scholarly journals Progression of the myeloid differentiation program is dominant to transforming growth factor-beta 1-induced apoptosis in M1 myeloid leukemic cells

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1036-1042 ◽  
Author(s):  
M Selvakumaran ◽  
JC Reed ◽  
D Liebermann ◽  
B Hoffman
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Terminal Differentiation ◽  
Leukemic Cells ◽  
Tgf Beta ◽  
Growth Factor Beta ◽  
Induced Apoptosis

Abstract Hematopoiesis is a profound example of cell homeostasis that is regulated throughout life. This process requires the participation of many factors, including positive and negative regulators of growth and differentiation, that determine survival, growth stimulation, differentiation, functional activation, and programmed cell death. Understanding the effects of multiple stimuli on specific cells at the molecular and cellular level is crucial towards understanding how the population of blood cells maintains a homeostatic state. Two appropriate stimuli for analysis, both of which are found in bone marrow, are differentiation-inducing cytokines, which induce terminal differentiation associated with growth arrest, ultimately culminating in programmed cell death, and transforming growth factor-beta 1 (TGF- beta 1), which induces rapid growth arrest and apoptosis of hematopoietic cells. Previously, we have shown, using M1 myeloblastic leukemic cells as a model system, that differentiation-inducing cytokines induce terminal differentiation associated with growth arrest and, only after 5 to 7 days, apoptosis, whereas TGF-beta 1 induces rapid growth arrest and apoptosis. In this report, we show that M1 myeloid leukemic cells treated concomitantly with the differentiation inducer interleukin-6 and TGF-beta 1 undergo terminal differentiation, in which modulators of the MyD118 gene product, previously shown to be a positive regulator of TGF-beta 1-induced apoptosis, are implicated to play a role in protecting the cells from TGF-beta 1-induced apoptosis. Furthermore, using M1 cell variants blocked at different stages after induction of differentiation, including M1myb and M1myc, as well as conditionally blocked M1mycer, it has been shown that the dominance of interleukin-6 to TGF-beta 1-induced apoptosis is dependent on the progression of the differentiation program. Further studies with M1 and the genetically engineered M1 cell variants will be instrumental towards molecularly dissecting the interaction of hematopoietic differentiation with a variety of apoptotic pathways.

scholarly journals Progression of the myeloid differentiation program is dominant to transforming growth factor-beta 1-induced apoptosis in M1 myeloid leukemic cells

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1036-1042 ◽  
Author(s):  
M Selvakumaran ◽  
JC Reed ◽  
D Liebermann ◽  
B Hoffman
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Terminal Differentiation ◽  
Leukemic Cells ◽  
Tgf Beta ◽  
Growth Factor Beta ◽  
Induced Apoptosis

Hematopoiesis is a profound example of cell homeostasis that is regulated throughout life. This process requires the participation of many factors, including positive and negative regulators of growth and differentiation, that determine survival, growth stimulation, differentiation, functional activation, and programmed cell death. Understanding the effects of multiple stimuli on specific cells at the molecular and cellular level is crucial towards understanding how the population of blood cells maintains a homeostatic state. Two appropriate stimuli for analysis, both of which are found in bone marrow, are differentiation-inducing cytokines, which induce terminal differentiation associated with growth arrest, ultimately culminating in programmed cell death, and transforming growth factor-beta 1 (TGF- beta 1), which induces rapid growth arrest and apoptosis of hematopoietic cells. Previously, we have shown, using M1 myeloblastic leukemic cells as a model system, that differentiation-inducing cytokines induce terminal differentiation associated with growth arrest and, only after 5 to 7 days, apoptosis, whereas TGF-beta 1 induces rapid growth arrest and apoptosis. In this report, we show that M1 myeloid leukemic cells treated concomitantly with the differentiation inducer interleukin-6 and TGF-beta 1 undergo terminal differentiation, in which modulators of the MyD118 gene product, previously shown to be a positive regulator of TGF-beta 1-induced apoptosis, are implicated to play a role in protecting the cells from TGF-beta 1-induced apoptosis. Furthermore, using M1 cell variants blocked at different stages after induction of differentiation, including M1myb and M1myc, as well as conditionally blocked M1mycer, it has been shown that the dominance of interleukin-6 to TGF-beta 1-induced apoptosis is dependent on the progression of the differentiation program. Further studies with M1 and the genetically engineered M1 cell variants will be instrumental towards molecularly dissecting the interaction of hematopoietic differentiation with a variety of apoptotic pathways.

scholarly journals The novel primary response gene MyD118 and the proto-oncogenes myb, myc, and bcl-2 modulate transforming growth factor beta 1-induced apoptosis of myeloid leukemia cells.

