Direct Binding of pRb/E2F-2 to GATA-1 Regulates Maturation and Terminal Cell Division during Erythropoiesis
Citation: Zahra Kadri, Ritsuko Shimizu, Osamu Ohneda, Leila Maouche-Chretien, Sylvie Gisselbrecht, Masayuki Yamamoto, Paul-Henri Romeo, Philippe Leboulch, Stany Chretien (2009/06) Direct Binding of pRb/E2F-2 to GATA-1 Regulates Maturation and Terminal Cell Division during Erythropoiesis. PLoS Biol (Volume 7) (RSS)
DOI (original publisher): 10.1371/journal.pbio.1000123
Semantic Scholar (metadata): 10.1371/journal.pbio.1000123
Sci-Hub (fulltext): 10.1371/journal.pbio.1000123
Internet Archive Scholar (search for fulltext): Direct Binding of pRb/E2F-2 to GATA-1 Regulates Maturation and Terminal Cell Division during Erythropoiesis
Download: http://dx.doi.org/10.1371/journal.pbio.1000123
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Summary
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.
Red blood cell production, or erythropoiesis, proceeds by a tight coupling of proliferation and differentiation. The earliest erythroid progenitor identifiable possesses remnant stem cell characteristics as it both self-renews and differentiates. Each progenitor gives rise to more than 10,000 cells, including secondary progenitors. Yet, during the next stage of differentiation, much of this renewal capability is lost, and terminal erythroid differentiation progresses in a stepwise manner through several stages separated by a single mitosis. The transcription factor GATA-1 is essential for erythroid differentiation because it induces the expression of all the known erythroid-specific genes. Here, we show that GATA-1 directly interacts with proteins that are central to the process of cell division: the retinoblastoma protein pRb and the transcription factor E2F. Specifically, E2F becomes inactivate after engaging in a GATA-1/pRb/E2F tricomplex. Another erythroid transcription factor, termed FOG-1, is able to displace pRb/E2F from this complex in vitro upon binding to GATA-1. We hypothesize that the liberated pRb/E2F can then be the target of subsequent regulation to ultimately release free E2F, which triggers cell division. The physiological role of this new pathway is evidenced by transgenic mouse experiments with GATA-1 mutants unable to bind pRb/E2F, which result in embryonic lethality by anemia.
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