Evi-1 promotes para-aortic splanchnopleural hematopoiesis through up-regulation of GATA-2 and repression of TGF-b signaling

Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Cancer Science (Impact Factor: 3.53). 08/2008; 99(7):1407-13. DOI: 10.1111/j.1349-7006.2008.00842.x
Source: PubMed

ABSTRACT Evi-1 is a zinc-finger transcriptional factor whose inappropriate expression leads to leukemic transformation in mice and humans. Recently, it has been shown that Evi-1 regulates proliferation of hematopoietic stem/progenitor cells at embryonic stage via GATA-2 up-regulation; however, detailed mechanisms underlying Evi-1-mediated early hematopoiesis are not fully understood. We therefore evaluated hematopoietic potential of Evi-1 mutants using a cultivation system of murine para-aortic splanchnopleural (P-Sp) regions, and found that both the first zinc finger domain and the acidic domain were required for Evi-1-mediated hematopoiesis. The hematopoietic potential of Evi-1 mutants was likely to be related to its ability to up-regulate GATA-2 expression. We also showed that the decreased colony forming capacity of Evi-1-deficient P-Sp cells was successfully recovered by inhibition of TGF-b signaling, using ALK5 inhibitor or retroviral transfer of dominant-negative-type Smad3. Our findings suggest that Evi-1 promotes hematopoietic stem/progenitor expansion at the embryonic stage through up-regulation of GATA-2 and repression of TGF-beta signaling.

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Available from: Tomohiko Sato, Dec 15, 2014
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    • "PRDM16 is similar in structure to PRDM3, which has been previously demonstrated to bind and thereby inactivate SMAD3 proteins through its DNA binding domain-1 (Zn-finger domain-1) and repress TGF-β cell growth-inhibitory signaling [102]. PRDM3 and PRDM16, however, bind SMADs and recruit CtBP, which in turn join histone deacetylases (HDACs) to deacetylate histones and repress SMAD mediated transcription [10,21,102,103,104,105]. "
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    • "Literature searches revealed that all 8 transcription factors have been implicated in hematopoiesis. In particular, Evi1 is an oncogenic transcription factor in myeloid leukemias, and may regulate normal hematopoiesis by interacting with transcription factors in the Gata family [60], [61]. Deletion of the ubiquitously expressed basic leucine zipper transcription factor AFT4 leads to severe anemia [62]. "
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    • "In addition, Evi-1 contains a highly acidic domain at the C-terminus, which is required for Evi-1-mediated P-Sp hematopoiesis (Sato et al., 2008). Each construct was transfected into COS7 cells together with D-0.5 reporter construct. "
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