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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protein product of the retinoblastoma tumor suppressor gene (RB) has been demonstrated to bind c-Myc protein (Myc) in vitro. To determine whether RB regulates Myc transcriptional activity in vivo, GAL4-Myc chimeric expression plasmids were generated and cotransfected with a RB expression plasmid and a GAL4-dependent reporter plasmid. RB stimulated GAL4-Myc-mediated transcription, dependent upon a domain(s) in the amino-terminus of Myc. The stimulation of Myc-mediated transcription by RB was cell-type specific and was inhibited by SV40 T-antigen, but not by a T-antigen mutant defective in RB-binding. Moreover, RB mutants containing mutations in domain B of RB pocket were significantly reduced in their ability to stimulate GAL4-Myc mediated transcription. To determine whether RB and Myc interact in vivo either directly or indirectly, a two hybrid system was used where GAL4-Rb and Myc-VP16 expression constructs were cotransfected with a GAL4-dependent reporter plasmid. A significant increase of GAL4-dependent transcription was observed, dependent upon the presence of both GAL4-Rb and Myc-VP16 fusion proteins. Mutational analysis of the Myc-VP16 chimeric proteins suggests that the amino-terminus of Myc is essential for the interaction with RB. These results demonstrate that RB can regulate Myc-mediated transcription in vivo in a cell-type specific manner through protein-protein interactions.
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PMID:The retinoblastoma susceptibility gene product regulates Myc-mediated transcription. 783 35

In higher plants, the plasma membrane proton pump (H(+)-ATPase) is encoded by a surprisingly large multigene family whose members are expressed in different tissues. Using an 18-amino acid epitope tag derived from the animal oncogene c-Myc, we have performed immunocytolocalization measurements of the protein expressed by one member of this family, AHA3 (Arabidopsis H(+)-ATPase isoform 3). Immunofluorescence studies with tissue sections of transgenic plants have revealed that c-Myc-tagged AHA3 is restricted to the plasma membrane of phloem companion cells, whereas other AHA isoproteins are more widely distributed in the plasma membrane of other cell types. Electron microscopy with immunogold-labeled tissue sections suggests that there is a high concentration of proton pumps in the plasma membrane of companion cells but a much lower concentration in the plasma membrane of sieve elements. Due to plasmodesmata connecting the plasma membrane of these two adjacent cell types, it is likely that the proton motive force generated by the proton pump in companion cells can serve to power the uptake of sugar by proton-coupled symporters in either the companion cell or sieve element cell. The abundance of the proton pump in the plasma membrane of companion cells supports an apoplastic model for phloem loading in which the metabolic energy that drives sugar uptake is consumed by AHA3 at the companion cell plasma membrane. These experiments with a genetically altered integral plasma membrane protein demonstrate the utility of using a short c-Myc sequence as an epitope tag in Arabidopsis. Furthermore, our results demonstrate that, using genes encoding individual members of a gene family, it is possible to label plasma membrane proteins immunologically in specific, differentiated cell types of higher plants.
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PMID:Immunocytological localization of an epitope-tagged plasma membrane proton pump (H(+)-ATPase) in phloem companion cells. 871 19

Ku is a heterodimeric protein composed of approximately 70- and approximately 80-kDa subunits (Ku70 and Ku80) originally identified as an autoantigen recognized by the sera of patients with autoimmune diseases. Ku has high binding affinity for DNA ends and that is why originally it was known as a DNA end binding protein, but now it is known to also bind the DNA structure at nicks, gaps, hairpins, as well as the ends of telomeres. It has been reported also to bind with sequence specificity to DNA and with weak affinity to RNA. Ku is an abundant nuclear protein and is present in vertebrates, insects, yeast, and worms. Ku contains ssDNA-dependent ATPase and ATP-dependent DNA helicase activities. It is the regulatory subunit of the DNA-dependent protein kinase that phosphorylates many proteins, including SV-40 large T antigen, p53, RNA-polymerase II, RP-A, topoisomerases, hsp90, and many transcription factors such as c-Jun, c-Fos, oct-1, sp-1, c-Myc, TFIID, and many more. It seems to be a multifunctional protein that has been implicated to be involved directly or indirectly in many important cellular metabolic processes such as DNA double-strand break repair, V(D)J recombination of immunoglobulins and T-cell receptor genes, immunoglobulin isotype switching, DNA replication, transcription regulation, regulation of heat shock-induced responses, regulation of the precise structure of telomeric termini, and it also plays a novel role in G2 and M phases of the cell cycle. The mechanism underlying the regulation of all the diverse functions of Ku is still obscure.
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PMID:Ku autoantigen: a multifunctional DNA-binding protein. 1075 64

