The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia

Summary: Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a dis...

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Autores principales:	Chun-Hao Su, Wei-Ju Liao, Wei-Chi Ke, Ruey-Bing Yang, Woan-Yuh Tarn
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Biological sciences Cell biology Functional aspects of cell biology Science Q
Acceso en línea:	https://doaj.org/article/388f54cf16314912a552e852fb3be6ea
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spelling	oai:doaj.org-article:388f54cf16314912a552e852fb3be6ea2021-11-20T05:10:45ZThe Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia2589-004210.1016/j.isci.2021.103368https://doaj.org/article/388f54cf16314912a552e852fb3be6ea2021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221013390https://doaj.org/toc/2589-0042Summary: Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder of platelet production. Rbm8aKOMK mice accumulated low-ploidy immature megakaryocytes in the bone marrow and exhibited defective platelet activation and aggregation. Accordingly, depletion of Y14 (RBM8A) in human erythroleukemia (HEL) cells compromised phorbol-ester-induced polyploidization. Notably, Y14/RBM8A deficiency induced both p53 and p21 in megakaryocytes and HEL cells. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKOMK megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Trp53 knockout partially restored megakaryocyte differentiation by reversing cell-cycle arrest and increased platelet counts of Rbm8aKOMK, indicating that excess p53 in part accounts for thrombocytopenia in TAR syndrome. This study provides evidence for the role of the Y14-p53 circuit in platelet production and a potential therapeutic strategy.Chun-Hao SuWei-Ju LiaoWei-Chi KeRuey-Bing YangWoan-Yuh TarnElsevierarticleBiological sciencesCell biologyFunctional aspects of cell biologyScienceQENiScience, Vol 24, Iss 11, Pp 103368- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biological sciences Cell biology Functional aspects of cell biology Science Q
spellingShingle	Biological sciences Cell biology Functional aspects of cell biology Science Q Chun-Hao Su Wei-Ju Liao Wei-Chi Ke Ruey-Bing Yang Woan-Yuh Tarn The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
description	Summary: Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder of platelet production. Rbm8aKOMK mice accumulated low-ploidy immature megakaryocytes in the bone marrow and exhibited defective platelet activation and aggregation. Accordingly, depletion of Y14 (RBM8A) in human erythroleukemia (HEL) cells compromised phorbol-ester-induced polyploidization. Notably, Y14/RBM8A deficiency induced both p53 and p21 in megakaryocytes and HEL cells. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKOMK megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Trp53 knockout partially restored megakaryocyte differentiation by reversing cell-cycle arrest and increased platelet counts of Rbm8aKOMK, indicating that excess p53 in part accounts for thrombocytopenia in TAR syndrome. This study provides evidence for the role of the Y14-p53 circuit in platelet production and a potential therapeutic strategy.
format	article
author	Chun-Hao Su Wei-Ju Liao Wei-Chi Ke Ruey-Bing Yang Woan-Yuh Tarn
author_facet	Chun-Hao Su Wei-Ju Liao Wei-Chi Ke Ruey-Bing Yang Woan-Yuh Tarn
author_sort	Chun-Hao Su
title	The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_short	The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_full	The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_fullStr	The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_full_unstemmed	The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_sort	y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/388f54cf16314912a552e852fb3be6ea
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The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia

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