Nicos A. Nicola
Walter and Eliza Hall Institute of Medical Research
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Nicos A. Nicola.
Nature | 1997
Robyn Starr; Tracy A. Willson; Elizabeth M. Viney; Leecia J. Murray; John Robert Rayner; Brendan J. Jenkins; Thomas J. Gonda; Warren S. Alexander; Donald Metcalf; Nicos A. Nicola; Douglas J. Hilton
Cytokines are secreted proteins that regulate important cellular responses such as proliferation and differentiation. Key events in cytokine signal transduction are well defined: cytokines induce receptor aggregation, leading to activation of members of the JAK family of cytoplasmic tyrosine kinases. In turn, members of theSTAT family of transcription factors are phosphorylated, dimerize and increase the transcription of genes with STAT recognition sites in their promoters. Less is known of how cytokine signal transduction is switched off. We have cloned a complementary DNA encoding a protein SOCS-1, containing an SH2-domain, by its ability to inhibit the macrophage differentiation of M1 cells in response to interleukin-6. Expression of SOCS-1 inhibited both interleukin-6-induced receptor phosphorylation and STAT activation. We have also cloned two relatives of SOCS-1, named SOCS-2 and SOCS-3, which together with the previously described CIS (ref. 5) form a new family of proteins. Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction.
Nature Immunology | 2003
Ben A. Croker; Danielle L. Krebs; Jian-Guo Zhang; Samuel Wormald; Tracy A. Willson; Edouard G. Stanley; Lorraine Robb; Christopher J. Greenhalgh; Irmgard Förster; Björn E. Clausen; Nicos A. Nicola; Donald Metcalf; Douglas J. Hilton; Andrew W. Roberts; Warren S. Alexander
Members of the suppressor of cytokine signaling (SOCS) family are potentially key physiological negative regulators of interleukin-6 (IL-6) signaling. To examine whether SOCS3 is involved in regulating this signaling, we have used conditional gene targeting to generate mice lacking Socs3 in the liver or in macrophages. We show that Socs3 deficiency results in prolonged activation of signal transducer and activator of transcription 1 (STAT1) and STAT3 after IL-6 stimulation but normal activation of STAT1 after stimulation with interferon-γ (IFN-γ). Conversely, IL-6-induced STAT activation is normal in Socs1-deficient cells, whereas STAT1 activation induced by IFN-γ is prolonged. Microarray analysis shows that the pattern of gene expression induced by IL-6 in Socs3-deficient livers mimics that induced by IFN-γ. Our data indicate that SOCS3 and SOCS1 have reciprocal functions in IL-6 and IFN-γ regulation and imply that SOCS3 has a role in preventing IFN-γ-like responses in cells stimulated by IL-6.
The EMBO Journal | 1999
Sandra E. Nicholson; Tracy A. Willson; Alison Farley; Robyn Starr; Jian-Guo Zhang; Manuel Baca; Warren S. Alexander; Donald Metcalf; Douglas J. Hilton; Nicos A. Nicola
SOCS‐1 (suppressor of cytokine signaling‐1) is a representative of a family of negative regulators of cytokine signaling (SOCS‐1 to SOCS‐7 and CIS) characterized by a highly conserved C‐terminal SOCS box preceded by an SH2 domain. This study comprehensively examined the ability of several SOCS family members to negatively regulate the gp130 signaling pathway. SOCS‐1 and SOCS‐3 inhibited both interleukin‐6 (IL‐6)‐ and leukemia inhibitory factor (LIF)‐induced macrophage differentiation of murine monocytic leukemic M1 cells and LIF induction of a Stat3‐responsive reporter construct in 293T fibroblasts. Deletion of amino acids 51–78 in the N‐terminal region of SOCS‐1 prevented inhibition of LIF signaling. The SOCS‐1 and SOCS‐3 N‐terminal regions were functionally interchangeable, but this did not extend to other SOCS family members. Mutation of SH2 domains abrogated the ability of both SOCS‐1 and SOCS‐3 to inhibit LIF signal transduction. Unlike SOCS‐1, SOCS‐3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS‐1 and SOCS‐3 act on the JAK–STAT pathway in different ways. Thus, although inhibition of signaling by SOCS‐1 and SOCS‐3 requires both the SH2 and N‐terminal domains, their mechanisms of action appear to be biochemically different.
