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 human B-myb gene encodes a transcriptional regulator that plays an important role in cell cycle progression, differentiation, and survival. To assess the in vivo role of B-myb, we investigated the phenotype of mouse transgenic lines in which B-Myb expression in lymphoid tissues was driven by the LCK proximal promoter. Overexpression of B-Myb had no measurable effect on the subsets of splenic and thymic lymphocytes, but was associated with increased expression of Fas ligand in NK and T cells. B-Myb-overexpressing splenocytes expressed higher IFN-gamma levels and contained higher percentages of cytokine-producing cells than wild-type (wt) splenocytes, as detected by Western blot analysis and ELISPOT assays, respectively. Ex vivo-cultured transgenic thymocytes and splenocytes had decreased survival compared with the corresponding cells from wt mice, possibly dependent on increased expression of Fas ligand. In addition, Fas ligand-dependent cytotoxicity of transgenic T and NK cells was significantly higher than that mediated by their wt counterparts. Together, these results indicate that B-Myb overexpression results in T and NK cell activation and increased cytotoxicity. Therefore, in addition to its well-established role in proliferation and differentiation, B-myb also appears to be involved in activation of NK and T cells and in their regulation of Fas/Fas ligand-mediated cytotoxicity
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PMID:B-Myb overexpression results in activation and increased Fas/Fas ligand-mediated cytotoxicity of T and NK cells. 1141 55

AtbHLH29 of Arabidopsis, encoding a bHLH protein, reveals a high similarity to the tomato FER which is proposed as a transcriptional regulator involved in controlling the iron deficiency responses and the iron uptake in tomato. For identification of its biological functions, AtbHLH29 was introduced into the genome of the tomato FER mutant T3238fer mediated by Agrobacterium tumefaciencs. Transgenic plants were regenerated and the stable integration of AtbHLH29 into their genomes was confirmed by Southern hybridization. Molecular analysis demonstrated that expression of the exogenous AtbHLH29 of Arabidopsis in roots of the FER mutant T3238fer enabled to complement the defect functions of FER. The transgenic plants regained the ability to activate the whole iron deficiency responses and showed normal growth as the wild type under iron-limiting stress. Our transformation data demonstrate that AtbHLH29 is a functional ortholog of the tomato FER and can completely replace FER in controlling the effective iron acquisition in tomato. Except of iron, FER protein was directly or indirectly involved in manganese homeostasis due to that loss functions of FER in T3238fer resulted in strong reduction of Mn content in leaves and the defect function on Mn accumulation in leaves was complemented by expression of AtbHLH29 in the transgenic plants. Identification of the similar biological functions of FER and AtbHLH29, which isolated from two systematically wide-diverged "strategy I" plants, suggests that FER might be a universal gene presented in all strategy I plants in controlling effective iron acquisition system in roots.
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PMID:AtbHLH29 of Arabidopsis thaliana is a functional ortholog of tomato FER involved in controlling iron acquisition in strategy I plants. 1611 51

Hypoxia promotes angiogenesis by modulating the transcriptional regulator hypoxia-inducible factor 1alpha (HIF-1alpha). HIF-1alpha is a master regulator of the hypoxic response, and its proangiogenic activities include, but are not limited to, regulation of vascular endothelial growth factor (VEGF). The remodeling of the vasculature during angiogenesis requires an initial destabilization step, which facilitates endothelial sprouting, followed by vessel growth, and restabilization through investment of smooth muscle cells. The complex dynamics of hypoxia-induced angiogenesis prompted us to investigate what aspects of this multi-step process are regulated by HIF-1alpha. To do so, we analyzed the molecular properties of aortic and coronary artery smooth muscle cells in response to forced expression of HIF-1alpha, and by treatment with cobalt chloride, which mimics hypoxia. Our results demonstrate that HIF-1alpha causes a marked reduction in the ability of smooth muscle cells to migrate and adhere to extracellular matrices. Analysis of focal adhesion proteins showed no significant difference in expression or localization of vinculin or focal adhesion kinase (FAK). However, investigation of FAK phosphorylation, a critical mediator of adhesion and migration, revealed tyrosine phosphorylation of FAK is diminished in the presence of HIF-1alpha and cobalt chloride. These results indicate that during hypoxia-induced vessel remodeling, HIF-1alpha functions to dampen adhesion and migration of smooth muscle cells by modulating FAK activity. We suggest that HIF-1alpha expression in smooth muscle cells may augment vessel sprouting by loosening smooth muscle cell attachments to the basement membrane and endothelial cells.
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PMID:Hypoxia-inducible factor 1alpha modulates adhesion, migration, and FAK phosphorylation in vascular smooth muscle cells. 1614 50

