芬兰赫尔辛基大学癌症研究中心的研究人员在寻找新的肿瘤抑制基因时,发现了一个重要的进化改变,这个改变发生在一个关键的发育信号途径中,该发现显示了复杂细胞间信号途径的一个潜在机制。
一般,有少量的进化保守基因控制动物物种的多样性发育。其中大多数基因最初主要发现于果蝇中,可以根据对突变体的分析来改变胚胎的发育模式。
在胚胎发育期间,细胞通过分泌型的胞外信号分子(生长因子或形态发生素)来调节彼此的生长和分化,这些分子能绑定其它细胞的表面受体。然后将这些细胞内信号途径受体组成蛋白中转给细胞核,激活转录因子,进而影响基因的表达并诱导细胞生长和分化。
大多数发育信号途径的信号转导分子和机制被认为是进化保守的,由于缺乏过渡类型,这些复杂信号途径在进化细节上还不清楚。
由于Hedgehog(Hh)信号途径在人类癌肿中没有发现,研究人员为不如动物克隆了一个果蝇的关键Hh信号途径调节因子——Costal-2。然而,对哺乳动物基因功能作进一步分析则显示出它并没有像Hh信号途径一样的功能,更不用说像肿瘤抑制基因一样了。
不过,研究人员发现在果蝇的Hh信号途径中具有微小作用的另一个基因(启动抑制子)对于哺乳动物Hh信号途径的调节来说非常重要。
该发现首次解释阐明了在不同物种间的主要保守信号途径,这将有助于解释进化生物学中复杂的信号途径。
By University of Helsinki, Cancer researchers at the University of Helsinki, in trying to find a novel tumor suppressor gene, instead found an important evolutionary change that occurred in a key developmental signalling pathway. The finding suggests a potential mechanism for evolution of complex intercellular signalling pathways.
A relatively small number of evolutionary conserved genes are responsible for controlling the development of the diverse range of animal species. Most of these genes have been originally identified in fruit fly, based on the analysis of mutations that alter the body pattern of a developing embryo.
During embryonic development, cells regulate the growth and differentiation of each other by secreting extracellular signalling molecules (growth factors or morphogens), which bind to receptors present on the surface of other cells. The receptors in turn activate intracellular signalling pathway composed of proteins that relay the signal to the nucleus, activating specialized proteins called transcription factors. The transcription factors then affect expression of genes that induce cell growth and differentiation.
The signal transduction molecules and mechanisms of major developmental signalling pathways are thought to be evolutionary conserved between invertebrates and vertebrates in such a way that if a signalling pathway is present in a given organism, it includes all the major classes of components found in humans. Because of the lack of intermediate forms, the evolution of these complex signalling pathways is not understood in detail, and the emergence of signalling pathways with multiple specific and essential components has even been used as an argument against evolution.
Because multiple components of the Hedgehog (Hh) signalling pathway are defective in human cancers, Markku Varjosalo in Professor Jussi Taipale's laboratory (the University of Helsinki and National Public Health Institute of Finland) cloned the gene for mammalian homolog of a key regulator of fruit fly Hh signalling pathway, Costal-2. However, further analysis of the function of the mammalian gene revealed that it did not function as a Hh pathway regulator, let alone as the tumor suppressor gene the researchers had hoped for. Instead, together with a group led by Prof. Rune Toftg錼d and Dr. Stephan Teglund from Karolinska Institutet, the researchers found that another gene (Suppressor of Fused), which has a minor role in Hh signalling in fruit fly is critical for Hh pathway regulation in mammals.
The finding is the first clear demonstration of a major difference in the function of conserved signalling pathways between species. The results also show that multi-component pathways evolve, in part, by the insertion of novel proteins between existing pathway components. This insertion mechanism can potentially explain a challenging aspect of evolutionary biology regarding the emergence of signalling pathways with multiple specific components.
- Developmental Cell Journal
原文见:http://www.rxpgnews.com/research/embryology/article_3377.shtml