Cross-talk of GATA-1 and P-TEFb in megakaryocyte differentiation

Kamaleldin E Elagib; Ivailo S Mihaylov; Lorrie L Delehanty; Grant C Bullock; Kevin D Ouma; Jill F Caronia; Sara L Gonias; Adam N Goldfarb

doi:10.1182/blood-2008-03-145722

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Cross-talk of GATA-1 and P-TEFb in megakaryocyte differentiation

Journal article

Open access

Peer reviewed

Cross-talk of GATA-1 and P-TEFb in megakaryocyte differentiation

Kamaleldin E Elagib, Ivailo S Mihaylov, Lorrie L Delehanty, Grant C Bullock, Kevin D Ouma, Jill F Caronia, Sara L Gonias and Adam N Goldfarb

Blood, Vol.112(13), pp.4884-4894

12/15/2008

DOI: 10.1182/blood-2008-03-145722

PMCID: PMC2597596

PMID: 18780834

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https://doi.org/10.1182/blood-2008-03-145722View

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Abstract

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.

Animals

Cell Differentiation

Cells, Cultured

Cyclin-Dependent Kinase 9 - antagonists & inhibitors

Cyclin-Dependent Kinase 9 - physiology

Down Syndrome

GATA1 Transcription Factor - genetics

GATA1 Transcription Factor - metabolism

Humans

Megakaryocytes - cytology

Mice

Mice, Knockout

Myeloproliferative Disorders

Positive Transcriptional Elongation Factor B - metabolism

Receptor Cross-Talk

Details

Title: Subtitle: Cross-talk of GATA-1 and P-TEFb in megakaryocyte differentiation
Creators: Kamaleldin E Elagib - University of Virginia
Ivailo S Mihaylov - University of Virginia
Lorrie L Delehanty - University of Virginia
Grant C Bullock - University of Virginia
Kevin D Ouma - University of Virginia
Jill F Caronia - University of Virginia
Sara L Gonias - University of Virginia
Adam N Goldfarb - University of Virginia
Resource Type: Journal article
Publication Details: Blood, Vol.112(13), pp.4884-4894
DOI: 10.1182/blood-2008-03-145722
PMID: 18780834
PMCID: PMC2597596
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: T32 CA009109 / NCI NIH HHS CA93735 / NCI NIH HHS R01 CA093735 / NCI NIH HHS R56 CA100057 / NCI NIH HHS CA100057 / NCI NIH HHS F32 HL0860046 / NHLBI NIH HHS R01 CA100057 / NCI NIH HHS
Language: English
Date published: 12/15/2008
Academic Unit: Pathology
Record Identifier: 9984697643502771

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