Basic transcription factor 3 (BTF3) acts as a transcription factor and modulator of apoptosis, and is differentially expressed in colorectal cancer and glioblastomas. In the present study, the expression of BTF3, as well as its role in apoptosis and gene transcription, was analyzed in pancreatic ductal adenocarcinoma (PDAC). QRT-PCR, immunohistochemistry, immunoblotting, and immunofluorescence analyses were carried out to investigate BTF3 mRNA/protein expression and localization. BTF3 silencing in pancreatic cancer cells was performed using specific siRNA molecules. Functional analyses were carried out using cell growth assays, apoptosis assays, and DNA array analysis. BTF3 and BTF3a exhibited 1.3-fold and 4.6-fold increased median mRNA levels in PDAC tissues, compared to normal pancreatic tissues. BTF3 localized mainly in the cytoplasm and nuclei of tubular complexes and pancreatic cancer cells. Pancreatic cancer cell lines expressed the mRNA and protein of BTF3a (27 kDa) and BTF3b (22 kDa) isoforms. BTF3 silencing using specific siRNA molecules did not influence apoptosis induced by chemotherapy or radiotherapy. In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis.
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PMID:Basic transcription factor 3 (BTF3) regulates transcription of tumor-associated genes in pancreatic cancer cells. 1731 87

Nurr1 (NR4A2) is an atypical nuclear receptor (NR) because of its inability to bind a ligand and to activate transcription following canonical NR rules. An affinity chromatography-based screen identified the glucocorticoid receptor (GR) as an interactant of Nurr1. The co-localization of these two NRs in the hippocampus and the substantia nigra, as well as their involvement in similar neurological processes led us to investigate the functional consequences of such a physical interaction. GR interfered with Nurr1 transcriptional activity, and Nurr1 association to GR confers glucocorticoid regulation to this orphan receptor. The N-terminal domain of Nurr1 interacts directly with GR, whereas several domains of GR can associate to Nurr1. The GR-mediated increase in Nurr1 transcriptional activity requires the N-terminal domain of GR, but not a functional DNA binding domain. Finally, SMRT and SRC2, two co-regulators of GR, modulated the transcriptional activity of the Nurr1-GR complex, but not that of Nurr1 alone. Our results therefore establish GR as a transcriptional regulator of Nurr1, and open new opportunities in the pharmacological regulation of Nurr1 by glucocorticoids in the CNS.
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PMID:The glucocorticoid receptor is a co-regulator of the orphan nuclear receptor Nurr1. 1798 26

In Bacillus subtilis the concentration of L-arginine is controlled by the transcriptional regulator AhrC, which interacts with 18 bp DNA operator sites called ARG boxes in the promoters of arginine biosynthetic and catabolic operons. AhrC is a 100 kDa homohexamer, with each subunit having two domains. The C-terminal domains form the core, mediating intersubunit interactions and binding of the co-repressor L-arginine, whilst the N-terminal domains contain a winged helix-turn-helix DNA-binding motif and are arranged around the periphery. The N-terminal domain of AhrC has been expressed, purified and characterized and it has been shown that the fragment still binds DNA operators as a recombinant monomer. The DNA-binding domain has also been crystallized and the crystal structure refined to 1.0 A resolution is presented.
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PMID:A high-resolution structure of the DNA-binding domain of AhrC, the arginine repressor/activator protein from Bacillus subtilis. 1800 39

In many bacteria, the concentration of L-arginine is controlled by a transcriptional regulator, the arginine repressor. In Bacillus subtilis this transcription factor is called AhrC and has roles in both the repression and activation of the genes involved in arginine metabolism. It interacts with 18 bp ARG boxes in the promoters of arginine biosynthetic and catabolic operons. AhrC is a hexamer and each subunit has two domains. The C-terminal domains form the core, mediating inter-subunit interactions and L-arginine binding, while the N-terminal domains contain a winged helix-turn-helix DNA-binding motif and are arranged around the periphery. Upon binding of the co-repressor L-arginine there is a approximately 15 degrees relative rotation between core C-terminal trimers. Here, we report the X-ray crystal structure of a dimer of the N-terminal domains of AhrC (NAhrC) in complex with an 18 bp DNA ARG box operator, refined to 2.85 A resolution. Comparison of the N-terminal domains within this complex with those of the free domain reveals that the flexible beta-wings of the DNA-binding motif in the free domain form a stable dimer interface in the protein-DNA complex, favouring correct orientation of the recognition helices. These are then positioned to insert into adjacent turns of the major groove of the ARG box, whilst the wings contact the minor groove. There are extensive contacts between the protein and the DNA phosphodiester backbone, as well as a number of direct hydrogen bonds between conserved amino acid side chains and bases. Combining this structure with other crystal structures of other AhrC components, we have constructed a model of the repression complex of AhrC at the B. subtilis biosynthetic argC operator and, along with transcriptome data, analysed the origins of sequence specificity and arginine activation.
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PMID:Structure and function of the arginine repressor-operator complex from Bacillus subtilis. 1845 86

