Cross-talk of GATA-1 and P-TEFb in megakaryocyte differentiation
| Autor: | Kevin D. Ouma, Grant C. Bullock, Jill F. Caronia, Lorrie L. Delehanty, Ivailo S. Mihaylov, Sara L. Gonias, Kamaleldin E. Elagib, Adam N. Goldfarb |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Positive Transcriptional Elongation Factor B
Hematopoiesis and Stem Cells Megakaryocyte differentiation Cellular differentiation Immunology Biology Biochemistry Mice Myeloproliferative Disorders Megakaryocyte medicine Animals Humans GATA1 Transcription Factor P-TEFb Transcription factor Cells Cultured Mice Knockout Cell Differentiation Cell Biology Hematology Receptor Cross-Talk Cyclin-Dependent Kinase 9 medicine.anatomical_structure Cancer research Cyclin-dependent kinase 9 Down Syndrome Megakaryocytes |
| Popis: | The transcription factor GATA-1 participates in programming the differentiation of multiple hematopoietic lineages. In megakaryopoiesis, loss of GATA-1 function produces complex developmental abnormalities and underlies the pathogenesis of megakaryocytic leukemia in Down syndrome. Its distinct functions in megakaryocyte and erythroid maturation remain incompletely understood. In this study, we identified functional and physical interaction of GATA-1 with components of the positive transcriptional elongation factor P-TEFb, a complex containing cyclin T1 and the cyclin-dependent kinase 9 (Cdk9). Megakaryocytic induction was associated with dynamic changes in endogenous P-TEFb composition, including recruitment of GATA-1 and dissociation of HEXIM1, a Cdk9 inhibitor. shRNA knockdowns and pharmacologic inhibition both confirmed contribution of Cdk9 activity to megakaryocytic differentiation. In mice with megakaryocytic GATA-1 deficiency, Cdk9 inhibition produced a fulminant but reversible megakaryoblastic disorder reminiscent of the transient myeloproliferative disorder of Down syndrome. P-TEFb has previously been implicated in promoting elongation of paused RNA polymerase II and in programming hypertrophic differentiation of cardiomyocytes. Our results offer evidence for P-TEFb cross-talk with GATA-1 in megakaryocytic differentiation, a program with parallels to cardiomyocyte hypertrophy. |
| Databáze: | OpenAIRE |
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