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Signaling by the Mpl receptor involves IKK and NF-kappaB.
- Source :
-
Journal of cellular biochemistry [J Cell Biochem] 2002; Vol. 85 (3), pp. 523-35. - Publication Year :
- 2002
-
Abstract
- Binding of tumor necrosis factor-alpha (TNF-alpha) to its receptor activates IKK complex, which leads to inducement of NF-kappaB activity. Here we report that activation of Mpl ligand is also linked to IKK and NF-kappaB activity. Mpl ligand, also known as thrombopoietin (TPO) or megakaryocyte growth and development factor (MGDF), induces megakaryocyte differentiation and inhibition of mitotic proliferation, followed by induction of polyploidization and fragmentation into platelets. The latter process is often observed in megakaryocytes undergoing apoptosis. Treatment of a Mpl ligand-responding megakaryocytic cell line with this cytokine led to an immediate, transient increase in IKK activity followed by a profound decrease in this kinase activity over time. This decrease was not due to an effect on the levels of the IKK regulatory components IKKalpha and IKKbeta. Proliferating megakaryocytes displayed a constitutive DNA-binding activity of NF-kappaB p50 homodimers and of NF-kappaB p50-p65 heterodimers. As expected, reduced IKK activity in Mpl ligand-treated cells was associated with a significant reduction in NF-kappaB DNA binding activity and in the activity of a NF-kappaB-dependent promoter. Our study is thus the first to identify a constitutive NF-kappaB activity in proliferating megakaryocytes as well as to describe a link between Mpl receptor signaling and IKK and NF-kappaB activities. Since a variety of proliferation-promoting genes and anti-apoptotic mechanisms are activated by NF-kappaB, retaining its low levels would be one potential mechanism by which inhibition of mitotic proliferation is maintained and apoptosis is promoted during late megakaryopoiesis.<br /> (Copyright 2002 Wiley-Liss, Inc.)
- Subjects :
- Animals
Apoptosis physiology
Bone Marrow Cells cytology
Bone Marrow Cells drug effects
Bone Marrow Cells metabolism
Cell Division
Cells, Cultured
DNA metabolism
Dimerization
Down-Regulation
I-kappa B Kinase
Megakaryocytes cytology
Megakaryocytes drug effects
Megakaryocytes physiology
Mice
NF-kappa B drug effects
NF-kappa B genetics
Polyploidy
Promoter Regions, Genetic
Protein Serine-Threonine Kinases drug effects
Protein Serine-Threonine Kinases genetics
Rats
Receptors, Thrombopoietin
Thrombopoietin genetics
Thrombopoietin pharmacology
Transcriptional Activation
NF-kappa B metabolism
Neoplasm Proteins metabolism
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins metabolism
Receptors, Cytokine metabolism
Signal Transduction physiology
Thrombopoietin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0730-2312
- Volume :
- 85
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of cellular biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 11967992
- Full Text :
- https://doi.org/10.1002/jcb.10141