Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells.

2.50
Hdl Handle:
http://hdl.handle.net/10541/88058
Title:
Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells.
Authors:
Francis, Julia M; Heyworth, Clare M; Spooncer, Elaine; Pierce, Andrew; Dexter, T Michael; Whetton, Anthony D
Abstract:
Transforming growth factor-beta1 (TGF-beta1) can inhibit cell proliferation or induce apoptosis in multipotent hematopoietic cells. To study the mechanisms of TGF-beta1 action on primitive hematopoietic cells, we used the interleukin-3 (IL-3)-dependent, multipotent FDCP-Mix cell line. TGF-beta1-mediated growth inhibition was observed in high concentrations of IL-3, while at lower IL-3 concentrations TGF-beta1 induced apoptosis. The proapoptotic effects of TGF-beta1 occur via a p53-independent pathway, since p53(null) FDCP-Mix demonstrated the same responses to TGF-beta1. IL-3 has been suggested to enhance survival via an increase in (antiapoptotic) Bcl-x(L) expression. In FDCP-Mix cells, neither IL-3 nor TGF-beta1 induced any change in Bcl-x(L) protein levels or the proapoptotic proteins Bad or Bax. However, TGF-beta1 had a major effect on Bcl-2 levels, reducing them in the presence of high and low concentrations of IL-3. Overexpression of Bcl-2 in FDCP-Mix cells rescued them from TGF-beta1-induced apoptosis but was incapable of inhibiting TGF-beta1-mediated growth arrest. We conclude that TGF-beta1-induced cell death is independent of p53 and inhibited by Bcl-2, with no effect on Bcl-x(L). The significance of these results for stem cell survival in bone marrow are discussed.
Affiliation:
Leukaemia Research Fund Cellular Development Unit, Department of Biomolecular Sciences, UMIST, Sackville St., Manchester, M60 1QD, United Kingdom.
Citation:
Transforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells. 2000, 275 (50):39137-45 J. Biol. Chem.
Journal:
The Journal of Biological Chemistry
Issue Date:
15-Dec-2000
URI:
http://hdl.handle.net/10541/88058
DOI:
10.1074/jbc.M007212200
PubMed ID:
10993901
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorFrancis, Julia Men
dc.contributor.authorHeyworth, Clare Men
dc.contributor.authorSpooncer, Elaineen
dc.contributor.authorPierce, Andrewen
dc.contributor.authorDexter, T Michaelen
dc.contributor.authorWhetton, Anthony Den
dc.date.accessioned2009-12-15T17:28:34Z-
dc.date.available2009-12-15T17:28:34Z-
dc.date.issued2000-12-15-
dc.identifier.citationTransforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells. 2000, 275 (50):39137-45 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid10993901-
dc.identifier.doi10.1074/jbc.M007212200-
dc.identifier.urihttp://hdl.handle.net/10541/88058-
dc.description.abstractTransforming growth factor-beta1 (TGF-beta1) can inhibit cell proliferation or induce apoptosis in multipotent hematopoietic cells. To study the mechanisms of TGF-beta1 action on primitive hematopoietic cells, we used the interleukin-3 (IL-3)-dependent, multipotent FDCP-Mix cell line. TGF-beta1-mediated growth inhibition was observed in high concentrations of IL-3, while at lower IL-3 concentrations TGF-beta1 induced apoptosis. The proapoptotic effects of TGF-beta1 occur via a p53-independent pathway, since p53(null) FDCP-Mix demonstrated the same responses to TGF-beta1. IL-3 has been suggested to enhance survival via an increase in (antiapoptotic) Bcl-x(L) expression. In FDCP-Mix cells, neither IL-3 nor TGF-beta1 induced any change in Bcl-x(L) protein levels or the proapoptotic proteins Bad or Bax. However, TGF-beta1 had a major effect on Bcl-2 levels, reducing them in the presence of high and low concentrations of IL-3. Overexpression of Bcl-2 in FDCP-Mix cells rescued them from TGF-beta1-induced apoptosis but was incapable of inhibiting TGF-beta1-mediated growth arrest. We conclude that TGF-beta1-induced cell death is independent of p53 and inhibited by Bcl-2, with no effect on Bcl-x(L). The significance of these results for stem cell survival in bone marrow are discussed.en
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAnimals-
dc.subject.meshApoptosis-
dc.subject.meshBlotting, Western-
dc.subject.meshCarrier Proteins-
dc.subject.meshCell Division-
dc.subject.meshCell Line-
dc.subject.meshCell Survival-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshElectrophoresis, Polyacrylamide Gel-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshHumans-
dc.subject.meshInterleukin-3-
dc.subject.meshMice-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshProto-Oncogene Proteins c-bcl-2-
dc.subject.meshTime Factors-
dc.subject.meshTransforming Growth Factor beta-
dc.subject.meshTransforming Growth Factor beta1-
dc.subject.meshTumor Suppressor Protein p53-
dc.subject.meshbcl-2-Associated X Protein-
dc.subject.meshbcl-Associated Death Protein-
dc.subject.meshbcl-X Protein-
dc.titleTransforming growth factor-beta 1 induces apoptosis independently of p53 and selectively reduces expression of Bcl-2 in multipotent hematopoietic cells.en
dc.typeArticleen
dc.contributor.departmentLeukaemia Research Fund Cellular Development Unit, Department of Biomolecular Sciences, UMIST, Sackville St., Manchester, M60 1QD, United Kingdom.en
dc.identifier.journalThe Journal of Biological Chemistryen

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