TY - JOUR
T1 - LRF Is an Essential Downstream Target of GATA1 in Erythroid Development and Regulates BIM-Dependent Apoptosis
AU - Maeda, Takahiro
AU - Ito, Keisuke
AU - Merghoub, Taha
AU - Poliseno, Laura
AU - Hobbs, Robin M.
AU - Wang, Guocan
AU - Dong, Lin
AU - Maeda, Manami
AU - Dore, Louis C.
AU - Zelent, Arthur
AU - Luzzatto, Lucio
AU - Teruya-Feldstein, Julie
AU - Weiss, Mitchell J.
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
We thank Agnes Viale and Julia Zhao for their help with microarray experiments; Irena Linkov and Katia Manova for IHC analysis; Bernessa Vassall for May-Giemsa staining; Jia-Hui Dong for performing mice work; Jan Hendrikx and other MSKCC Flow Cytometry core facility members for assistance with FACS analysis and cell sorting; Yu Yao for performing Lrf promoter Reporter assay; Ainara Egia for histology and IHC assistance; Nicola Hawe, Carmela Gurrieri, Jose Costoya, Francesco Piazza, Luipa Khandker, Ilhem Guernah, Kyoko Ito, Linda DiSantis, Stuart Megan, Thomas Naughton, and other P.P.P. lab members for assistance, advice, and helpful discussion. We also thank Margaret VanMeter for providing us with the Phospho Stat5 FACS protocol. This work is supported in part by NCI grant CA-102142 (to P.P.P.).
PY - 2009/10/20
Y1 - 2009/10/20
N2 - 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.
AB - 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.
KW - DEVBIO
UR - http://www.scopus.com/inward/record.url?scp=70350061670&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70350061670&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2009.09.005
DO - 10.1016/j.devcel.2009.09.005
M3 - Article
C2 - 19853566
AN - SCOPUS:70350061670
SN - 1534-5807
VL - 17
SP - 527
EP - 540
JO - Developmental cell
JF - Developmental cell
IS - 4
ER -