Abstract:
:Here, we demonstrate that elevation of intracellular cyclic AMP (cAMP) in vascular endothelial cells (ECs) by either a direct activator of adenylyl cyclase or endogenous cAMP-mobilizing G protein-coupled receptors inhibited the tyrosine phosphorylation of STAT proteins by an interleukin 6 (IL-6) receptor trans-signaling complex (soluble IL-6Ralpha/IL-6). This was associated with the induction of suppressor of cytokine signaling 3 (SOCS-3), a bona fide inhibitor in vivo of gp130, the signal-transducing component of the IL-6 receptor complex. Attenuation of SOCS-3 induction in either ECs or SOCS-3-null murine embryonic fibroblasts abolished the inhibitory effect of cAMP, whereas inhibition of SHP-2, another negative regulator of gp130, was without effect. Interestingly, the inhibition of STAT phosphorylation and SOCS-3 induction did not require cAMP-dependent protein kinase activity but could be recapitulated upon selective activation of the alternative cAMP sensor Epac, a guanine nucleotide exchange factor for Rap1. Consistent with this hypothesis, small interfering RNA-mediated knockdown of Epac1 was sufficient to attenuate both cAMP-mediated SOCS-3 induction and inhibition of STAT phosphorylation, suggesting that Epac activation is both necessary and sufficient to observe these effects. Together, these data argue for the existence of a novel cAMP/Epac/Rap1/SOCS-3 pathway for limiting IL-6 receptor signaling in ECs and illuminate a new mechanism by which cAMP may mediate its potent anti-inflammatory effects.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Sands WA,Woolson HD,Milne GR,Rutherford C,Palmer TMdoi
10.1128/MCB.00207-06subject
Has Abstractpub_date
2006-09-01 00:00:00pages
6333-46issue
17eissn
0270-7306issn
1098-5549pii
26/17/6333journal_volume
26pub_type
杂志文章abstract::Expression of the acute-phase response genes, such as that for alpha-1 acid glycoprotein (AGP), involves both positive and negative transcription factors. A positive transcription factor, AGP/EBP, and a negative transcription factor, factor B, have been identified as the two most important factors responsible for the ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.14.9.6068
更新日期:1994-09-01 00:00:00
abstract::Different point mutations in the nucleolar protein fibrillarin (Nop1p in Saccharomyces cerevisiae) can inhibit different steps in ribosome synthesis. A screen for mutations that are synthetically lethal (sl) with the nop1-5 allele, which inhibits pre-rRNA processing, identified NOP56. An independent sl mutation screen...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.17.12.7088
更新日期:1997-12-01 00:00:00
abstract::Rapid kinetic techniques were employed to measure the transport of adenine in adenine phosphoribosyltransferase-deficient L929 and Chinese hamster ovary (CHO) cells in zero-trans entry and exit and equilibrium exchange procedures. The kinetic parameters of transport were computed by fitting appropriate integrated rate...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.3.1.82
更新日期:1983-01-01 00:00:00
abstract::Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that was identified through its rapid induction by mitogens in fibroblasts. Studies of TTP-deficient mice and cells derived from them showed that TTP could bind to certain AU-rich elements in mRNAs, leading to increases in the rates of mRNA deadenylation and d...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00945-06
更新日期:2006-12-01 00:00:00
abstract::Several eukaryotic transcription factors such as Sp1 or Oct1 contain glutamine-rich domains that mediate transcriptional activation. In human cells, promoter-proximally bound glutamine-rich activation domains activate transcription poorly in the absence of acidic type activators bound at distal enhancers, but synergis...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.20.8.2774-2782.2000
更新日期:2000-04-01 00:00:00
abstract::Histone H1 is an abundant and essential component of chromatin whose precise role in regulating gene expression is poorly understood. Here, we report that a major target of H1-mediated regulation in embryonic stem (ES) cells is the X-linked Rhox homeobox gene cluster. To address the underlying mechanism, we examined t...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00734-10
更新日期:2011-03-01 00:00:00
abstract::DHCR24/seladin-1, a crucial enzyme in sterol synthesis, is of lower abundance in brain areas affected by Alzheimer's disease. While high levels of DHCR24/seladin-1 exert antiapoptotic function by conferring resistance against oxidative stress, the molecular mechanism for this protective effect is not fully understood....
