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Selective impairment of platelet activation to collagen in the absence of GATA1.
- Source :
-
Blood [Blood] 2005 Jun 01; Vol. 105 (11), pp. 4369-76. Date of Electronic Publication: 2005 Feb 08. - Publication Year :
- 2005
-
Abstract
- Defects in the X-linked DNA-binding megakaryocyte transcription factor GATA1 cause thrombocytopenia and abnormal platelet function. However, detailed studies of GATA1 function in platelet activation are lacking. Here, we studied platelets from GATA1-deficient mice and from a male patient (S14) with a bleeding diathesis attributed to a single amino acid substitution (R216Q) in the N-terminal GATA1 zinc finger that alters binding to DNA. In both cases there was inhibition of aggregation to collagen and decreased tyrosine phosphorylation of glycoprotein VI (GPVI)-signaling proteins. This effect was more marked in GATA1-deficient murine platelets, where it was associated with a significant reduction in surface GPVI expression. Moreover, both human and murine GATA1-mutant platelets showed reduced adhesion and aggregate formation on a collagen matrix at an intermediate rate of shear, although this could not be accounted solely by the thrombocytopenia and altered GPVI expression, indicating that GATA1 regulates additional factors important for platelet activation under shear. In contrast, there was no inhibition of responses to G protein-coupled receptor agonists in GATA1-perturbed platelets. Our results are consistent with GATA1 regulating some but not all pathways of platelet activation, leading to an impairment of aggregate formation under flow, which cannot be attributed solely to the thrombocytopenia.
- Subjects :
- Animals
DNA-Binding Proteins deficiency
DNA-Binding Proteins genetics
Erythroid-Specific DNA-Binding Factors
GATA1 Transcription Factor
Hemorrhagic Disorders genetics
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation, Missense
Phosphorylation
Platelet Activation drug effects
Platelet Aggregation
Platelet Membrane Glycoproteins
Stress, Mechanical
Thrombocytopenia etiology
Thrombocytopenia genetics
Transcription Factors deficiency
Transcription Factors genetics
Collagen pharmacology
DNA-Binding Proteins physiology
Platelet Activation genetics
Transcription Factors physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 105
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 15701726
- Full Text :
- https://doi.org/10.1182/blood-2004-10-4098