Transforming Growth Factor-β1 Induces Apoptosis Independently of p53 and Selectively Reduces Expression of Bcl-2 in Multipotent Hematopoietic Cells

Francis, Julia M.; Heyworth, Clare M.; Spooncer, Elaine; Pierce, Andrew; Dexter, T. M.; Whetton, Anthony D.

doi:10.1074/jbc.m007212200

Cited by 58 publications

(40 citation statements)

References 62 publications

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“…Stimulation and inhibition of expression of proand anti-apoptotic Bcl family members, respectively, with subsequent caspase activation has been implicated in TGF-b-induced apoptosis (Fig. 3) (Motyl et al, 1998;Francis et al, 2000;Chipuk et al, 2001;Kim et al, 2001). In addition, TGF-b-mediated induction of Id3 expression in primary B lymphocyte progenitors (Kee et al, 2001), TIEG in mink lung epithelial and Hep3B cells (Chalaux et al, 1999;Ribeiro et al, 1999), and TGFb-stimulated clone 22 (TSC-22) in gastric carcinoma cells (Ohta et al, 1997), have been implicated in apoptosis.…”

Section: Regulation Of Apoptosis By Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

400

278

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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Section: Regulation Of Apoptosis By Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

400

278

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“…It is well known that low level of TGF-b1 maintain the multiple di erentiation potentials of hematopoietic stem/progenitor cells, which is associated with its negative controlling e ect on cells cycling (Batard et al, 2000). Accordingly, in another study, TGF-b1 was found to slow down the growth of human umbilical cord CD34 + CD38 7 Lin 7 blood cells in vitro, accompanied by the up-modulation of cell cycle inhibitor p21, while independent of its downregulating e ect on Bcl-2 expression Francis et al, 2000). It was recently suggested that the G1 checkpoint regulator p21 is one key factor required for the maintenance of this quiescent status, for BM cells homozygous null for p21 failed to long-term repopulate the hematopoietic system of lethally irradiated mice.…”

Section: Regulation By Stromal Cells and Cytokinesmentioning

confidence: 99%

Hematopoietic cytokines, transcription factors and lineage commitment

2002

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The past two decades have witnessed signi®cant advances in our understanding of the cellular physiology and molecular regulation of hematopoiesis. At the heart of stem cell self-renewal and lineage commitment decisions lies the relative expression levels of lineage-speci®c transcription factors. The expression of these transcription factors in early stem cells may be promiscuous and uctuate, but ultimately comes under the in¯uence of extracellular regulatory signals in the form of hematopoietic cytokines. In this review, we ®rst summarize our current understanding of the phenotypic characterization of hematopoietic stem cells. Next, we describe key known transcription factors which govern stem cell selfrenewal and lineage commitment decisions. Finally, we review data concerning the role of speci®c cytokines in in¯uencing these decisions. From this review, a picture emerges in which stem cell fate decisions are governed by the integrated e ects of intrinsic transcription factors and external signaling pathways initiated by regulatory cytokines.

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“…In addition, the proapoptotic Bcl-2 family protein Bim is a Smad3-dependent TGFb-induced protein in B lymphocytes (Wildey et al, 2003), whose binding to Bcl-X L increases during TGFb-induced apoptosis (Ohgushi et al, 2005). Furthermore, Bad and Bid (Kim et al, 2004) undergo caspase-dependent cleavage to more potently apoptotic forms after TGFb stimulation, while the antiapoptotic proteins Bcl-X L and Bcl-2 have been demonstrated to undergo TGFb-mediated downregulation in several cell types (Saltzman et al, 1998;Francis et al, 2000;Chipuk et al, 2001;Kanamaru et al, 2002). Finally, TGFb may antagonise survival signalling through the physical interaction of Smad3 with Akt (Conery et al, 2004;Remy et al, 2004).…”

Section: Introductionmentioning

confidence: 99%