Baonza Antonio, Murawsky Christopher M, Travers Andrew A, Freeman Matthew
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
Nat Cell Biol. 2002 Dec;4(12):976-80. doi: 10.1038/ncb887.
Cell division in animals must be regulated; during development, for example, proliferation often occurs in spatially and temporally restricted patterns, and loss of mitotic control underlies cancer. The epidermal growth factor receptor (EGFR) has been implicated extensively in the control of cell proliferation in metazoans; in addition, hyperactivity of the EGFR and its three relatives, ErbB2-ErbB4, are implicated in many cancers. But little is known about how these receptor tyrosine kinases regulate the cell cycle. In the developing Drosophila melanogaster imaginal eye disc, there is a single patterned mitosis that sweeps across the eye disc epithelium in the third larval instar. This 'second mitotic wave' is triggered by EGFR signalling and depends on expression of String, the Drosophila homologue of Cdc25 phosphatase, the ultimate regulator of mitosis in all eukaryotic cells. Here we show that two antagonistic transcriptional regulators, Pointed, an activator, and Tramtrack69, a repressor, directly regulate the transcription of string. The activity of at least one of these regulators, Pointed, is controlled by EGFR signalling. This establishes a molecular mechanism for how intercellular signalling can control string expression, and thereby cell proliferation.
动物体内的细胞分裂必须受到调控；例如，在发育过程中，细胞增殖常常以空间和时间受限的模式发生，而有丝分裂控制的丧失是癌症的基础。表皮生长因子受体（EGFR）在后生动物的细胞增殖控制中发挥了广泛作用；此外，EGFR及其三个相关蛋白ErbB2 - ErbB4的过度活跃与许多癌症有关。但是，关于这些受体酪氨酸激酶如何调节细胞周期，我们所知甚少。在发育中的黑腹果蝇成虫眼盘中，在第三龄幼虫期有一个单一模式的有丝分裂过程，它会扫过眼盘上皮细胞。这个“第二次有丝分裂波”由EGFR信号触发，并依赖于String的表达，String是Cdc25磷酸酶的果蝇同源物，而Cdc25磷酸酶是所有真核细胞中有丝分裂的最终调节因子。在这里，我们表明两个相互拮抗的转录调节因子，激活因子Pointed和抑制因子Tramtrack69，直接调节string的转录。这些调节因子中至少有一个，即Pointed的活性受EGFR信号控制。这就建立了一种分子机制，解释了细胞间信号如何控制string的表达，进而控制细胞增殖。
