Direct binding of pRb/E2F-2 to GATA-1 regulates maturation and terminal cell division during erythropoiesis.
How cell proliferation subsides as cells terminally differentiate remains largely enigmatic, although this phenomenon is central to the existence of multicellular organisms. Here, we show that GATA-1, the master transcription factor of erythropoiesis, forms a tricomplex with the retinoblastoma protein (pRb) and E2F-2. This interaction requires a LXCXE motif that is evolutionary conserved among GATA-1 orthologs yet absent from the other GATA family members. GATA-1/pRb/E2F-2 complex formation stalls cell proliferation and steers erythroid precursors towards terminal differentiation. This process can be disrupted in vitro by FOG-1, which displaces pRb/E2F-2 from GATA-1. A GATA-1 mutant unable to bind pRb fails to inhibit cell proliferation and results in mouse embryonic lethality by anemia. These findings clarify the previously suspected cell-autonomous role of pRb during erythropoiesis and may provide a unifying molecular mechanism for several mouse phenotypes and human diseases associated with GATA-1 mutations.
Kadri
Zahra
Z
CEA, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses, France.
Shimizu
Ritsuko
R
Ohneda
Osamu
O
Maouche-Chretien
Leila
L
Gisselbrecht
Sylvie
S
Yamamoto
Masayuki
M
Romeo
Paul-Henri
PH
Leboulch
Philippe
P
Chretien
Stany
S
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D049109:Cell Proliferation; D050703:E2F2 Transcription Factor / Q000378:metabolism*; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis; D050982:GATA1 Transcription Factor / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D050703:E2F2 Transcription Factor; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C498432:ZFPM1 protein, human