The Saccharomyces cerevisiae vacuolar ATPase (V-ATPase) is composed of at least 13 polypeptides organized into two distinct domains, V(1) and V(0), that are structurally and mechanistically similar to the F(1)-F(0) domains of the F-type ATP synthases. The peripheral V(1) domain is responsible for ATP hydrolysis and is coupled to the mechanism of proton translocation. The integral V(0) domain is responsible for the translocation of protons across the membrane and is composed of five different polypeptides. Unlike the F(0) domain of the F-type ATP synthase, which contains 12 copies of a single 8-kDa proteolipid, the V-ATPase V(0) domain contains three proteolipid species, Vma3p, Vma11p, and Vma16p, with each proteolipid contributing to the mechanism of proton translocation (Hirata, R., Graham, L. A., Takatsuki, A., Stevens, T. H., and Anraku, Y. (1997) J. Biol. Chem. 272, 4795-4803). Experiments with hemagglutinin- and c-Myc epitope-tagged copies of the proteolipids revealed that each V(0) complex contains all three species of proteolipid with only one copy each of Vma11p and Vma16p but multiple copies of Vma3p. Since the proteolipids of the V(0) complex are predicted to possess four membrane-spanning alpha-helices, twice as many as a single F-ATPase proteolipid subunit, only six V-ATPase proteolipids would be required to form a hexameric ring-like structure similar to the F(0) domain. Therefore, each V(0) complex will likely be composed of four copies of the Vma3p proteolipid in addition to Vma11p and Vma16p. Structural differences within the membrane-spanning domains of both V(0) and F(0) may account for the unique properties of the ATP-hydrolyzing V-ATPase compared with the ATP-generating F-type ATP synthase.
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PMID:Molecular characterization of the yeast vacuolar H+-ATPase proton pore. 1082 80

The c-Myc transactivation domain was used to affinity purify tightly associated nuclear proteins. Two of these proteins were identified as TIP49 and a novel related protein called TIP48, both of which are highly conserved in evolution and contain ATPase/helicase motifs. TIP49 and TIP48 are complexed with c-Myc in vivo, and binding is dependent on a c-Myc domain essential for oncogenic activity. A missense mutation in the TIP49 ATPase motif acts as a dominant inhibitor of c-Myc oncogenic activity but does not inhibit normal cell growth, indicating that functional TIP49 protein is an essential mediator of c-Myc oncogenic transformation. The TIP49 and TIP48 ATPase/helicase proteins represent a novel class of cofactors recruited by transcriptional activation domains that function in diverse pathways.
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PMID:An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c-Myc. 1088 73

The c-myc gene is frequently over-expressed in human cancers and is involved in regulation of proliferation, differentiation and apoptosis. c-Myc is a transcription factor that acts primarily by regulating the expression of other genes. However, it has been very difficult to identify bona fide c-Myc target genes that explain its diverse biological activities. The recent generation of c-myc deficient Rat1A fibroblasts with a profound and stable growth defect provides a new system to search for genes that can substitute for c-myc in proliferation. In this study, we have attempted to identify genes that rescue the slow growth phenotype of c-myc null cells through introduction of a series of potent cell cycle regulatory genes and several retroviral cDNA expression libraries. None of the candidate genes tested, including SV40 T-antigen and adenovirus E1A, caused reversal of the c-myc null growth defect. Furthermore, extensive screens with high-complexity retroviral cDNA libraries from three different tissue sources revealed that only c-myc and N-myc rescued the c-myc null slow-growth phenotype. Our data support the notion that there are no functional equivalents of the myc family of proto-oncogenes and also suggest that there are no c-Myc-activated genes that alone can substitute for c-Myc in control of cell proliferation.
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PMID:A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts. 1091 89

