A cross-talk between stromal cell-derived factor-1 and transforming growth factor-beta controls the quiescence/cycling switch of CD34(+) progenitors through FoxO3 and mammalian target of rapamycin.
Stem Cells
; 26(12): 3150-61, 2008 Dec.
Article
em En
| MEDLINE
| ID: mdl-18757300
ABSTRACT
Cell cycle regulation plays a fundamental role in stem cell biology. A balance between quiescence and proliferation of hematopoietic stem cells in interaction with the microenvironment is critical for sustaining long-term hematopoiesis and for protection against stress. We analyzed the molecular mechanisms by which stromal cell-derived factor-1 (SDF-1) exhibited a cell cycle-promoting effect and interacted with transforming growth factor-beta (TGF-beta), which has negative effects on cell cycle orchestration of human hematopoietic CD34(+) progenitor cells. We demonstrated that a low concentration of SDF-1 modulated the expression of key cell cycle regulators such as cyclins, cyclin-dependent kinase inhibitors, and TGF-beta target genes, confirming its cell cycle-promoting effect. We showed that a cross-talk between SDF-1- and TGF-beta-related signaling pathways involving phosphatidylinositol 3-kinase (PI3K)/Akt phosphorylation participated in the control of CD34(+) cell cycling. We demonstrated a pivotal role of two downstream effectors of the PI3K/Akt pathway, FoxO3a and mammalian target of rapamycin, as connectors in the SDF-1-/TGF-beta-induced control of the cycling/quiescence switch and proposed a model integrating a dialogue between the two molecules in cell cycle progression. Our data shed new light on the signaling pathways involved in SDF-1 cell cycle-promoting activity and suggest that the balance between SDF-1- and TGF-beta-activated pathways is critical for the regulation of hematopoietic progenitor cell cycle status.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
/
Fator de Crescimento Transformador beta
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Fatores de Transcrição Forkhead
/
Quimiocina CXCL12
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article