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Biomedical subjects

A Larner

Publications and source records attributed to A Larner.

10 recordsLinked to original sources
PubMed1998

Stimulation of Stat5 by granulocyte colony-stimulating factor (G-CSF) is modulated by two distinct cytoplasmic regions of the G-CSF receptor.

In a manner similar to many other cytokines, treatment of cells with granulocyte CSF (G-CSF) has been shown to induce the tyrosine phosphorylation of the STAT proteins. Activation of Stat1 and Stat5 by G-CSF requires the membrane-proximal cytoplasmic domain of the receptor, including box1 and box2, while G-CSF-stimulated tyrosine phosphorylation of Stat3 also requires a region distal to box 2. In this study, we show that although the membrane-proximal 55 amino acids of the G-CSF receptor are sufficient for activation of Stat5, the maximal rate of Stat5 activation requires an additional 30 amino acids of the cytoplasmic domain. In contrast, the distal carboxyl-terminal region of the receptor appears to down-regulate Stat5 activation in that deletion of this carboxyl terminus results in increased amplitude and prolonged duration of Stat5 activation by G-CSF. Significantly, expression of a truncated dominant-negative Stat5 protein in hemopoietic cells not only inhibits G-CSF-dependent cell proliferation, but also suppresses cell survival upon G-CSF withdrawal. We further show that a potential protein tyrosine phosphatase may play a critical role in the down-regulation of G-CSF-stimulated Stat5 activation. These results demonstrate that two distinct cytoplasmic regions of the G-CSF receptor are involved in the regulation of the intensity and duration of Stat5 activation, and that Stat5 may be an important player in G-CSF-mediated cell proliferation and survival.

Animals↗
PubMed1996

Interferon signal transduction.

The interferon signal transduction pathway initiates at a cell surface receptor and mediates the activation of target genes in the nucleus. The binding of interferon to a transmembrane receptor stimulates the activation of associated tyrosine kinases of the Janus kinase (JAK) family. Subsequently, latent cytoplasmic transcription factors are activated by tyrosine phosphorylation and function as signal transducers and activators of transcription (STATs). Advances in the field of interferon research have contributed to our understanding of signal transduction induced by many cytokines that also use JAK/STAT signaling pathways to activate early response genes. The specificity of signal activation by distinct cytokines that share these signaling components, and the molecular interaction of the signaling components with each other and their respective cytokine receptors represent major areas of research that are beginning to be elucidated. Signaling molecules other than the JAKs and STATs have also been found to be activated following interferon binding. In addition, the induction of type I interferon stimulated genes by double-stranded RNA in the absence of interferon provides another pathway of specific gene activation.

Animals↗
PubMed1995

Vaccinia virus B18R gene encodes a type I interferon-binding protein that blocks interferon alpha transmembrane signaling.

Poxviruses encode a large number of proteins that attenuate the inflammatory and immune responses to infection. In this report we demonstrate that a number of orthopoxviruses express a type I interferon (IFN)-binding protein, which is encoded by the B18R open reading frame in the WR strain of vaccinia virus. The B18R protein has significant regions of homology with the alpha subunits of the mouse, human, and bovine type I IFN receptors, bound human IFN alpha 2 with high affinity, and inhibited transmembrane signaling as demonstrated by inhibition of Fc receptor factor gamma 1/gamma 2 and interferon-stimulated gene factor-3 formation as well as inhibition of the IFN alpha antiviral response. Among viral host response modifiers, the B18R protein is unique inasmuch as it exists as a soluble extracellular as well as a cell surface protein and thus should effectively block both autocrine and paracrine functions of IFN.

Amino Acid Sequence↗
PubMed1992

Substance P and multiple sclerosis.

Multiple sclerosis is an inflammatory disease which affects the white matter of the central nervous system (CNS). The aetiology of this condition is unknown but it is generally believed to represent an autoimmunological response to a component of myelin triggered by an environmental factor, in a genetically susceptible individual. The natural history of the disease, in terms of clinical disability, is unpredictable, and the factors responsible unknown. Substance P is an undecapeptide that acts as a neurotransmitter in the CNS and as a regulator of immune responses. The recent discovery of substance P immunoreactive astrocytes in multiple sclerosis plaques raises the possibility that this peptide may be important both in the development of plaques and in governing the natural history of the disease.

Autoimmunity↗
PubMed1988

Contrasting interactions between phorbol ester and insulin on the regulation of glycogen synthase activity and p33 mRNA accumulation in rat hepatoma cells.

We have compared the effect of phorbol 12-myristate 13-acetate (PMA) with that of insulin on three targets of insulin action in H4IIEC3 (H4) rat hepatoma cells. These parameters are the phosphorylation state and tyrosine kinase activity of the insulin receptor, the activation state of glycogen synthase, and the accumulation of p33 mRNA. Under conditions where insulin treatment of H4 cells clearly activated receptor serine and tyrosine phosphorylation on the insulin receptor beta-subunit in situ, activated receptor tyrosine kinase activity in vitro, and activated glycogen synthase and p33 mRNA accumulation in situ, PMA alone did not influence the insulin receptor phosphorylation state or tyrosine kinase activity and did not affect glycogen synthase activity, but markedly increased p33 mRNA accumulation. When PMA was added in the presence of insulin, particularly if PMA was preincubated, the receptor phosphorylation state and the tyrosine kinase activity again were not affected, but insulin-activated glycogen synthase was significantly diminished or abolished. In contrast, increased p33 mRNA accumulation by PMA was additive with that of insulin. Thus, under conditions where no effect was observed on the insulin receptor phosphorylation state or the tyrosine kinase activity, PMA acted in an insulin-antagonistic manner on glycogen synthase and in an insulin-like manner on p33 mRNA accumulation, indicating that these actions of PMA are unrelated to early events in the pathway of the insulin action. Effects on glycogen synthase are most readily explained by an effect of protein kinase C-activated phosphorylation of glycogen synthase.