We have proposed that hyperglycemia-induced dedifferentiation of beta-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. beta-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1 alpha), beta-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCC beta, and sarcoplasmic reticulum Ca(2+)-ATPase 3). Conversely, genes normally suppressed in beta-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce beta-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of beta-cell phenotype with decreased expression of beta-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the beta-cell phenotype found in diabetes.
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PMID:Critical reduction in beta-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes. 1243 14

T cells develop through distinct stages directed by a series of signals. We explored the roles of SWI/SNF-like BAF chromatin remodeling complexes in this process by progressive deletion of the ATPase subunit, Brg, through successive stages of early T cell development. Brg-deficient cells were blocked at each of the developmental transitions examined. Bcl-xL overexpression suppressed cell death without relieving the developmental blockades, leading to the accumulation of Brg-deleted cells that were unexpectedly cell cycle arrested. These defects resulted partly from the disruptions of pre-TCR and potentially Wnt signaling pathways controlling the expression of genes such as c-Kit and c-Myc critical for continued development. Our studies indicate that BAF complexes dynamically remodel chromatin to propel sequential developmental transitions in response to external signals.
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PMID:Sequential roles of Brg, the ATPase subunit of BAF chromatin remodeling complexes, in thymocyte development. 1293 48

The c-Myc oncoprotein is a transcription factor that controls genes involved in cell growth, apoptosis and oncogenesis. We and others recently showed that the F-box protein Skp2 interacts with c-Myc and participates in its ubiquitylation and proteasomal degradation. Surprisingly, Skp2 was also found to act as a positive cofactor for c-Myc-regulated transcription. Further, Skp2, ubiquitylated proteins and subunits of the proteasome were demonstrated to be associated with a c-Myc target promoter in vivo. We show here that c-Myc interacts with Skp2 as part of the SCFSkp2 E3 ubiquitin ligase complex. Further, c-Myc interacts with the Sug1, an AAA ATPase subunit of the 19S regulatory particle of the proteasome. Inhibition of Sug1 expression by siRNA reduced transcription from a Myc target promoter to the same extent as c-Myc or Skp2 siRNA, implicating Sug1in this process. Taken together these findings suggest a role of the ubiquitin/proteasome system in c-Myc-regulated transcription. A hypothetical model discussing the link between ubiquitylation and transcription will be presented.
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PMID:Implication of the ubiquitin/proteasome system in Myc-regulated transcription. 1296 25

Beta-catenin has a key role in Wnt signaling via effects on T-cell factor (TCF)-mediated transcription. Mutational defects in beta-catenin regulation are seen in many cancers, leading to elevated beta-catenin levels, enhanced binding of beta-catenin to TCFs, and increased expression of TCF-regulated genes. Factors cooperating with beta-catenin in transcription of TCF-regulated genes are not well defined. TIP49, an ATPase previously implicated as a cofactor for oncogenic transformation by c-Myc, has been shown to bind to beta-catenin. We found that expression of an ATPase-deficient mutant form of TIP49 (TIP49D302N) substantially inhibited beta-catenin-mediated neoplastic transformation of immortalized rat epithelial cells and anchorage-independent growth of human colon cancer cells with deregulated beta-catenin. The TIP49D302N mutant inhibited beta-catenin-mediated activation of TCF-dependent cellular genes. Similar inhibition of the expression of beta-catenin/TCF-dependent genes was seen with small interfering RNA approaches against endogenous TIP49. TIP49 was found in complexes with chromatin remodeling and histone-modifying factors and cofactors, including the TIP60 histone acetylase-associated proteins transactivation/transformation-domain associated protein (TRRAP) and BAF53. Using chromatin immunoprecipitation methods, the TIP49, TIP60, and TRRAP proteins were found to interact with sequences in the regulatory region of the gene for ITF-2, a TCF-dependent cellular gene. The ability of TIP49D302N to inhibit ITF-2 gene expression was linked to decreased acetylation of histones in the vicinity of the TCF-binding sites in the ITF-2 promoter region. We suggest that TIP49 is an important cofactor in beta-catenin/TCF gene regulation in normal and neoplastic cells, likely functioning in chromatin remodeling.
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PMID:TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling. 1469 87


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