Nature | 2000
Donald Metcalf; Christopher J. Greenhalgh; Elizabeth M. Viney; Tracy A. Willson; Robyn Starr; Nicos A. Nicola; Douglas J. Hilton; Warren S. Alexander
Suppressor of cytokine signalling-2 (SOCS-2) is a member of the suppressor of cytokine signalling family, a group of related proteins implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal-transduction pathway. Here we use mice unable to express SOCS-2 to examine its function in vivo. SOCS-2-/- mice grew significantly larger than their wild-type littermates. Increased body weight became evident after weaning and was associated with significantly increased long bone lengths and the proportionate enlargement of most organs. Characteristics of deregulated growth hormone and insulin-like growth factor-I (IGF-I) signalling, including decreased production of major urinary protein, increased local IGF-I production, and collagen accumulation in the dermis, were observed in SOCS-2-deficient mice, indicating that SOCS-2 may have an essential negative regulatory role in the growth hormone/IGF-I pathway.
Trends in Biochemical Sciences | 2002
Benjamin T. Kile; Brenda A. Schulman; Warren S. Alexander; Nicos A. Nicola; Helene M. Martin; Douglas J. Hilton
Although initially identified in the suppressor of cytokine signaling (SOCS) family of proteins, the C-terminal SOCS box has now been identified in more than 40 proteins in nine different families. Growing evidence suggests that the SOCS box, similar to the F-box, acts as a bridge between specific substrate-binding domains and the more generic proteins that comprise a large family of E3 ubiquitin protein ligases. In this way, SOCS proteins regulate protein turnover by targeting proteins for polyubiquitination and, therefore, for proteasome-mediated degradation.
Journal of Biological Chemistry | 1998
Timothy E. Adams; Johnny A. Hansen; Robyn Starr; Nicos A. Nicola; Douglas J. Hilton; Nils Billestrup
Four members (SOCS-1, SOCS-2, SOCS-3, and CIS) of a family of cytokine-inducible, negative regulators of cytokine receptor signaling have recently been identified. To address whether any of these genes are induced in response to growth hormone (GH), serum-starved 3T3-F442A fibroblasts were incubated with GH for various time points, and the expression of the SOCS gene family was analyzed by Northern blotting. GH stimulated the rapid, transient induction ofSOCS-3 mRNA, peaking 30 min after the initiation of GH exposure and declining to basal levels by 2 h. Expression of the other SOCS genes (SOCS-1, SOCS-2,CIS) was also up-regulated by GH, although to a lesser extent than SOCS-3 and with differing kinetics.SOCS-3 expression was also strongly induced in 3T3-F442A cells treated with leukemia-inhibitory factor (LIF), with weaker induction of SOCS-1 and CIS being observed. The preferential induction of SOCS-3 mRNA was also observed in hepatic RNA isolated from the livers of mice that had received a single supraphysiological dose of GH intraperitoneally. Co-transfection studies revealed that constitutive expression of SOCS-1 and SOCS-3, but not SOCS-2 or CIS, blocked GH-induced transactivation of the GH-responsive serine protease inhibitor 2.1 gene promoter.
Proceedings of the National Academy of Sciences of the United States of America | 2001
Andrew W. Roberts; Lorraine Robb; Steven Rakar; Lynne Hartley; Leonie A. Cluse; Nicos A. Nicola; Donald Metcalf; Douglas J. Hilton; Warren S. Alexander
Mice lacking suppressor of cytokine signaling 3 (SOCS3) exhibited embryonic lethality with death occurring between days 11 and 13 of gestation. At this stage, SOCS3−/− embryos were slightly smaller than wild type but appeared otherwise normal, and histological analysis failed to detect any anatomical abnormalities responsible for the lethal phenotype. Rather, in all SOCS3−/− embryos examined, defects were evident in placental development that would account for their developmental arrest and death. The placental spongiotrophoblast layer was significantly reduced and accompanied by increased numbers of giant trophoblast cells. Delayed branching of the chorioallantois was evident, and, although embryonic blood vessels were present in the labyrinthine layer of SOCS3−/− placentas, the network of embryonic vessels and maternal sinuses was poorly developed. Yolk sac erythropoiesis was normal, and, although the SOCS3−/− fetal liver was small at day 12.5 of gestation (E12.5), normal frequencies of erythroblasts and hematopoietic progenitor cells, including blast forming unit-erythroid (BFU-E) and, colony forming unit-erythroid (CFU-E) were present at both E11.5 and E12.5. Colony formation for both BFU-E and CFU-E from SOCS3−/− mice displayed wild-type quantitative responsiveness to erythropoietin (EPO), in the presence or absence of IL-3 or stem cell factor (SCF). These data suggest that SOCS3 is required for placental development but dispensable for normal hematopoiesis in the mouse embryo.