Animals↗
PubMed1986

Interferon-stimulated transcription: isolation of an inducible gene and identification of its regulatory region.

A human gene (termed ISG-54K) that is induced from near undetectable levels to high transcriptional activity by alpha- and beta-interferons has been cloned. The genomic structure and nucleotide sequence of the coding region were determined and the RNA initiation site was identified. The 5' portion of the gene was fused with a heterologous gene lacking an active promoter in recombinant plasmid and adenoviral vectors. These fusion genes were used to assess the activity of the ISG-54K promoter in response to interferon. RNA was formed in HeLa cells from recombinant plasmids only in response to interferon. Furthermore, in human diploid fibroblasts, infection with the recombinant adenovirus vector resulted in a 50-fold increase in specific RNA in response to interferon, followed by a subsequent decrease, imitating the natural regulated transcriptional cycle of the endogenous gene.

Amino Acid Sequence↗
PubMed1980

Concanavalin A-stimulated Ca2+ uptake in rat splenocytes.

Commercially available concanavalin A binds Ca2+ with high apparent affinity. In order to dissociate concanavalin A stimulated Ca2+ uptake (defined as an increased association of 45Ca2+ with cells) in rat splenocytes and Ca2+ binding to cell-bound concanavalin A, conditions were developed to remove more than 75% of the bound concanavalin A. Under these conditions concanavalin A treated cells showed a considerable increase in 45Ca2+ uptake over control. The concanavalin A stimulated uptake of 45Ca2+ occurred within minutes, and required concentrations of concanavalin A which promoted [3H]thymidine uptake into these cells. Succinyl concanavalin A was less potent in promoting Ca2+ uptake than concanavalin A. Sodium periodate inhibited Ca2+ uptake at concentrations which promoted 3H-thymidine incorporation into splenocytes. It is concluded that concanavalin A promotes Ca2+ uptake which is not due to binding of 45Ca2+ to concanavalin A. Although the concanavalin A-promoted Ca2+ uptake occurs at lectin concentrations that cause lymphocyte proliferation as measured by 3H-thymidine incorporation, the role of Ca2+ in this event remains unclear.

Animals↗
PubMed1977

Pressor and stereoidogenic actions of [des-Asp1]angiotensin I dependency on conversion to angiotensin III.

In the conscious rat, angiotensin III, [des-Asp1]angiotensin II, stimulates aldosterone biosynthesis and exhibits 30-50% of the pressor potency of angiotensin II. A potential precursor of the biologically active heptapeptide is [des-Asp1]angiotensin I, the C-terminal nonapeptide of angiotensin I. The in vivo pressor and the in vivo and in vitro steroidogenic actions of [des-Asp1]angiotensin I were investigated in the presence and absence of an inhibitor of converting enzyme. The pressor responses to [des-Asp1]angiotensin I and [des-Asp1]angiotensin II were similar and showed comparable changes in responsiveness when the rats were maintained on diets with different sodium content. The pressor activity of [des-Asp1]angiotensin I was attenuated progressively by pretreatment with increasing doses of converting enzyme inhibitor and was totally abolished in five of seven rats at an inhibitor dose of 1,200 microng/kg. In isolated zona glomerulosa cells from rats on normal sodium diets, angiotensin I and [des-Asp1]angiotensin I had only weak steroidogenic effects relative to angiotensin III. The administration of [des-Asp1]angiotensin I, 1 nmol/kg, subcutaneously to six rats on normal sodium diets resulted in a rise in the 6-hour urinary aldosterone excretion from 46.5 +/- 6.6 to 99.5 +/- 11.8 ng (P less than 0.01). Treatment with converting enzyme inhibitor (2 mg/kg) prevented this steroidogenic response to [des-Asp1]angiotensin I. These in vivo studies in the conscious rat show that the administration of [des-Asp1]angiotensin I results in increases in both blood pressure and urinary aldosterone excretion which are dependent on the hydrolysis of the nonapeptide by converting enzymes to angiotensin III. If [des-Asp1]angiotensin I is formed in this species, then it will be an immediate precursor of angiotensin III.

Adrenal Cortex↗
PubMed1976

Role of converting enzyme in the cardiovascular and adrenal cortical responses to (des-Asp1)-angiotensin I.

(Des-Asp1)-angiotensin I, angiotensin II and III were evaluated for pressor activities in conscious nephrectomized rats and for steroidogenic actions in rat adrenal zona glomerulosa. The pressor effect of this angiotensin nonapeptide was similar to that found with mole-equivalent doses of angiotensin III (one-third as active as angiotensin II) and was significantly attenuated by pretreatment with the 0. jararaca nonapeptide converting enzyme inhibitor. Hence, (des-Asp1)-angiotensin I is a substrate for converting enzyme in vivo, and the rapid conversion indicates that an alternate pathway for the formation of angiotensin III could exist. (Des-Asp1)-angiotensin I possessed only 0.1% of the activity of angiotensin III as a steroidogenic agent in cell suspensions of rat adrenal zona glomerulosa. Angiotensin I was a weak steroidogenic agent in vitro (1%) and was not blocked by an inhibitor of converting enzyme. Adrenal cells dispersed from the outer zone of the cortex would appear to be devoid of significant converting enzyme activity.

Adrenal Glands↗