The objectives of this project are to characterize the molecular control of myeloid leukemia cells by first establishing the nature of the specific glycoproteins (colony-stimulating factors, CSFs) controlling cell division and differentiation of normal granulocytes and macrophages, then determining the actions of the CSFs on leukemia cells. We have established that four glycoproteins interact to control normal mouse granulocytes and macrophages: GM-CSF, M-CSF, G-CSF, and MultiCSF (IL-3). All four have been purified to homogeneity in small amounts. cDNAs have been cloned for GM-CSF and Multi-CSF with bacterial expression and the recombinant material has similar in vitro and in vivo properties to the native molecules. We have established that G-CSF can suppress myeloid leukemic cells by enforcing terminal differentiation. Using ?125?I-labeled G-CSF, we have shown that receptor numbers on leukemia cells are similar to those on normal GM precursor cells. Differentiation-unresponsive leukemia cells have been shown to lack membrane receptors for G-CSF. These studies will be extended using radiolabeled GM-CSF, and the genetic elements controlling GM-CSF will be sequenced and analyzed. Amino acid sequence data has been obtained from purified G-CSF and attempts are in progress to clone a cDNA for G-CSF, a first step towards the mass production of G-CSF. (M)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA022556-11
Application #
3165859
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1978-03-01
Project End
1990-04-30
Budget Start
1988-05-01
Budget End
1989-04-30
Support Year
11
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Walter and Eliza Hall Institute Medical Research
Department
Type
DUNS #
City
Victoria
State
Country
Australia
Zip Code
3050
Nicola, Nicos A; Babon, Jeffrey J (2015) Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev 26:533-44
Babon, Jeffrey J; Varghese, Leila N; Nicola, Nicos A (2014) Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol 26:13-9
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
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
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
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
Metcalf, Donald (2013) The colony-stimulating factors and cancer. Cancer Immunol Res 1:351-6
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
White, Christine A; Nicola, Nicos A (2013) SOCS3: An essential physiological inhibitor of signaling by interleukin-6 and G-CSF family cytokines. JAKSTAT 2:e25045
Kershaw, Nadia J; Murphy, James M; Lucet, Isabelle S et al. (2013) Regulation of Janus kinases by SOCS proteins. Biochem Soc Trans 41:1042-7

Showing the most recent 10 out of 287 publications