Abstract
A matured megakaryocyte releases thousands of platelets through a drastic morphological change, proplatelet formation (PPF). The megakaryocyte/erythrocyte-specific transcription factor, p45 NF-E2, is essential for initiating PPF, but the factor regulating PPF has not been identified. Here we report that estradiol synthesized in megakaryocytes triggers PPF. We demonstrate that a key enzyme for steroid hormone biosynthesis, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), is a target of p45 NF-E2, and rescues PPF of p45 NF-E2-deficient megakaryocytes. We also show that estradiol is synthesized within megakaryocytes, and that extracellular estradiol stimulates PPF, inhibition of 3beta-HSD activity blocks PPF, and estrogen receptor antagonists inhibit platelet production in vivo. We conclude that autocrine estradiol action regulates platelet production by triggering PPF.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors
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3-Hydroxysteroid Dehydrogenases / genetics
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3-Hydroxysteroid Dehydrogenases / metabolism
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Animals
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Base Sequence
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Blood Platelets / cytology*
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Cell Line
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DNA Primers
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DNA-Binding Proteins / metabolism
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Enzyme Inhibitors / pharmacology
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Erythroid-Specific DNA-Binding Factors
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Estradiol / physiology*
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Immunohistochemistry
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Megakaryocytes / cytology*
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Mice
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Molecular Sequence Data
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NF-E2 Transcription Factor
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NF-E2 Transcription Factor, p45 Subunit
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Transcription Factors / metabolism
Substances
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DNA Primers
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DNA-Binding Proteins
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Enzyme Inhibitors
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Erythroid-Specific DNA-Binding Factors
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NF-E2 Transcription Factor
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NF-E2 Transcription Factor, p45 Subunit
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Nfe2 protein, mouse
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Transcription Factors
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Estradiol
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3-Hydroxysteroid Dehydrogenases