Cell | 1985
Francesca Walker; Nicos A. Nicola; Donald Metcalf; Antony W. Burgess
Granulocytes and macrophages can be produced in vitro when progenitor cells from mouse bone marrow are stimulated by any of four distinct colony stimulating factors, Multi-CSF (IL-3), GM-CSF, G-CSF, and M-CSF (CSF-1). At 0 degrees C the four CSFs do not cross-compete for binding to bone marrow cells, indicating that each has a specific cell surface receptor. However, at 21 degrees C or 37 degrees C, Multi-CSF inhibits binding of the other three CSFs and GM-CSF inhibits binding of G-CSF and M-CSF. Rather than competing directly for receptor binding, the binding of Multi-CSF, GM-CSF, or G-CSF to their own receptor induces the down-modulation (and thus activation) of other CSF receptors at 37 degrees C. The pattern and potency of down-modulation activity exhibited by each type of CSF parallels the pattern and potency of its biological activity. We propose a model in which the biological interactions of the four CSFs are explained by their ability to down-modulate and activate lineage-specific receptors.
Immunity | 2004
Ben A. Croker; Donald Metcalf; Lorraine Robb; Wei Wei; Sandra Mifsud; Ladina DiRago; Leonie A. Cluse; Kate D. Sutherland; Lynne Hartley; Emily Williams; Jian-Guo Zhang; Douglas J. Hilton; Nicos A. Nicola; Warren S. Alexander; Andrew W. Roberts
To determine the importance of suppressor of cytokine signaling-3 (SOCS3) in the regulation of hematopoietic growth factor signaling generally, and of G-CSF-induced cellular responses specifically, we created mice in which the Socs3 gene was deleted in all hematopoietic cells. Although normal until young adulthood, these mice then developed neutrophilia and a spectrum of inflammatory pathologies. When stimulated with G-CSF in vitro, SOCS3-deficient cells of the neutrophilic granulocyte lineage exhibited prolonged STAT3 activation and enhanced cellular responses to G-CSF, including an increase in cloning frequency, survival, and proliferative capacity. Consistent with the in vitro findings, mutant mice injected with G-CSF displayed enhanced neutrophilia, progenitor cell mobilization, and splenomegaly, but unexpectedly also developed inflammatory neutrophil infiltration into multiple tissues and consequent hind-leg paresis. We conclude that SOCS3 is a key negative regulator of G-CSF signaling in myeloid cells and that this is of particular significance during G-CSF-driven emergency granulopoiesis.
Cell | 1985
Wendy D. Cook; Donald Metcalf; Nicos A. Nicola; Antony W. Burgess; Francesca Walker
Abelson virus has been used to transform cells of a murine, factor-dependent myeloid cell line (FD). Factor-independent (FI) cell lines were derived, which expressed the viral genome and were tumorigenic in syngeneic mice. Karyotypic analysis of FI cells before and after passage in vivo indicated that the tumorigenic cells were derived from FD cells. Northern gel analysis of mRNA, bioassay of culture supernatants, and the density-independent growth of the FI cells indicated that the transformation had not induced the synthesis of the hemopoietic growth factors normally required to support the FD cells, that is, granulocyte-macrophage CSF or Multi-CSF. The FD and FI cells displayed similar numbers of cell surface receptors for Multi-CSF (IL-3) and GM-CSF. We conclude that Abelson virus transformation of this line from factor-dependence to factor-independence and tumorigenicity did not involve autocrine stimulation.