Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF): Receptor biology, signal transduction, and neutrophil activation

doi:10.1016/0268-960X(92)90007-D

Blood Reviews

Volume 6, Issue 1, March 1992, Pages 43-57

https://doi.org/10.1016/0268-960X(92)90007-D Get rights and content

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are two of the growing number of recognized cytokines involved in the regulation of hematopoiesis. The purification of these factors and the subsequent cloning of the cDNAs which encode these proteins have led to their widespread clinical use in the setting of therapy or disease-induced myelosuppression. Although originally purified on the basis of their colony-stimulating properties, GM-CSF and G-CSF may also play important roles in the regulation of effector cell function. The mechanisms underlying progenitor cell proliferation and effector cell stimulation remain poorly understood. However, the characterization of the GM-CSF and G-CSF receptors and recent work in signal transduction are helping to elucidate these mechanisms. This paper will review the biology of the GM-CSF and G-CSF receptors, the mechanisms of post-receptor signal transduction, and the resultant effects on neutrophil function. In addition, the current and potential clinical uses of these factors will be examined in light of their ability to activate and perhaps enhance the function of neutrophils.

References (196)

Y.C. Yang et al.
The human genes for GM-CSF and IL-3 are closely linked in tandem on chromosome 5
Blood
(1988)
C.A. Westbrook et al.
Report of the chromosome 5 workshop
Genomics
(1991)
N.A. Nicola et al.
Purification of a factor inducing differentiation in murine myelo-monocytic leukemia cells: identification as granulocyte-colony-stimulating factor (G-CSF)
Journal of Biological Chemistry
(1983)
M.L. Summar et al.
Protein kinase C: a new linkage marker for growth hormone and for COL1A1
Genomics
(1989)
J.F. DiPersio et al.
Characterization of the soluble human granulocyte-macrophage colony-stimulating factor receptor complex
The Journal of Biological Chemistry
(1991)
S.A. Cannistra et al.
Differentiation-associated expression of two functionally distinct classes of granulocyte-macrophage colony-stimulating factor receptors by human myeloid cells
The Journal of Biological Chemistry
(1990)
N Onetto-Pothier et al.
Characterization of granulocyte-macrophage colony-stimulating factor receptor on the blast cells of acute myeloblastic leukemia
Blood
(1990)
T Gesner et al.
Identification through chemical cross-linking of distinct granulocyte-macrophage colony-stimulating factor and interleukin-3 receptors on myeloid leukemic cells, KG-1
Blood
(1989)
G.C. Baldwin et al.
Non-hematopoietic tumor cells express functional GM-CSF receptors
Blood
(1989)
J.F. Bazan
A novel family of growth factor receptors: a common binding domain in the growth hormone, prolactin, erythropoietin and IL-6 receptors, and the p75 IL-2 receptor beta-chain
Biochemical and Biophysical Research Communications
(1989)

A.D. DAndrea et al.

Expression cloning of the murine erythropoietin receptor

Cell

(1989)

D Cosman et al.

A new cytokine receptor superfamily

Trends in Biochemical Sciences

(1990)

T Taga et al.

Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130

Cell

(1989)

R Fukunaga et al.

Expression cloning of a receptor for murine granulocyte colony-stimulatig factor

Cell

(1990)

C.A. Jacobs et al.

Characterization and pharmacokinetic parameters of recombinant soluble interleukin-4 receptor

Blood

(1991)

B Mosley et al.

The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane bound forms

Cell

(1989)

B Mosley et al.

The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane-bound forms

Cell

(1989)

D Novick et al.

Purification of soluble cytokine receptors from normal human urine by ligand-affinity and immunoaffinity chromatography

Journal of Chromatography

(1990)

R.G. Goodwin et al.

Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily

Cell

(1990)

M Souyri et al.

A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors

Cell

(1990)

B.R. Avalos et al.

Human granulocyte colony-stimulating factor: biological activities and receptor characterization on hematopoietic cells and small cell lung cancer lines

Blood

(1990)

L.M. Budel et al.

Granulocyte colony-stimulating factor receptors in human acute myelocytic leukemia

Blood

(1989)

J Inazawa et al.

Assignment of the human granulocyte colony-stimulating factor receptor gene (CSF3R) to chromosome 1 at region p35-p34.3

Genomics

(1991)

J.A. Symons et al.

A soluble form of the interleukin-1 receptor produced by a human B cell line

FEBS Letters

(1990)

B.C. Gliniak et al.

Expression of the M-CSF receptor is controlled post-transcriptionally by the dominant actions of GM-CSF or multi-CSF

Cell

(1990)

T.R. Bradley et al.

The growth of mouse bone marrow cells in vitro

Australian Journal of Experimental Biology and Medical Science

(1966)

Y Ichikawa et al.

In vitro control of the development of macrophage and granulocyte colonies

D Metcalf

The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells

Nature

(1989)

N.M. Gough et al.

Molecular cloning of cDNA encoding a murine haematopoietic growth regulator, granulocyte-macrophage colony stimulating factor

Nature

(1984)

G.G. Wong et al.

Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins

Science

(1985)

D Metcalf

The molecular control of blood cells

(1988)

D.P. Barlow et al.

Close genetic and physical linkage between the murine haemopoietic growth factor genes GM-CSF and multi-CSF (IL-3)

The EMBO Journal

(1987)

S.J. O'Brien

Genetic Maps: Locus Maps of Complex Genomes

M.M. Le Beau et al.

