Signaling pathways implicated in hematopoietic progenitor cell proliferation and differentiation.
The objective of this study was to investigate the signal transduction pathways associated with the clonal development of myeloid and erythroid progenitor cells. The contribution of particular signaling molecules of protein tyrosine kinases (PTKs), mitogen-activated protein (MAP) kinase, and PI-3 kinase signaling to the growth of murine bone marrow colony forming unit-granulocyte-macrophage (CFU-GM) and erythroid (burst forming unit-erythroid [BFU-E] and colony forming unit-erythroid [CFU-E]) progenitors was examined in studies performed in the presence or absence of specific signal transduction inhibitors. The results clearly pointed to different signal transducing intermediates that are involved in cell proliferation and differentiation depending on the cell lineage, as well as on the progenitors' maturity. Lineage-specific differences were obtained when chemical inhibitors specific for receptor- or nonreceptor-PTKs, as well as for the main groups of distinctly regulated MAPK cascades, were used because all of these compounds suppressed the growth of erythroid progenitors, with no major effects on myeloid progenitors. At the same time, differential involvement of MEK/extracellular signal-regulated kinase (ERK) MAPK transduction pathway was observed in the proliferation and/or differentiation of early, BFU-E, and late, CFU-E, erythroid progenitor cells. The results also demonstrated that phosphatydylinositol (PI)-3 kinase and nuclear factor kappaB (NF-kappaB) transcriptional factor were required for maintenance of both myeloid and erythroid progenitor cell function. Overall, the data obtained indicated that committed hematopoietic progenitors express a certain level of constitutive signaling activity that participates in the regulation of normal steady-state hematopoiesis and point to the importance of evaluating the impact of signal transduction inhibitors on normal bone marrow when used as potential therapeutic agents.
Bugarski
Diana
D
The Institute for Medical Research, Dr Subotića 4, 11129 Beograd, Serbia and Montenegro. dianab@imi.bg.ac.yu
Krstic
Aleksandra
A
Mojsilovic
Slavko
S
Vlaski
Marija
M
Petakov
Marijana
M
Jovcic
Gordana
G
Stojanovic
Nevenka
N
Milenkovic
Pavle
P
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D003114:Colony-Forming Units Assay; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D004920:Erythropoiesis; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D038042:Myelopoiesis; D016328:NF-kappa B / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction
D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases