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  • The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia.

The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia.

iScience (2021-11-25)
Chun-Hao Su, Wei-Ju Liao, Wei-Chi Ke, Ruey-Bing Yang, Woan-Yuh Tarn
ABSTRACT

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.

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PMA, for use in molecular biology applications, ≥99% (HPLC)
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Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301, clone JBW301, Upstate®, from mouse
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Pifithrin-α, A cell-permeable chemical inhibitor of p53.
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1 ea
1 Available to ship on 16 December 2024
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€162.00