Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases
Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases
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DOI：
10.1182/blood-2008-03-147967
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发表时间：
2009-02-19
期刊：
影响因子：
20.3
通讯作者：
Osborne, Barbara A.
中科院分区：
文献类型：
--
作者：
Joshi, Ila;Minter, Lisa M.;Osborne, Barbara A.
Notch信号传导在正常淋巴细胞发育和功能中起作用。已在人类T细胞急性淋巴细胞白血病（T-ALL）中鉴定了导致异常下游信号传导的激活Notch1突变。虽然这突出了Notch信号传导对T-ALL发病机制的贡献，但Notch调节正常和白血病T细胞增殖和存活的机制尚未完全了解。我们的研究结果确定了Notch信号在T细胞细胞周期G（1）-S进程中的作用。在这里，我们表明，G（1）蛋白，细胞周期蛋白D3，CDK4，和CDK6的表达，是Notch依赖的在体外和体内，我们概述了一个可能的机制，通过CSL（CBF-1，哺乳动物;无毛的抑制，果蝇; Lag-1，秀丽隐杆线虫），以及一个非经典的Notch信号通路，调节细胞周期蛋白D3在活化的T细胞中的表达。虽然细胞周期蛋白D3的表达有助于Notch依赖性人T-ALL细胞系的细胞周期进展，但CDK4或CDK6与细胞周期蛋白D3的异位表达显示了对这些细胞系中γ-分泌酶抑制剂（GSI）诱导的G（1）停滞的部分拯救。重要的是，细胞周期蛋白D3和CDK4在Notch依赖性T细胞淋巴瘤中高度过表达，证明了细胞周期抑制剂和GSI在治疗人类T细胞恶性肿瘤中的组合使用。（血。2009; 113：1689 - 1698）
Notch signaling plays a role in normal lymphocyte development and function. Activating Notch1-mutations, leading to aberrant downstream signaling, have been identified in human T-cell acute lymphoblastic leukemia (T-ALL). While this highlights the contribution of Notch signaling to T-ALL pathogenesis, the mechanisms by which Notch regulates proliferation and survival in normal and leukemic T cells are not fully understood. Our findings identify a role for Notch signaling in G(1)-S progression of cell cycle in T cells. Here we show that expression of the G(1) proteins, cyclin D3, CDK4, and CDK6, is Notch-dependent both in vitro and in vivo, and we outline a possible mechanism for the regulated expression of cyclin D3 in activated T cells via CSL (CBF-1, mammals; suppressor of hairless, Drosophila melanogaster; Lag-1, Caenorhabditis elegans), as well as a noncanonical Notch signaling pathway. While cyclin D3 expression contributes to cell-cycle progression in Notch-dependent human T-ALL cell lines, ectopic expression of CDK4 or CDK6 together with cyclin D3 shows partial rescue from gamma-secretase inhibitor (GSI)-induced G(1) arrest in these cell lines. Importantly, cyclin D3 and CDK4 are highly overexpressed in Notch-dependent T-cell lymphomas, justifying the combined use of cell-cycle inhibitors and GSI in treating human T-cell malignancies. (Blood. 2009; 113: 1689-1698)