1994 ◽  
Vol 14 (4) ◽  
pp. 2352-2360 ◽  
Author(s):  
M Selvakumaran ◽  
H K Lin ◽  
R T Sjin ◽  
J C Reed ◽  
D A Liebermann ◽  
...  
Keyword(s):  
Cell Death ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Primary Response ◽  
Tgf Beta ◽  
Response Gene ◽  
Primary Response Gene ◽  
Growth Factor Beta ◽  
Induced Apoptosis

Cell numbers are regulated by a balance among proliferation, growth arrest, and programmed cell death. A profound example of cell homeostasis, controlled throughout life, is the complex process of blood cell development, yet little is understood about the intracellular mechanisms that regulate blood cell growth arrest and programmed cell death. In this work, using transforming growth factor beta 1 (TGF beta 1)-treated M1 myeloid leukemia cells and genetically engineered M1 cell variants, the regulation of growth arrest and apoptosis was dissected. Blocking of early expression of MyD118, a novel differentiation primary response gene also shown to be a primary response gene induced by TGF beta 1, delayed TGF beta 1-induced apoptosis, demonstrating that MyD118 is a positive modulator of TGF beta 1-mediated cell death. Elevated expression of bcl-2 blocked the TGF beta 1-induced apoptotic pathway but not growth arrest induced by TGF beta 1. Deregulated expression of either c-myc or c-myb inhibited growth arrest and accelerated apoptosis, demonstrating for the first time that c-myb plays a role in regulating apoptosis. In all cases, the apoptotic response was correlated with the level of MyD118 expression. Taken together, these findings demonstrate that the primary response gene MyD118 and the c-myc, c-myb, and bcl-2 proto-oncogenes interact to modulate growth arrest and apoptosis of myeloid cells.

scholarly journals The novel primary response gene MyD118 and the proto-oncogenes myb, myc, and bcl-2 modulate transforming growth factor beta 1-induced apoptosis of myeloid leukemia cells

1994 ◽  
Vol 14 (4) ◽  
pp. 2352-2360
Author(s):  
M Selvakumaran ◽  
H K Lin ◽  
R T Sjin ◽  
J C Reed ◽  
D A Liebermann ◽  
...  
Keyword(s):  
Cell Death ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Primary Response ◽  
Tgf Beta ◽  
Response Gene ◽  
Primary Response Gene ◽  
Growth Factor Beta ◽  
Induced Apoptosis

Cell numbers are regulated by a balance among proliferation, growth arrest, and programmed cell death. A profound example of cell homeostasis, controlled throughout life, is the complex process of blood cell development, yet little is understood about the intracellular mechanisms that regulate blood cell growth arrest and programmed cell death. In this work, using transforming growth factor beta 1 (TGF beta 1)-treated M1 myeloid leukemia cells and genetically engineered M1 cell variants, the regulation of growth arrest and apoptosis was dissected. Blocking of early expression of MyD118, a novel differentiation primary response gene also shown to be a primary response gene induced by TGF beta 1, delayed TGF beta 1-induced apoptosis, demonstrating that MyD118 is a positive modulator of TGF beta 1-mediated cell death. Elevated expression of bcl-2 blocked the TGF beta 1-induced apoptotic pathway but not growth arrest induced by TGF beta 1. Deregulated expression of either c-myc or c-myb inhibited growth arrest and accelerated apoptosis, demonstrating for the first time that c-myb plays a role in regulating apoptosis. In all cases, the apoptotic response was correlated with the level of MyD118 expression. Taken together, these findings demonstrate that the primary response gene MyD118 and the c-myc, c-myb, and bcl-2 proto-oncogenes interact to modulate growth arrest and apoptosis of myeloid cells.

scholarly journals Transforming growth factor beta abrogates the effects of hematopoietins on eosinophils and induces their apoptosis.

