Cytokines are secreted regulators that control the production, maturation and functional activation of blood cells that are essential for hemostasia and host defense from infection. These beneficial actions of cytokines have been harnessed clinically, for example the use of G-CSF to promote recovery of white blood cells in patients receiving cancer chemotherapy, or EPO to treat anemia. In addition, deregulation of cytokines, their receptors or intracellular signal transduction pathways is associated with autoimmunity and cancer. The importance of negative regulation of cytokine signaling cascades has come clearly into focus with our identification and characterization of the family of Suppressors of Cytokine Signaling (SOCS) proteins. Our long-term objective is to identify the specific cytokines regulated by individual SOCS proteins and the cells and biological systems dependent on SOCS regulation. We seek to define the biochemical basis of SOCS action via elucidation of the structures of, and physical interactions between, SOCS proteins and the signaling machinery and to define the disease contexts in which manipulation of SOCS proteins may prove clinically beneficial. Our focus here is on S0CS3, the key negative regulator of G-CSF and IL-6 that is required to prevent spontaneous inflammatory disease. Applying a multidlsciplinary approach employing biochemical and structural biological tools, cell biology and genetically modified mouse models, our major goals are: defining the specific roles of S0CS3 in relevant mouse models of inflammation and hematopoietic malignancy, understanding the shared or overlapping physiological roles of S0CS3 with other SOCS family members, and defining the functions of protein domains within the overall actions of S0CS3, along with discovery of novel protein targets of S0CS3 action.

Public Health Relevance

Successful outcomes will provide new strategies for intervention in cytokine-related diseases, particularly cancer and inflammation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Mufson, R Allan
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Walter and Eliza Hall Institute Medical Research
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VIC, -3052
Nicola, Nicos A; Babon, Jeffrey J (2015) Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev 26:533-44
Kedzierski, Lukasz; Clemens, E Bridie; Bird, Nicola L et al. (2015) SOCS4 is dispensable for an efficient recall response to influenza despite being required for primary immunity. Immunol Cell Biol 93:909-13
Babon, Jeffrey J; Varghese, Leila N; Nicola, Nicos A (2014) Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol 26:13-9
Kershaw, Nadia J; Laktyushin, Artem; Nicola, Nicos A et al. (2014) Reconstruction of an active SOCS3-based E3 ubiquitin ligase complex in vitro: identification of the active components and JAK2 and gp130 as substrates. Growth Factors 32:1-10
Babon, Jeffrey J; Lucet, Isabelle S; Murphy, James M et al. (2014) The molecular regulation of Janus kinase (JAK) activation. Biochem J 462:1-13
Varghese, Leila N; Ungureanu, Daniela; Liau, Nicholas P D et al. (2014) Mechanistic insights into activation and SOCS3-mediated inhibition of myeloproliferative neoplasm-associated JAK2 mutants from biochemical and structural analyses. Biochem J 458:395-405
Kedzierski, Lukasz; Linossi, Edmond M; Kolesnik, Tatiana B et al. (2014) Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection. PLoS Pathog 10:e1004134
Linossi, Edmond M; Chandrashekaran, Indu R; Kolesnik, Tatiana B et al. (2013) Suppressor of Cytokine Signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1. PLoS One 8:e70536
Metcalf, Donald (2013) The colony-stimulating factors and cancer. Cancer Immunol Res 1:351-6
Nicola, Nicos A (2013) A (selective) history of Australian involvement in cytokine biology. Cytokine Growth Factor Rev 24:179-87

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