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Runx转录因子与细胞增殖和分化之间的发育平衡。

Runx transcription factors and the developmental balance between cell proliferation and differentiation.

作者信息

Coffman James A

机构信息

Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, MO 64110, USA.

出版信息

Cell Biol Int. 2003;27(4):315-24. doi: 10.1016/s1065-6995(03)00018-0.

Abstract

The runt box (Runx) is a highly conserved DNA binding and protein-protein interaction domain that defines a family of heterodimeric transcription factors with essential roles in metazoan development. The first member of this family to be identified was the Drosophila regulatory gene runt, which was named by virtue of its function in establishing segmentation patterns during embryogenesis, and subsequently discovered to have additional functions in sex determination and neurogenesis. A second Drosophila Runx gene, lozenge, is required for cell patterning in the eye and for hematopoiesis. The genome project has revealed the existence of two additional Drosophila Runx genes, which to date have not been functionally characterized. Other invertebrate species with well-characterized Runx transcription factors include the nematode Caenorhabditis elegans and the sea urchin Strongylocentrotus purpuratus, each of which apparently contains only a single Runx gene. There are three Runx genes in mammals; Runx1 is required for definitive hematopoiesis and is a frequently mutated gene in human leukemia, Runx2 is required for osteogenesis and is associated with cleidocranial dysplasia, and Runx3 controls neurogenesis in the dorsal root ganglia and cell proliferation in the gastric epithelium, and is frequently deleted or silenced in human gastric cancer. Studies using mammalian systems and sea urchins indicate that Runx proteins have essential functions in both cell proliferation and differentiation, and in mammals they are both proto-oncogenes and tumor suppressors. Thus, a central question concerning the cell biology of Runx proteins is how are the opposing functions of this class of transcription factors regulated during development? Here I review current knowledge of Runx protein structure, function and regulation, and outline directions for future research aimed at understanding how Runx protein function is modulated during the transition from cell proliferation to differentiation in animal development.

摘要

矮小框(Runx)是一个高度保守的DNA结合和蛋白质-蛋白质相互作用结构域,它定义了一类异二聚体转录因子家族,这些转录因子在后生动物发育中起着至关重要的作用。该家族中第一个被鉴定的成员是果蝇调控基因矮小(runt),它因其在胚胎发育过程中建立体节模式的功能而得名,随后发现它在性别决定和神经发生中还有其他功能。果蝇的第二个Runx基因菱形(lozenge),是眼睛中的细胞模式形成和造血所必需的。基因组计划揭示了另外两个果蝇Runx基因的存在,迄今为止它们尚未进行功能表征。其他具有特征明确的Runx转录因子的无脊椎动物物种包括线虫秀丽隐杆线虫和海胆紫球海胆,它们显然都只含有一个Runx基因。哺乳动物中有三个Runx基因;Runx1是确定造血所必需的,并且是人类白血病中经常发生突变的基因,Runx2是骨生成所必需的,并且与锁骨颅骨发育不全相关,Runx3控制背根神经节中的神经发生和胃上皮中的细胞增殖,并且在人类胃癌中经常缺失或沉默。使用哺乳动物系统和海胆进行的研究表明,Runx蛋白在细胞增殖和分化中都具有重要功能,在哺乳动物中它们既是原癌基因又是肿瘤抑制因子。因此,关于Runx蛋白细胞生物学的一个核心问题是,这类转录因子的相反功能在发育过程中是如何被调节的?在这里,我回顾了关于Runx蛋白结构、功能和调节的当前知识,并概述了未来研究的方向,旨在了解在动物发育过程中从细胞增殖到分化的转变过程中Runx蛋白功能是如何被调节的。

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