In hematopoiesis, the need to continuously generate large numbers of maturing cells of eight distinct lineages from small numbers of stem cells requires a highly complex series of events. Hematopoietic stem cells (HSC), which can remain quiescent for months, must retain the abilities to differentiate into all lineages, to self-renew and to long-term repopulation marrow (LTRA). Numerous critical interactions controlling hematopoiesis are regulated by soluble or extracellular mediators which can have overlapping, additive and/or opposing functions on a given cell type. Transforming growth factor beta-1 (TGF-b1) is one of these critical regulators of hematopoiesis since our in vitro and in vivo work indicates that TGF-b is a regulator of all stages of hematopoiesis. A current priority is to further define the physiological relevance of TGF-b and determine the mechanisms by which it exerts its varied and complex effects. Important questions remain to be answered. Are the pleiotropic effects of TGF-b on hematopoiesis caused by distinct roles for intracellular mediators, Smad2 and Smad3, or crosstalk with other signal transduction pathways? What are the relative contributions of autocrine and paracrine TGF-b in HSC regulation? Can alteration of intracellular TGF-b signals alter differentiation outcomes? We have found that TGF-b1 regulates both HSC quiesence and survival through autocrine and paracrine mechanisms. Furthermore, neutralization of autocrine TGF-b in HSC causes a more rapid engraftment with fewer cells needed for bone marrow transplantation. In contrast, neutralization of autocrine TGF-b in human HSC in the presence of stem cell factor stimulates the production of erythroid progenitors in the absence of erythropoietin. Defining the mechanism(s) of autocrine TGF-b actions on regulating HSC will present new therapeutic opportunities. Furthermore, we have found that Smad2/3 are intracellular sensors that regulate commitment to myeloid differentiation in response to pharmacologic agents. All trans retinoic acid (ATRA) stimulates granulocytic differentiation by stimulating a phosphatase activity which dephosphorylates Smad2/3;while vitamin D3 stimulates monocytic differentiation through phosphorylation of Smad2/3. In addition, crosstalk between different members of the MAPK signaling pathways and the Smad pathway alters the outcomes of myeloid and erythroid differentiation. In addition, we have shown that Smad2 and Smad3 have different effects on early hematopoietic function. Thus, attenuation of specific signals has profound effects on hematopoietic outcomes. Since alterations in TGF-b, its receptors and downstream effectors (SMADs) have all been implicated in tumorigenesis, these studies could provide insights into malignant processes. TGF-b1 inhibits proliferation by restricting passage through the G1 phase of the cell cycle, in part through rapid transcriptional activation of genes such as cell cycle inhibitors. We recently found the tuberlin sclerosis gene product 2, another tumor suppressor gene that causes growth arrest in G1, directly interacts with Smad2 an transcriptional activation mediated by TGF-b (manuscript in press). Moreover, we have shown that tuberin is a powerful stimulator of TGF-b1-regulated transcription and differentiation events in the myeloid cells. Thus, the losses of functional tuberin and/or Smads can result in uncontrolled cell proliferation with a block in differentiation. Thus, subtle yet chronic changes in TGF-b1 regulation can lead to pathophysiological states. This ability of two tumor suppressor gene families to collaborate in cellular functions provides an exciting and important new avdenue of study pertaining to the development of cancers. This was recently recognized by congress in that it asked the NCI to study Tuberous sclerosis complex (TSC),a genetic disorder that triggers uncontrollable tumor growth in multiple organs of the body, including the brain, heart, kidneys, lungs, liver, eyes or skin. In light of its similarities to the uncontrolled growth of cancer cells. Many scientists believe that determining the cause of tumor growth in TSC could open the way for cures and treatments for cancer as well. The Committee encourages NCI to support programs examining the molecular and cellular basis of TSC, and the role of TSC in tumor development. Its ability to interact with TGF-beta pathway is an new link in understanding this process.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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