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00584-07
更新日期:2008-01-01 00:00:00
abstract::Trabecular myocardium accounts for the majority of the ventricles during early cardiogenesis, but compact myocardium is the primary component at later developmental stages. Elucidation of the genes regulating compact myocardium development is essential to increase our understanding of left ventricular noncompaction (L...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00829-12
更新日期:2012-12-01 00:00:00
abstract::The endoplasmic reticulum (ER) is the major cellular compartment where folding and maturation of secretory and membrane proteins take place. When protein folding needs exceed the capacity of the ER, the unfolded protein response (UPR) pathway modulates gene expression and downregulates protein translation to restore h...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00260-09
更新日期:2009-08-01 00:00:00
abstract::Nucleosomes were reconstituted in vitro with several singly end-labeled restriction fragments derived from a cloned somatic-type 5S RNA gene of Xenopus laevis and purified nucleosome core particles from Xenopus cultured cells or chicken erythrocytes. Nucleosome locations were determined by digestion of the reconstitut...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.7.5.1612
更新日期:1987-05-01 00:00:00
abstract::A culture system was developed which permitted the differentiation of chicken lens epithelial cells to lentoid bodies which contained several cell layers, accumulated high levels of delta-crystallin, and produced extensive gap junctions. This differentiation process was prevented when the cells were infected with a te...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.8.4.1414
更新日期:1988-04-01 00:00:00
abstract::The cytoplasmic domain of the cloned erythropoietin (EPO) receptor (EPOR) contains no protein kinase motif, yet addition of EPO to EPO-responsive cells causes an increase in protein-tyrosine phosphorylation. Here we show that addition of EPO or interleukin-3 (IL-3) to an IL-3-dependent cell line expressing the wild-ty...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.12.2.706
更新日期:1992-02-01 00:00:00
abstract::Individuals with the inherited cancer predisposition syndrome neurofibromatosis 2 (NF2) develop several central nervous system (CNS) malignancies, including glial cell neoplasms (ependymomas). Recent studies have suggested that the NF2 protein, merlin (or schwannomin), may regulate receptor tyrosine kinase signaling, ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01392-08
更新日期:2009-03-01 00:00:00
abstract::Posttranslational modifications (PTMs) can alter many fundamental properties of a protein. One or combinations of them have been known to regulate the dynamics of many cellular pathways and consequently regulate all vital processes. Understandably, pathogens have evolved sophisticated strategies to subvert these mecha...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00397-15
更新日期:2015-09-01 00:00:00
abstract::The structure of replication origins in metazoans is only nominally similar to that in model organisms, such as Saccharomyces cerevisiae. By contrast to the compact origins of budding yeast, in metazoans multiple elements act as replication start sites or control replication efficiency. We first reported that replicat...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.23.5.1832-1842.2003
更新日期:2003-03-01 00:00:00
abstract::Alpha-catenin, an integral part of cadherin-catenin adhesion complexes, is a major binding partner of beta-catenin, a key component of the Wnt pathway, which activates T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription and is often upregulated in cancers. Recently, we identified an alpha-catenin-related ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.24.6.2410-2422.2004
更新日期:2004-03-01 00:00:00
abstract::RNA interference with one of the eight Caenorhabditis elegans linker histone genes triggers desilencing of a repetitive transgene and developmental defects in the hermaphrodite germ line. These characteristics are similar to the phenotype of the C. elegans Polycomb group genes mes-2, mes-3, mes-4, and mes-6 (M. A. Jed...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01713-06
更新日期:2007-03-01 00:00:00
abstract::We analyzed the Burkitt's lymphoma line BL64 in which a reciprocal translocation joins the immunoglobulin kappa light-chain locus on chromosome 2 to the c-myc gene on chromosome 8. The breakpoints on the two marker chromosomes 8+ and 2p- occurred 5' of the Js segment within the conserved nonamer and heptamer recombina...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.7.6.2037
更新日期:1987-06-01 00:00:00
