Billing Matilda, Rörby Emma, May Gillian, Tipping Alex J, Soneji Shamit, Brown John, Salminen Marjo, Karlsson Göran, Enver Tariq, Karlsson Stefan
Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
Stem Cell Group, University College London Cancer Institute, London, United Kingdom.
Exp Hematol. 2016 May;44(5):399-409.e5. doi: 10.1016/j.exphem.2016.02.001. Epub 2016 Feb 10.
Transforming growth factor β (TGFβ) is a potent inhibitor of hematopoietic stem and progenitor cell proliferation. However, the precise mechanism for this effect is unknown. Here, we have identified the transcription factor Gata2, previously described as an important regulator of hematopoietic stem cell function, as an early and direct target gene for TGFβ-induced Smad signaling in hematopoietic progenitor cells. We also report that Gata2 is involved in mediating a significant part of the TGFβ response in primitive hematopoietic cells. Interestingly, the cell cycle regulator and TGFβ signaling effector molecule p57 was found to be upregulated as a secondary response to TGFβ. We observed Gata2 binding upstream of the p57 genomic locus, and importantly, loss of Gata2 abolished TGFβ-stimulated induction of p57 as well as the resulting growth arrest of hematopoietic progenitors. Our results connect key molecules involved in hematopoietic stem cell self-renewal and reveal a functionally relevant network, regulating proliferation of primitive hematopoietic cells.
转化生长因子β（TGFβ）是造血干细胞和祖细胞增殖的强效抑制剂。然而，这种作用的确切机制尚不清楚。在这里，我们已确定转录因子Gata2（先前被描述为造血干细胞功能的重要调节因子）是造血祖细胞中TGFβ诱导的Smad信号的早期直接靶基因。我们还报告称，Gata2参与介导原始造血细胞中TGFβ反应的很大一部分。有趣的是，细胞周期调节因子和TGFβ信号效应分子p57被发现作为对TGFβ的次级反应而上调。我们观察到Gata2结合在p57基因组位点的上游，重要的是，Gata2的缺失消除了TGFβ刺激的p57诱导以及造血祖细胞由此产生的生长停滞。我们的结果连接了参与造血干细胞自我更新的关键分子，并揭示了一个功能相关的网络，调节原始造血细胞的增殖。
