Molecular mechanism of transforming growth factor β–mediated cell-cycle modulation in primary human CD34+ progenitors

Dao, Mo A.; Hwa, Joseph; Nolta, Jan A.

doi:10.1182/blood.v99.2.499

Cited by 35 publications

(23 citation statements)

References 42 publications

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“…In addition, we found that Myc/ ERT efficiently induced the expression of cyclin D2, cyclin D3, and cyclin E and promoted the growth of HSCs. In addition, previous reports suggested that c-Myc would transcriptionally repress the expression of p21 WAF1 , which plays a crucial role in the quiescence of HSCs (19,51), and of p15 INK4b , which is induced by transforming growth factor-␤ signaling (52,53). Together, these results imply that the c-myc could be a master regulator of the cell cycle in both Notch1-and HOXB4-induced self-renewal of HSCs.…”

Section: Discussionsupporting

confidence: 55%

Roles for c-Myc in Self-renewal of Hematopoietic Stem Cells

Satoh

Matsumura

Tanaka

et al. 2004

Journal of Biological Chemistry

138

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Section: Discussionsupporting

confidence: 55%

Roles for c-Myc in Self-renewal of Hematopoietic Stem Cells

Satoh

Matsumura

Tanaka

et al. 2004

Journal of Biological Chemistry

138

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“…CDKIs that are often seen to be up-regulated by TGF␤ in epithelial and neural progenitor cells (e.g., p15, p27, and p21) are not immediate targets of this cytokine in hematopoietic cells, and neither p21 nor p27 is necessary for TGF␤ to affect cytostasis in immature hematopoietic cells (8,34,35). p15 does not appear to be an early target of TGF␤ in CB-CD34ϩ cells (or in the M091 cells at any time), suggesting that the delayed up-regulation of p15 sometimes seen in these cells in response to TGF␤ (36,37) is a consequence of earlier events. The strong TGF␤-mediated up-regulation of p57 that we observed in immature human hematopoietic cells is not seen in many epithelial cell types (18), further demonstrating that critical aspects of TGF␤-signaling are cell type specific.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor β-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation

Scandura

Boccuni

Massagué

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

228

195

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Transforming growth factor β (TGFβ) is one of few known negative regulators of hematopoiesis, yet the mechanisms by which it affects cell cycle arrest and stem cell quiescence are poorly understood. Induction of the cyclin-dependent kinase inhibitors, p15INK4b (p15) and p21WAF1 (p21) is important for TGFβ-mediated cytostasis in epithelial cells but not in hematopoietic cells. Using primary human hematopoietic cells and microarray analysis, we identified p57KIP2 (p57) as the only cyclin-dependent kinase inhibitor induced by TGFβ. Up-regulation of p57 mRNA and protein occurs before TGFβ-induced G 1 cell cycle arrest, requires transcription, and is mediated via a highly conserved region of the proximal p57 promoter. The up-regulation of p57 is essential for TGFβ-induced cell cycle arrest in these cells, because two different small interfering RNAs that prevent p57 up-regulation block the cytostatic effects of TGFβ on human hematopoietic cells. Reduction of basal p57 expression by this approach also allows hematopoietic cells to proliferate more readily in the absence of TGFβ. p57 is a putative tumor suppressor gene whose expression is frequently silenced by promoter hypermethylation in hematologic malignancies. Our studies identify a molecular pathway by which TGFβ mediates its cytostatic effects on human hematopoietic cells and suggests an explanation for the frequent silencing of p57 expression.

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“…[46][47][48] Several studies have implicated that TGF-b may act through mechanisms involving the cip/kip inhibitors of CDKs (p21 Cip1 / p27 Kip1 ). [49][50][51] However, there is also data supporting a model whereby TGF-b can exert growth arrest independent of this class of cell cycle regulators. 52 It is also known that TGF-b can directly control the expression of the stem cell antigen CD34, 53,54 and in specific contexts, can prohibit differentiation via mechanisms not linked to cell cycle arrest.…”

Section: Ink4bmentioning

confidence: 99%

Transforming growth factor-β signaling in normal and malignant hematopoiesis

Letterio

2003

Leukemia

123

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Transforming growth factor-b (TGF-b) is perhaps the most potent endogenous negative regulator of hematopoiesis. The intracellular signaling events mediating the effects of TGF-b are multiple, involving extensive crosstalk between Smad-dependent and MAP-kinase-dependent pathways. We are only beginning to understand the importance of the balance between these cascades as a determinant of the response to TGF-b, and have yet to determine the roles that disruption in TGF-b signaling pathways might play in leukemogenesis. This review summarizes current knowledge regarding the function of TGF-b in normal and malignant hematopoiesis. The principal observations made by gene targeting studies in mice are reviewed, with an emphasis on how a disruption of this pathway in vivo can affect blood cell development and immune homeostasis. We overview genetic alterations that lead to impaired TGF-b signaling in hematopoietic neoplasms, including the suppression of Smad-dependent transcriptional responses by oncoproteins such as Tax and Evi-1, and fusion proteins such as AML1/ETO. We also consider mutations in genes encoding components of the core cell cycle machinery, such as p27 Kip1 and p15INK4A , and emphasize their impact on the ability of TGF-b to induce G1 arrest. The implications of these observations are discussed, and opinions regarding important directions for future research on TGF-b in hematopoiesis are provided.

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Molecular mechanism of transforming growth factor β–mediated cell-cycle modulation in primary human CD34+ progenitors

Cited by 35 publications

References 42 publications

Roles for c-Myc in Self-renewal of Hematopoietic Stem Cells

Roles for c-Myc in Self-renewal of Hematopoietic Stem Cells

Transforming growth factor β-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation

Transforming growth factor-β signaling in normal and malignant hematopoiesis

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