Phenotypic changes in airway smooth muscle occur with airway inflammation and asthma. These changes may be induced by alterations in the extracellular matrix that initiate signaling pathways mediated by integrin receptors. We hypothesized that integrin-linked kinase (ILK), a multidomain protein kinase that binds to the cytoplasmic tail of beta-integrins, may be an important mediator of signaling pathways that regulate the growth and differentiation state of airway smooth muscle. We disrupted signaling pathways mediated by ILK in intact differentiated tracheal muscle tissues by depleting ILK protein using ILK antisense. The depletion of ILK protein increased the expression of the smooth muscle differentiation marker genes myosin heavy chain (SmMHC), SM22alpha, and calponin and increased the expression of SmMHC protein. Conversely, the overexpression of ILK protein reduced the mRNA levels of SmMHC, SM22alpha, and calponin and SmMHC protein. Analysis by chromatin immunoprecipitation showed that the binding of the transcriptional regulator serum response factor (SRF) to the promoters of SmMHC, SM22alpha, and calponin genes was increased in ILK-depleted tissues and decreased in tissues overexpressing ILK. ILK depletion also increased the amount of SRF that localized within the nucleus. ILK depletion and overexpression, respectively, decreased and increased the activation of its downstream substrate protein kinase B (PKB/Akt). The pharmacological inhibition of Akt activity also increased SRF binding to the promoters of smooth muscle-specific genes and increased expression of smooth muscle proteins, suggesting that ILK may exert its effects by regulating the activity of Akt. We conclude that ILK is a critical regulator of airway smooth muscle differentiation. ILK may mediate signals from integrin receptors that control airway smooth muscle differentiation in response to alterations in the extracellular matrix.
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PMID:Integrin-linked kinase regulates smooth muscle differentiation marker gene expression in airway tissue. 1880 60

The human Mixed-Lineage-Leukemia-5 (MLL5) gene is located in a genomic region frequently deleted in patients with myeloid malignancies and encodes a widely expressed nuclear protein most closely related to MLL1, a Trithorax transcriptional regulator with established involvement in leukemogenesis. Although the physiologic function of MLL5 is completely unknown, domain structure and homology to transcriptional regulators with histone methyltransferase activity suggest a role in epigenetic gene regulation. To investigate physiologic functions of Mll5, we have generated a knockout mouse mutant using Cre/loxP technology. Adult homozygous Mll5-deficient mice are obtained at reduced frequency because of postnatal lethality. Surviving animals display a variety of abnormalities, including male infertility, retarded growth, and defects in multiple hematopoietic lineages. Interestingly, Mll5(-/-) mice die of sublethal whole-body irradiation but can be rescued with wild-type bone marrow grafts. Flow cytometric ana-lysis, bone marrow reconstitution, and in vivo BrdU-labeling experiments reveal numerical, functional, and cell-cycle defects in the lineage-negative Sca-1(+), Kit(+) (LSK) population, which contains short- and long-term hematopoietic stem cells. Together, these in vivo findings establish several nonredundant functions for Mll5, including an essential role in regulating proliferation and functional integrity of hematopoietic stem/progenitor cells.
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PMID:Impaired function of primitive hematopoietic cells in mice lacking the Mixed-Lineage-Leukemia homolog MLL5. 1922 Oct 41

The past few years have witnessed considerable advances in our understanding of the mechanisms underlying the induction of central tolerance. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process by virtue of promiscuous expression of tissue-restricted autoantigens. This brief review covers progress of the last two years in deciphering the functional interrelationship among TEC development, promiscuous gene expression, and central tolerance. We discuss new insights into signaling pathways directing the differentiation and homeostasis of mTECs, and new clues to the molecular regulation of promiscuous gene expression (pGE), including the role of the transcriptional regulator autoimmune regulator (AIRE). Furthermore, we emphasize the importance of promiscuous expression of particular tissue-restricted self-antigens in preventing organ-specific autoimmunity and evaluate new data supporting the threshold model of central tolerance.
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PMID:The thymus medulla slowly yields its secrets. 1907 47


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