Issack P S, Ziff E B
Howard Hughes Medical Institute, Department of Biochemistry and Kaplan Cancer Center, New York University Medical Center, New York 10016, USA.
Cell Growth Differ. 1998 Oct;9(10):837-45.
Nerve growth factor induces PC12 cells to differentiate from a chromaffin cell to a sympathetic neuronal phenotype. In contrast, PC12 cells, which stably express Wnt-1, a secreted signaling factor required for development of mammalian midbrain and cerebellum, fail to express differentiation-specific genes in response to nerve growth factor. Analysis of factors binding to E box-containing regulatory elements of the terminal differentiation gene encoding peripherin suggested a differentiation-specific control of expression of helix-loop-helix transcriptional regulators. Specifically, the MASH-1 (mammalian achaete-scute homologue) helix-loop-helix transcription factor, which plays a positive role in neuronal differentiation, is reduced in Wnt-1/PC12 cells, and HES-1, a negative regulator of MASH-1, is increased. These data suggest that the differentiation block may result from induction of HES-1. Wnt-1/PC12 cells also proliferate more rapidly and express increased levels of cyclin D1. Thus, Wnt-1 may block the differentiation and enhance the proliferation of PC12 cells by activating HES-1 and cyclin D1 and repressing MASH-1.
神经生长因子诱导PC12细胞从嗜铬细胞分化为交感神经元表型。相反，稳定表达Wnt-1（哺乳动物中脑和小脑发育所需的一种分泌型信号因子）的PC12细胞，对神经生长因子无反应，无法表达分化特异性基因。对与编码外周蛋白的终末分化基因中含E盒的调控元件结合的因子进行分析，提示了对螺旋-环-螺旋转录调节因子表达的分化特异性控制。具体而言，在神经元分化中起正向作用的MASH-1（哺乳动物achaete-scute同源物）螺旋-环-螺旋转录因子在Wnt-1/PC12细胞中减少，而MASH-1的负调节因子HES-1增加。这些数据表明，分化阻滞可能是由HES-1的诱导所致。Wnt-1/PC12细胞增殖也更快，且细胞周期蛋白D1表达水平升高。因此，Wnt-1可能通过激活HES-1和细胞周期蛋白D1并抑制MASH-1来阻断PC12细胞的分化并增强其增殖。