1994 ◽  
Vol 179 (3) ◽  
pp. 1041-1045 ◽  
Author(s):  
R Alam ◽  
P Forsythe ◽  
S Stafford ◽  
Y Fukuda
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Dependent Manner ◽  
Tgf Beta ◽  
Gm Csf ◽  
Eosinophil Survival ◽  
Growth Factor Beta ◽  
Induced Apoptosis ◽  
And Function

Hematopoietins, interleukin (IL)-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) have previously been shown to prolong eosinophil survival and abrogate apoptosis. The objective of this study was to investigate the effect of transforming growth factor beta (TGF-beta) on eosinophil survival and apoptosis. Eosinophils from peripheral blood of mildly eosinophilic donors were isolated to > 97% purity using discontinuous Percoll density gradient. Eosinophils were cultured with hematopoietins with or without TGF-beta for 4 d and their viability was assessed. We confirmed previous observations that hematopoietins prolonged eosinophil survival and inhibited apoptosis. TGF-beta at concentrations > or = 10(-12) M abrogated the survival-prolonging effects of hematopoietins in a dose-dependent manner and induced apoptosis as determined by DNA fragmentation in agarose gels. The effect of TGF-beta was blocked by an anti-TGF-beta antibody. The anti-TGF-beta antibody also prolonged eosinophil survival on its own. The culture of eosinophils with IL-3 and GM-CSF stimulated the synthesis of GM-CSF and IL-5, respectively, suggesting an autocrine mechanism of growth factor production. TGF-beta inhibited the synthesis of GM-CSF and IL-5 by eosinophils. TGF-beta did not have any effect on the expression of GM-CSF receptors on eosinophils. We also studied the effect of TGF-beta on eosinophil function and found that TGF-beta inhibited the release of eosinophil peroxidase. Thus, TGF-beta seems to inhibit eosinophil survival and function. The inhibition of endogenous synthesis of hematopoietins may be one mechanism by which TGF-beta blocks eosinophil survival and induces apoptosis.

scholarly journals Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1750-1757 ◽  
Author(s):  
J Lotem ◽  
L Sachs
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Myeloid Leukemia ◽  
Transforming Growth Factor ◽  
Leukemic Cells ◽  
Tgf Beta ◽  
Gm Csf ◽  
Cytotoxic Compounds ◽  
Growth Factor Beta ◽  
Induction Of Apoptosis

Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.

scholarly journals Transforming growth factor-beta 1 cooperates with anti-immunoglobulin for the induction of apoptosis in group I (biopsy-like) Burkitt lymphoma cell lines

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 1147-1154 ◽  
Author(s):  
I MacDonald ◽  
H Wang ◽  
R Grand ◽  
RJ Armitage ◽  
WC Fanslow ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Burkitt Lymphoma ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Tgf Beta ◽  
Group I ◽  
Growth Factor Beta

Group I Burkitt lymphoma (BL) cell lines, which retain the original biopsy phenotype, have been shown to enter apoptosis in response to a number of external stimuli including serum deprivation, thermal shock, addition of calcium ionophore, and ligation of surface immunoglobulin (Ig) by antibody. Transforming growth factor-beta 1 (TGF beta 1) is known to cause growth arrest in BL lines. Here we show that while it is by itself capable of promoting some degree of apoptosis in group IBL cells, TGF beta 1 cooperates with anti-immunoglobulin to this end. Trimeric soluble recombinant human CD40 ligand (sCD40L) was able to inhibit apoptosis induced by the combination of agonists to some degree, but such rescue proved to be short-lived. Both TGF beta 1 and anti-Ig individually caused BL cells to undergo growth arrest at the G1 phase of cell cycle before their entry into apoptosis: the consequence of sCD40L addition was to maintain the cells in cycle for longer. No induction of the apoptosis-protecting gene, bcl-2, occurred in the presence of sCD40L. These findings are discussed, particularly highlighting the relationship existing between survival and the cell cycle. The strong cooperative effects observed between anti-Ig and TGF beta 1 in promoting apoptosis and the inability of CD40 to signal for long-term rescue raise the potential for a novel therapeutic attack on B-cell lymphoma.

