 cell numbers. To address this issue, we crossed a transgene expressing a low dosage of Btk (Btk(low)) in B cells to lyn(-/-)Btk(-/-) mice. Conventional B cell populations were restored to levels similar to those in lyn(-/-) mice. These cells were as hypersensitive to BCR cross-linking as lyn(-/-) B cells as measured by proliferation, Ca(2+) flux, and activation of extracellular signal-regulated kinase and Akt. However, lyn(-/-)Btk(low) mice did not produce anti-ssDNA, anti-dsDNA, anti-histone, or anti-histone/DNA IgM or IgG. They also lacked B-1 cells and did not exhibit splenomegaly. Thus, B cell hyperresponsiveness is insufficient for autoimmunity in lyn(-/-) mice. These studies implicate B-1 and/or myeloid cells as key contributors to the lyn(-/-) autoimmune phenotype.
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PMID:Reduced dosage of Bruton's tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice. 1290 86

Insulin stimulates sodium transport across A6 epithelial cell monolayers. Activation of phosphatidylinositol 3-kinase (PI 3-kinase) was suggested as an early step in the insulin-stimulated sodium reabsorption (Ref. 35). To establish that the stimulation of the PI 3-kinase signaling cascade is causing stimulation of apical epithelial Na channel, we added permeant forms of phosphatidylinositol (PI) phosphate (P) derivatives complexed with a histone carrier to A6 epithelium. Only PIP(3) and PI(3,4)P(2) but not PI(4,5)P(2) stimulated sodium transport, although each of them penetrated into A6 cell monolayers as assessed using fluorescent permeant phosphoinositides derivatives. By Western blot analysis of A6 cell extracts, the inositol 3-phosphatase PTEN and the protein kinase B PKB were both detected. To further establish that the stimulation of sodium transport induced by insulin is related to PIP(3) levels, we transfected A6 cells with human PTEN cDNA and observed a 30% decrease in the natriferic effect of insulin. Similarly, the increase in sodium transport observed by addition of permeant PIP(3) was also reduced by 30% in PTEN-overexpressing cells. PKB, a main downstream effector of PI 3-kinase, was phosphorylated at both Thr 308 and Ser 473 residues upon insulin stimulation of the A6 cell monolayer. PKB phosphorylation in response to insulin stimulation was reduced in PTEN-overexpressing cells. Permeant PIP(3) also increased PKB phosphorylation. Taken together, the present results establish that the d-3-phosphorylated phosphoinositides PIP(3) and PI(3,4)P(2) mediate the effect of insulin on sodium transport across A6 cell monolayers.
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PMID:Phosphatidylinositol 3,4,5-trisphosphate: an early mediator of insulin-stimulated sodium transport in A6 cells. 1510 98

Valproic acid (VPA) is an anti-epileptic drug that has been associated with polycystic ovary syndrome (PCOS)-like symptoms, including increased ovarian androgen production. The hyperandrogenemia likely reflects the stimulatory action of VPA on theca cell androgen synthesis and has been correlated to its activity as a histone deacteylase inhibitor in these cells. To determine whether VPA induces a PCOS-like genomic phenotype, we compared the gene expression profiles of untreated (UNT) normal, VPA-treated normal, and UNT PCOS theca cells. Hierarchal cluster analysis demonstrated similarities in the gene expression profiles of VPA-treated normal and PCOS theca cells. Statistical analysis identified 1,050 transcripts that have significantly altered mRNA abundance in both VPA-treated normal and UNT PCOS theca cells compared with normal UNT theca cells. Among these 1,050 transcripts were cAMP-GEFII and TRB3, which have increased and decreased mRNA abundance, respectively. The altered abundance of these two mRNAs was correlated to increased basal and insulin-induced phosphorylation of protein kinase B (Akt/PKB). Thus these studies indicate that VPA- and PCOS-induced changes in gene expression enhance Akt/PKB signal transduction in human theca cells. Furthermore, common changes in gene expression in PCOS and VPA-treated normal theca cells suggest a possible mechanism for the development of PCOS-like symptoms, including increased steroid synthesis and arrested follicle development in women receiving chronic VPA therapy.
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PMID:Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects. 1559 77

Pollutant particles induce apoptosis and inflammation, but the relationship between these two biological processes is not entirely clear. In this study, we compared the proapoptotic and proinflammatory effects of four particles: residual oil fly ash (ROFA), St. Louis particles SRM 1648 (SL), Chapel Hill PM10 (CHP), and Mount St. Helens dust (MSH). Human alveolar macrophages (AM) were incubated with these particles at 100 microg/ml. Cell death was assessed by annexin V (AV) expression, histone release, nuclear morphology, caspase 3-like activity and release of caspase 1 for apoptosis, and propidium iodide (PI) for necrosis, and inflammation was measured by interleukin (IL)-1beta and IL-6. We found that particle effects on these cell death measurements varied, and ROFA affected most (four out of five) endpoints, including nuclear morphological changes. CHP and SL also caused necrosis. For cytokine release, the potency was CHP > SL > ROFA > MSH. The proapoptotic and proinflammatory effects induced by the whole particles were unaltered after the particles were washed with water. The water-soluble fraction was relatively inactive, as were individual soluble metals (V, Ni, Fe). ROFA-induced nuclear fragmentation was associated with upregulation and mitochondrial release of apoptosis-inducing factor (AIF), a caspase-independent chromatin condensation factor, and upregulation of DNase II, a lysosomal acid endonuclease. These results indicate that the potential for particles to induce apoptosis does not correlate with their proinflammatory properties, although active components for both processes reside in the water-insoluble core. Both apoptosis and inflammatory endpoints should be included when the toxicity of different pollutant particles is assessed.
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PMID:Apoptotic and inflammatory effects induced by different particles in human alveolar macrophages. 1576 74

We reported previously that 23% of human lung adenocarcinoma cell lines were unresponsive to IFN-gamma. To extend this finding to cancer cells derived from distinct tissues of origin, we assessed IFN-gamma receptor signaling in the LNCaP human prostate adenocarcinoma cell line, which in previous experiments by others failed to induce a range of IFN-dependent biological responses. In this report, we show that LNCaP cells fail to respond to either IFN-gamma or IFN-alpha because of an impairment in the proximal signaling events downstream of both IFN-gamma and IFN-alpha/beta receptors that lead to the activation of STAT1. Furthermore, we show that LNCaP insensitivity to the IFNs is a result of the absence of expression of the JAK1 kinase, an obligate component shared by both IFN-gamma and IFN-alpha/beta receptors. JAK1 was undetectable in LNCaP cells at both protein and message levels. Treatment of LNCaP cells with a combination of inhibitors of DNA methyltransferases and histone deacetylases induced expression of JAK1 message. These results identify the molecular basis for IFN insensitivity in the LNCaP cell line and suggest that epigenetic silencing of key immunologic signaling components may be one mechanism by which tumor cells evade immune detection and elimination.
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PMID:IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. 1583 80


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