Joshi Ila, Minter Lisa M, Telfer Janice, Demarest Renée M, Capobianco Anthony J, Aster Jon C, Sicinski Piotr, Fauq Abdul, Golde Todd E, Osborne Barbara A
Program in Molecular and Cell Biology, University of Massachusetts, Amherst, MA 01003, USA.
Blood. 2009 Feb 19;113(8):1689-98. doi: 10.1182/blood-2008-03-147967. Epub 2008 Nov 10.
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.
Notch信号通路在正常淋巴细胞的发育和功能中发挥作用。在人类T细胞急性淋巴细胞白血病（T-ALL）中已发现激活的Notch1突变会导致异常的下游信号传导。虽然这突出了Notch信号通路对T-ALL发病机制的作用，但Notch在正常和白血病T细胞中调节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信号通路在T细胞细胞周期G(1)-S进程中的作用。在此我们表明，G(1)蛋白细胞周期蛋白D3、细胞周期蛋白依赖性激酶4（CDK4）和细胞周期蛋白依赖性激酶6（CDK6）的表达在体外和体内均依赖于Notch，并且我们概述了通过CSL（哺乳动物中的CBF-1；果蝇中的无翅抑制因子；秀丽隐杆线虫中的Lag-1）在活化T细胞中调节细胞周期蛋白D3表达的一种可能机制，以及一种非经典的Notch信号通路。虽然细胞周期蛋白D3的表达有助于Notch依赖性人类T-ALL细胞系中的细胞周期进程，但在这些细胞系中，CDK4或CDK6与细胞周期蛋白D3的异位表达显示出部分挽救γ-分泌酶抑制剂（GSI）诱导的G(1)期阻滞的作用。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，这证明在治疗人类T细胞恶性肿瘤时联合使用细胞周期抑制剂和GSI是合理的。