Assignment of the GM-CSF, CSF-1, and FMS genes to human chromosome 5 provides evidence for linkage of a family of genes regulating hematopoiesis and for their involvement in the deletion (5q) in myeloid disorders

S Miyatake et al.

Structure of the chromosomal gene for granulocyte-macrophage colony stimulating factor: comparison of the mouse and human genes

The EMBO Journal

(1985)

S Nagata et al.

Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor

Nature

(1986)

L.M. Souza et al.

Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells

Science

(1986)

M Tsuchiya et al.

Isolation and characterization of the cDNA for murine granulocyte colony-stimulating factor

R.N. Simmers et al.

Localization of the G-CSF gene on chromosome 17 proximal to the breakpoint in the t(15;17) in acute promyelocytic leukemia

Blood

(1987)

L Longo et al.

Mapping of chromosome 17 breakpoints in acute myeloid leukemias

Oncogene

(1990)

D.J. Tweardy et al.

Molecular cloning and characterization of a cDNA for human granulocyte colony-stimulating factor (G-CSF) from a glioblastoma multiforme cell line and localization of the G-CSF gene to chromosome band 17q21

Oncogene Research

(1987)

D Acampora et al.

The human HOX gene family

Nucleic Acids Research

(1989)

K Huebner et al.

The nerve growth factor receptor gene is at human chromosome region 17q12–17q22, distal to the chromosome 17 breakpoint in acute leukemias

M Tsai-Pflugfelder et al.

Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21–22

M.G. Mattei et al.

Mapping of the human retinoic acid receptor to the q21 band of chromosome 17

Human Genetics

(1988)

H de-The et al.

The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus

Nature

(1990)

P.F. Bray et al.

Platelet glycoprotein IIb. Chromosomal localization and tissue expression

Journal of Clinical Investigation

(1987)

D.M. Sosnoski et al.

Chromosomal localization of the genes for the vitronectin and fibronectin receptors alpha subunits and for platelet glycoproteins IIb and IIIa

Journal of Clinical Investigation

(1988)

J Inazawa et al.

Assignment of the human myeloperoxidase gene (MPO) to bands q21.3–q23 of chromosome 17

Cytogenetics and Cell Genetics

(1989)

S.R. Zaki et al.

Chromosomal localization of the human myeloperoxidase gene by in situ hybridization using oligonucleotide probes

Genes, Chromosomes and Cancer

(1990)

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF): Receptor biology, signal transduction, and neutrophil activation

Abstract

Blood

Genomics

Journal of Biological Chemistry

Genomics

The Journal of Biological Chemistry

The Journal of Biological Chemistry

Blood

Blood

Blood

Biochemical and Biophysical Research Communications

Cell

Trends in Biochemical Sciences

Cell

Cell

Blood

Cell

Cell

Journal of Chromatography

Cell

Cell

Blood

Blood

Genomics

FEBS Letters

Cell

The growth of mouse bone marrow cells in vitro

Australian Journal of Experimental Biology and Medical Science

In vitro control of the development of macrophage and granulocyte colonies

The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells

Nature

Molecular cloning of cDNA encoding a murine haematopoietic growth regulator, granulocyte-macrophage colony stimulating factor

Nature

Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins

Science

The molecular control of blood cells

Close genetic and physical linkage between the murine haemopoietic growth factor genes GM-CSF and multi-CSF (IL-3)

The EMBO Journal

Genetic Maps: Locus Maps of Complex Genomes

Assignment of the GM-CSF, CSF-1, and FMS genes to human chromosome 5 provides evidence for linkage of a family of genes regulating hematopoiesis and for their involvement in the deletion (5q) in myeloid disorders

Structure of the chromosomal gene for granulocyte-macrophage colony stimulating factor: comparison of the mouse and human genes

The EMBO Journal

Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor

Nature

Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells

Science

Isolation and characterization of the cDNA for murine granulocyte colony-stimulating factor

Localization of the G-CSF gene on chromosome 17 proximal to the breakpoint in the t(15;17) in acute promyelocytic leukemia

Blood

Mapping of chromosome 17 breakpoints in acute myeloid leukemias

Oncogene

Molecular cloning and characterization of a cDNA for human granulocyte colony-stimulating factor (G-CSF) from a glioblastoma multiforme cell line and localization of the G-CSF gene to chromosome band 17q21

Oncogene Research

The human HOX gene family

Nucleic Acids Research

The nerve growth factor receptor gene is at human chromosome region 17q12–17q22, distal to the chromosome 17 breakpoint in acute leukemias

Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21–22

Mapping of the human retinoic acid receptor to the q21 band of chromosome 17

Human Genetics

The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus

Nature

Platelet glycoprotein IIb. Chromosomal localization and tissue expression

Journal of Clinical Investigation

Chromosomal localization of the genes for the vitronectin and fibronectin receptors alpha subunits and for platelet glycoproteins IIb and IIIa

Journal of Clinical Investigation

Assignment of the human myeloperoxidase gene (MPO) to bands q21.3–q23 of chromosome 17

Cytogenetics and Cell Genetics

Chromosomal localization of the human myeloperoxidase gene by in situ hybridization using oligonucleotide probes

Genes, Chromosomes and Cancer