LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis

Takahiro Maeda; Keisuke Ito; Taha Merghoub; Laura Poliseno; Robin M Hobbs; Guocan Wang; Lin Dong; Manami Maeda; Louis C Dore; Arthur Zelent; Lucio Luzzatto; Julie Teruya-Feldstein; Mitchell J Weiss; Pier Paolo Pandolfi

doi:10.1016/j.devcel.2009.09.005

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LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis

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LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis

Takahiro Maeda, Keisuke Ito, Taha Merghoub, Laura Poliseno, Robin M Hobbs, Guocan Wang, Lin Dong, Manami Maeda, Louis C Dore, Arthur Zelent, …

Developmental cell, Vol.17(4), pp.527-540

2009-10-20

DOI: https://doi.org/10.1016/j.devcel.2009.09.005

PMCID: PMC3134301

PMID: 19853566

Abstract

DEVBIO

GATA-1-dependent transcription is essential for erythroid differentiation and maturation. Suppression of programmed cell death is also thought to be critical for this process; however, the link between these two features of erythropoiesis has remained elusive. Here, we show that the POZ-Krüppel family transcription factor, LRF (also known as Zbtb7a/Pokemon), is a direct target of GATA1 and plays an essential antiapoptotic role during terminal erythroid differentiation. We find that loss of Lrf leads to lethal anemia in embryos, due to increased apoptosis of late-stage erythroblasts. This programmed cell death is Arf and p53 independent and is instead mediated by upregulation of the proapoptotic factor Bim. We identify Lrf as a direct repressor of Bim transcription. In strong support of this mechanism, genetic Bim loss delays the lethality of Lrf-deficient embryos and rescues their anemia phenotype. Thus, our data define a key transcriptional cascade for effective erythropoiesis, whereby GATA-1 suppresses BIM-mediated apoptosis via LRF.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.225 Hematologic Diseases; 1.225.626 Sickle Cell Disease
Web Of Science research areas: Cell Biology; Developmental Biology
ESI research areas: Molecular Biology & Genetics

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Title: LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis
Creators: Takahiro Maeda - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Keisuke Ito - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Taha Merghoub - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Laura Poliseno - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Robin M Hobbs - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Guocan Wang - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Lin Dong - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Manami Maeda - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Louis C Dore - Children's Hospital of Philadelphia, Division of Hematology, University of Pennsylvania, Philadelphia, PA 19104, USA
Arthur Zelent - Leukemia Research Fund Center at the Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK
Lucio Luzzatto - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Julie Teruya-Feldstein - Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Mitchell J Weiss - Children's Hospital of Philadelphia, Division of Hematology, University of Pennsylvania, Philadelphia, PA 19104, USA
Pier Paolo Pandolfi - Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Publication Details: Developmental cell, Vol.17(4), pp.527-540
Publisher: Elsevier Inc
Language: English
Resource Type: Journal article
PMID: 19853566
PMCID: PMC3134301
Record Identifier: 991031614900602976