SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis.
Blood
; 118(3): 723-35, 2011 Jul 21.
Article
em En
| MEDLINE
| ID: mdl-21596846
ABSTRACT
Megakaryopoiesis is a complex process that involves major cellular and nuclear changes and relies on controlled coordination of cellular proliferation and differentiation. These mechanisms are orchestrated in part by transcriptional regulators. The key hematopoietic transcription factor stem cell leukemia (SCL)/TAL1 is required in early hematopoietic progenitors for specification of the megakaryocytic lineage. These early functions have, so far, prevented full investigation of its role in megakaryocyte development in loss-of-function studies. Here, we report that SCL critically controls terminal megakaryocyte maturation. In vivo deletion of Scl specifically in the megakaryocytic lineage affects all key attributes of megakaryocyte progenitors (MkPs), namely, proliferation, ploidization, cytoplasmic maturation, and platelet release. Genome-wide expression analysis reveals increased expression of the cell-cycle regulator p21 in Scl-deleted MkPs. Importantly, p21 knockdown-mediated rescue of Scl-mutant MkPs shows full restoration of cell-cycle progression and partial rescue of the nuclear and cytoplasmic maturation defects. Therefore, SCL-mediated transcriptional control of p21 is essential for terminal maturation of MkPs. Our study provides a mechanistic link between a major hematopoietic transcriptional regulator, cell-cycle progression, and megakaryocytic differentiation.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Trombocitopenia
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Células-Tronco Hematopoéticas
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Megacariócitos
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Proteínas Proto-Oncogênicas
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Trombopoese
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Inibidor de Quinase Dependente de Ciclina p21
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Fatores de Transcrição Hélice-Alça-Hélice Básicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article