Habib Tania, Park Heon, Tsang Mark, de Alborán Ignacio Moreno, Nicks Andrea, Wilson Leslie, Knoepfler Paul S, Andrews Sarah, Rawlings David J, Eisenman Robert N, Iritani Brian M
Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
J Cell Biol. 2007 Nov 19;179(4):717-31. doi: 10.1083/jcb.200704173. Epub 2007 Nov 12.
Deregulated expression of the Myc family of transcription factors (c-, N-, and L-myc) contributes to the development of many cancers by a mechanism believed to involve the stimulation of cell proliferation and inhibition of differentiation. However, using B cell-specific c-/N-myc double-knockout mice and E(mu)-myc transgenic mice bred onto genetic backgrounds (recombinase-activating gene 2-/- and Btk-/- Tec-/-) whereby B cell development is arrested, we show that Myc is necessary to stimulate both proliferation and differentiation in primary B cells. Moreover, Myc expression results in sustained increases in intracellular Ca2+ ([Ca2+]i), which is required for Myc to stimulate B cell proliferation and differentiation. The increase in [Ca2+]i correlates with constitutive nuclear factor of activated T cells (NFAT) nuclear translocation, reduced Ca2+ efflux, and decreased expression of the plasma membrane Ca2+-adenosine triphosphatase (PMCA) efflux pump. Our findings demonstrate a revised model whereby Myc promotes both proliferation and differentiation, in part by a remarkable mechanism whereby Myc amplifies Ca2+ signals, thereby enabling the concurrent expression of Myc- and Ca2+-regulated target genes.
转录因子Myc家族（c-Myc、N-Myc和L-Myc）的表达失调通过一种被认为涉及刺激细胞增殖和抑制分化的机制，促成了许多癌症的发生。然而，利用在B细胞特异性c-/N-Myc双敲除小鼠和培育于基因背景（重组酶激活基因2-/-和Btk-/- Tec-/-，B细胞发育在此背景下停滞）上的E(μ)-Myc转基因小鼠，我们发现Myc对于刺激原代B细胞的增殖和分化都是必需的。此外，Myc的表达导致细胞内Ca2+（[Ca2+]i）持续增加，而这是Myc刺激B细胞增殖和分化所必需的。[Ca2+]i的增加与活化T细胞核因子（NFAT）的组成型核转位、Ca2+外流减少以及质膜Ca2+-三磷酸腺苷酶（PMCA）外流泵的表达降低相关。我们的研究结果表明了一种修正模型，即Myc促进增殖和分化，部分是通过一种显著的机制，即Myc放大Ca2+信号，从而使得Myc和Ca2+调节的靶基因能够同时表达。