scholarly journals Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1750-1757 ◽  
Author(s):  
J Lotem ◽  
L Sachs
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Myeloid Leukemia ◽  
Transforming Growth Factor ◽  
Leukemic Cells ◽  
Tgf Beta ◽  
Gm Csf ◽  
Cytotoxic Compounds ◽  
Growth Factor Beta ◽  
Induction Of Apoptosis

Abstract Transforming growth factor-beta 1 (TGF-beta 1) induces cell death in myeloid leukemia by apoptosis. In the M1 myeloid leukemia, this induction of apoptosis was inhibited by granulocyte colony-stimulating factor (G-CSF) or interleukin-6 (IL-6) and to a lesser extent by IL-1 alpha. IL-3 and stem cell factor/mast cell growth factor (SCF) showed only a marginal effect, and granulocyte-macrophage and macrophage CSFs (GM-CSF and M-CSF, respectively) were inactive. The induction of apoptosis by TGF-beta 1 in a different myeloid leukemia (7-M12) was inhibited by GM-CSF and IL-3 but not by the other cytokines. In the absence of TGF-beta 1, both M1 and 7-M12 leukemic cells were independent of hematopoietic cytokines for cell viability and growth. The cytotoxic compounds vincristine, vinblastine, adriamycin, cytosine arabinoside, cycloheximide, and sodium azide, some of which are used in cancer chemotherapy, induced cell death by apoptosis in both leukemias. As with TGF-beta 1, apoptosis induced by these cytotoxic compounds was inhibited by GM-CSF (7-M12 leukemia) and by G-CSF or IL-6 (M1 leukemia). Cyclosporine A decreased cell multiplication in M1 cells without inducing apoptosis, and G-CSF and IL-6 inhibited the cytostatic effect of cyclosporine A. It is suggested that the clinical use of cytokines to correct therapy-associated myelosuppression should be carefully timed to avoid protection of malignant cells from the cytotoxic action of the therapeutic compounds.

scholarly journals Identification of a novel transforming growth factor-beta (TGF-beta 5) mRNA in Xenopus laevis.

1990 ◽  
Vol 265 (2) ◽  
pp. 1089-1093 ◽  
Author(s):  
P Kondaiah ◽  
M J Sands ◽  
J M Smith ◽  
A Fields ◽  
A B Roberts ◽  
...  
Keyword(s):  
Growth Factor ◽  
Xenopus Laevis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tgf Beta ◽  
Growth Factor Beta

scholarly journals Purification of the transforming growth factor-beta (TGF-beta) binding proteoglycan betaglycan.

1991 ◽  
Vol 266 (34) ◽  
pp. 23282-23287
Author(s):  
J.L. Andres ◽  
L. Rönnstrand ◽  
S. Cheifetz ◽  
J. Massagué
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Tgf Beta ◽  
Growth Factor Beta

scholarly journals Recombinant type 1 transforming growth factor beta precursor produced in Chinese hamster ovary cells is glycosylated and phosphorylated.

1988 ◽  
Vol 8 (5) ◽  
pp. 2229-2232 ◽  
Author(s):  
A M Brunner ◽  
L E Gentry ◽  
J A Cooper ◽  
A F Purchio
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Chinese Hamster Ovary ◽  
Transforming Growth Factor ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Tgf Beta ◽  
Ovary Cells ◽  
Growth Factor Beta

Analyses of cDNA clones coding for simian type 1 transforming growth factor beta (TGF-beta 1) suggest that there are three potential sites for N-linked glycosylation located in the amino terminus of the precursor region. Analysis of [3H]glucosamine-labeled serum-free supernatants from a line of Chinese hamster ovary cells which secrete high levels of recombinant TGF-beta 1 indicate that the TGF-beta 1 precursor, but not the mature form, is glycosylated. Digestion with neuraminidase resulted in a shift in migration of the two TGF-beta 1 precursor bands, which suggests that they contain sialic acid residues. Endoglycosidase H had no noticeable effect. Treatment with N-glycanase produced two faster-migrating sharp bands, the largest of which had a molecular weight of 39 kilodaltons. TGF-beta 1-specific transcripts produced by SP6 polymerase programmed the synthesis of a 42-kilodalton polypeptide which, we suggest, is the unmodified protein backbone of the precursor. Labeling with 32Pi showed that the TGF-beta 1 precursor was phosphorylated in the amino portion of the molecule.

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