Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context.
Transforming growth factor-beta (TGF-beta) is a pleiotropic regulator of all stages of hematopoieis. The three mammalian isoforms (TGF-beta1, 2 and 3) have distinct but overlapping effects on hematopoiesis. Depending on the differentiation stage of the target cell, the local environment and the concentration and isoform of TGF-beta, in vivo or in vitro, TGF-beta can be pro- or antiproliferative, pro- or antiapoptotic, pro- or antidifferentiative and can inhibit or increase terminally differentiated cell function. TGF-beta is a major regulator of stem cell quiescence, at least in vitro. TGF-beta can act directly or indirectly through effects on the bone marrow microenvironment. In addition, paracrine and autocrine actions of TGF-beta have overlapping but distinct regulatory effects on hematopoietic stem/progenitor cells. Since TGF-beta can act in numerous steps in the hematopoietic cascade, loss of function mutations in hematopoeitic stem cells (HSC) have different effects on hematopoiesis than transient blockade of autocrine TGF-beta1. Transient neutralization of autocrine TGF-beta in HSC has therapeutic potential. In myeloid and erythroid leukemic cells, autocrine TGF-beta1 and/or its Smad signals controls the ability of these cells to respond to various differentiation inducers, suggesting that this pathway plays a role in determining the cell fate of leukemic cells.
Ruscetti
Francis W
FW
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA. Ruscettif@ncifcrf.gov
Akel
Salem
S
Bartelmez
Stephen H
SH
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000209:etiology; D020935:MAP Kinase Signaling System; D051379:Mice; D015398:Signal Transduction; D051785:Smad Proteins; D015534:Trans-Activators / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
D004268:DNA-Binding Proteins; D051785:Smad Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D048049:Extracellular Signal-Regulated MAP Kinases