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

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37CA022556-32
Application #
7784323
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mufson, R Allan
Project Start
1978-03-01
Project End
2015-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
32
Fiscal Year
2010
Total Cost
$237,320
Indirect Cost
Name
Walter and Eliza Hall Institute Medical Research
Department
Type
DUNS #
753236256
City
Parkville
State
Country
Australia
Zip Code
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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