Autocrine β-related interferon controls c-myc suppression and growth arrest during hematopoietic cell differentiation

doi:10.1016/0092-8674(86)90857-3

Cell

Volume 46, Issue 1, 4 July 1986, Pages 31-40

https://doi.org/10.1016/0092-8674(86)90857-3 Get rights and content

Abstract

Different hematopoietic cells produce minute amounts of β-related interferon (IFN) following induction of differentiation by chemical or natural inducers. The endogenous IFN binds to type I cell surface receptors and modulates gene expression in the producer ceils. We show that self-induction of two members of the IFN-induced gene family differs in the dose response sensitivity and the prolonged kinetics of mRNA accumulation from the response to exogenous IFN-β₁. Production and response to endogenous IFN are also detected when bone marrow precursor cells differentiate to macrophages after exposure to colony stimulating factor 1. In M1 myeloid cells induced to differentiate by lung-conditioned medium, addition of antibodies against IFN-β partially abrogates the reduction of c-myc mRNA and the loss in cell proliferative activity, which both occur during differentiation. The endogenous IFN therefore functions as an autocrine growth inhibitor that participates in controlling c-myc suppression and the specific $G0 G1$ arrest during terminal differentiation of hematopoietic cells.

References (41)

R.L. Friedman et al.
Transcriptional and posttranscriptional regulation of interferon-induced gene expression in human cells
Cell
(1984)
J.S. Huang et al.
Transforming protein of Simian Sarcoma virus stimulates autocrine cell growth of SSV-transformed cells through PDGF cell-surface receptors
Cell
(1984)
N.A. Nicola et al.
Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells
J. Biol. Chem.
(1983)
L.M. Shulman et al.
Antibodies to chromosome 21 coded cell surface components block binding of human α interferon to human cells
Virology
(1984)
J.N. Zullo et al.
Platelet-derived growth factor and double-stranded ribonucleic acids stimulate expression of the same genes in 3T3 cells
Cell
(1985)
M.A. Anzano et al.
Increased secretion of type β transforming growth factor accompanies viral transformation of cells
Mol. Cell. Biol.
(1985)
W.S. Bullough
Mitotic and functional heomeoastatis: a speculative review
Cancer Res.
(1965)
F. Cuttitta et al.
Bombesin-like peptides can function as autocrine growth factors in human small cell lung cancer
Nature
(1985)
T.M. Dexter et al.
Conditions controlling the proliferation of hematopoietic stem cells in vitro
J. Cell. Physiol.
(1977)
M. Einat et al.
Close link between reduction of c-myc expression by interferon and $G0 G_{1}$ arrest
Nature
(1985)

M. Einat et al.

Inhibitory effects of interferon on the expression of genes regulated by platelet-derived growth factor

M. Fellous et al.

Interferon-dependent induction of mRNA for the major histocompatibility antigens in human fibroblasts and lymphoblastoid cells

M. Friedman-Einat et al.

Initial characterization of a spontaneous interferon secreted during growth and differentiation of Friend erythroleukemia cells

Mol. Cell. Biol.

(1982)

T.J. Gonda et al.

Expression of myb, myc and fos proto-oncogenes during the differentiation of murine myeloid leukemia

Nature

(1984)

I. Gresser et al.

Role of interferon in pathogenesis of virus diseases in mice as demonstrated by use of anti-interferon serum

J. Exp. Med.

(1976)

Y. Ichikawa

Differentiation of a cell line of myeloid leukemia

J. Cell. Physiol.

(1969)

G.J. Jonak et al.

Selective reduction of c-myc mRNA in Daudi cells by human α-interferon

A. Kimchi

Increased levels of interferon-induced (2′–5′) oligoadenylate synthetase in mature T-lymphocytes and in differentiated Friend erythroleukemic cells

J. Interferon Res.

(1981)

A. Kimchi et al.

Kinetics of induction of three translation-regulatory enzymes by interferon

H.M. Lachman et al.

Expression of c-myc changes during differentiation of mouse erythroleukemia cells

Nature

(1984)

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Cell

ArticleAutocrine β-related interferon controls c-myc suppression and growth arrest during hematopoietic cell differentiation

Abstract

Cell

Cell

J. Biol. Chem.

Virology

Cell

Increased secretion of type β transforming growth factor accompanies viral transformation of cells

Mol. Cell. Biol.

Mitotic and functional heomeoastatis: a speculative review

Cancer Res.

Bombesin-like peptides can function as autocrine growth factors in human small cell lung cancer

Nature

Conditions controlling the proliferation of hematopoietic stem cells in vitro

J. Cell. Physiol.

Close link between reduction of c-myc expression by interferon and G0G1 arrest

Nature

Inhibitory effects of interferon on the expression of genes regulated by platelet-derived growth factor

Interferon-dependent induction of mRNA for the major histocompatibility antigens in human fibroblasts and lymphoblastoid cells

Initial characterization of a spontaneous interferon secreted during growth and differentiation of Friend erythroleukemia cells

Mol. Cell. Biol.

Expression of myb, myc and fos proto-oncogenes during the differentiation of murine myeloid leukemia

Nature

Role of interferon in pathogenesis of virus diseases in mice as demonstrated by use of anti-interferon serum

J. Exp. Med.

Differentiation of a cell line of myeloid leukemia

J. Cell. Physiol.

Selective reduction of c-myc mRNA in Daudi cells by human α-interferon

Increased levels of interferon-induced (2′–5′) oligoadenylate synthetase in mature T-lymphocytes and in differentiated Friend erythroleukemic cells

J. Interferon Res.

Kinetics of induction of three translation-regulatory enzymes by interferon

Expression of c-myc changes during differentiation of mouse erythroleukemia cells

Nature

Article
Autocrine β-related interferon controls c-myc suppression and growth arrest during hematopoietic cell differentiation

Close link between reduction of c-myc expression by interferon and $G0 G_{1}$ arrest