abstract::Selective and accurate transcription of purified genes by RNA polymerase II requires multiple factors. The factor designated TFIID was purified extensively from HeLa cell nuclear extracts by using a simple and novel complementation assay. Thus, TFIID was preferentially inactivated by mild heat treatment of a nuclear e...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.8.10.4028
更新日期:1988-10-01 00:00:00
abstract::The mSin3A-histone deacetylase corepressor is a multiprotein complex that is recruited by DNA binding transcriptional repressors. Sin3 has four paired amphipathic alpha helices (PAH1 to -4) that are protein-protein interaction motifs and is the scaffold upon which the complex assembles. We identified a novel mSin3A-in...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.21.13.4110-4118.2001
更新日期:2001-07-01 00:00:00
abstract::Topoisomerase I cleavage complexes can be induced by a variety of DNA damages and by the anticancer drug camptothecin. We have developed a ligation-mediated PCR (LM-PCR) assay to analyze replication-mediated DNA double-strand breaks induced by topoisomerase I cleavage complexes in human colon carcinoma HT29 cells at t...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.20.11.3977-3987.2000
更新日期:2000-06-01 00:00:00
abstract::The metabolic lifetime of mRNA can be specified by specific cis-acting elements within mRNA. One type of element is an adenylate- and uridylate-rich element (ARE) found in the 3' untranslated region of many highly unstable mRNAs for mammalian early-response genes (ERGs). Among the better-characterized members of the E...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.14.12.8471
更新日期:1994-12-01 00:00:00
abstract::Activation of the macrophage cell line RAW 264.7 with lipopolysaccharide (LPS) transiently activates protein kinase C zeta (PKC zeta) and Jun N-terminal kinase (JNK) through a phosphoinositide-3-kinase (PI3-kinase)-dependent pathway. Incubation of LPS-treated cells with the cyclopentenone 15-deoxy-Delta(12,14)-prostag...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.23.4.1196-1208.2003
更新日期:2003-02-01 00:00:00
abstract::The first processing step in the maturation of mouse precursor rRNA involves cleavage at nucleotide ca. +650, at the 5' border of a 200-nucleotide region that is conserved across mammals and contains the sequences that direct the processing. To identify the relevant sequence elements, we used rRNAs with small internal...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.11.1.458
更新日期:1991-01-01 00:00:00
abstract::Using an in vitro binding-site selection assay, we have demonstrated that c-Myc-Max complexes bind not only to canonical CACGTG or CATGTG motifs that are flanked by variable sequences but also to noncanonical sites that consist of an internal CG or TG dinucleotide in the context of particular variations in the CA--TG ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.13.9.5216
更新日期:1993-09-01 00:00:00
abstract::The interferon (IFN)-induced double-stranded RNA-activated protein kinase PKR mediates inhibition of protein synthesis through phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) and is also involved in the induction of the IFN gene through the activation of the transcription factor NF-k...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.20.13.4532-4542.2000
更新日期:2000-07-01 00:00:00
abstract::Tumor suppressor genes regulate the antiviral host defense through molecular mechanisms that are not yet well explored. Here, we show that the tumor suppressor retinoblastoma (Rb) protein positively regulates Toll-like receptor 3 (TLR3) expression, the sensing receptor for viral double-stranded RNA and poly(I · C). TL...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.06454-11
更新日期:2012-04-01 00:00:00
abstract::The Id subfamily of helix-loop-helix (HLH) proteins plays a fundamental role in the regulation of cellular proliferation and differentiation. The major mechanism by which Id proteins are thought to inhibit differentiation is through interaction with other HLH proteins and inhibition of their DNA-binding activity. Howe...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.21.2.524-533.2001
更新日期:2001-01-01 00:00:00
abstract::Hypoxia induces apoptosis but also triggers adaptive mechanisms to ensure cell survival. Here we show that the prosurvival effects of hypoxia-inducible factor 1 (HIF-1) in endothelial cells are mediated by neuron-derived orphan receptor 1 (NOR-1). The overexpression of NOR-1 decreased the rate of endothelial cells und...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00945-09
更新日期:2009-11-01 00:00:00
abstract::Ribonucleotide reductase (RNR), which catalyzes the rate-limiting step for deoxyribonucleotide production required for DNA synthesis, is an alpha2beta2 tetramer consisting of two large and two small subunits. RNR2 encodes a small subunit and is essential for mitotic viability in Saccharomyces cerevisiae. We have clone...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.17.10.6105
更新日期:1997-10-01 00:00:00