转录因子KLF14的功能研究
发布时间：2018-10-11 17:26
【摘要】：中心体的过度复制是肿瘤细胞的典型特征之一。然而,引起中心体过度复制的原因仍未研究透彻。在生理和病理学领域,转录因子KLF家族的功能已经被广泛研究。近年来,KLF14作为脂代谢的重要调控者已经引起了广泛关注,但是其真正的生理学功能仍需大量、深入的研究。在本论文中,我们构建了KLF14基因敲除的小鼠,并发现KLF14的缺失会导致中心体的过度复制、基因组的不稳定性和自发肿瘤的产生。分子水平上,我们发现KLF14能转录抑制PLK4。PLK4是中心体复制的主要调控因子,对中心粒复制的起始以及新中心粒的组装至关重要。瞬时基因沉默KLF14会导致PLK4转录水平和蛋白水平都上升。而且,KLF14的缺失会导致AOM/DSS诱导的结肠癌恶化程度更高。这些结果表明KLF14的缺失会引起PLK4表达上升,促进中心体复制,并最终导致自发肿瘤的产生。目前对“中心体过度复制和基因组不稳定性是肿瘤发生的重要原因之一”这一论点仍存在争议。我们的研究则支持了这一论点。综上所述,我们的研究证实转录因子KLF14是一个重要的肿瘤抑制因子,为肿瘤药物的开发提供了新的思路。
[Abstract]:Excessive replication of centrosome is one of the typical characteristics of tumor cells. However, the causes of excessive centrosome replication have not been thoroughly studied. The function of transcription factor KLF family has been widely studied in physiology and pathology. In recent years, KLF14 as an important regulator of lipid metabolism has attracted extensive attention, but its true physiological function still needs a lot of in-depth research. In this paper, we constructed KLF14 knockout mice and found that the deletion of KLF14 leads to excessive replication of centrosome, genomic instability and spontaneous tumor production. At the molecular level, we found that KLF14 transcriptional inhibition of PLK4.PLK4 is the main regulatory factor for centrosomal replication, which is very important for the initiation of centroid replication and the assembly of new centroids. Transient gene silencing of KLF14 results in an increase in PLK4 transcription and protein levels. Moreover, loss of KLF14 can lead to a higher degree of deterioration of colon cancer induced by AOM/DSS. These results suggest that the deletion of KLF14 can induce the increase of PLK4 expression, promote centrosomal replication, and eventually lead to spontaneous tumor. The argument that centrosomal overreplication and genomic instability are one of the major causes of tumorigenesis is still controversial. Our research supports this argument. In conclusion, our study confirmed that transcription factor KLF14 is an important tumor suppressor, which provides a new idea for the development of tumor drugs.
【学位授予单位】：华东师范大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.2
本文编号：2264628
[Abstract]:Excessive replication of centrosome is one of the typical characteristics of tumor cells. However, the causes of excessive centrosome replication have not been thoroughly studied. The function of transcription factor KLF family has been widely studied in physiology and pathology. In recent years, KLF14 as an important regulator of lipid metabolism has attracted extensive attention, but its true physiological function still needs a lot of in-depth research. In this paper, we constructed KLF14 knockout mice and found that the deletion of KLF14 leads to excessive replication of centrosome, genomic instability and spontaneous tumor production. At the molecular level, we found that KLF14 transcriptional inhibition of PLK4.PLK4 is the main regulatory factor for centrosomal replication, which is very important for the initiation of centroid replication and the assembly of new centroids. Transient gene silencing of KLF14 results in an increase in PLK4 transcription and protein levels. Moreover, loss of KLF14 can lead to a higher degree of deterioration of colon cancer induced by AOM/DSS. These results suggest that the deletion of KLF14 can induce the increase of PLK4 expression, promote centrosomal replication, and eventually lead to spontaneous tumor. The argument that centrosomal overreplication and genomic instability are one of the major causes of tumorigenesis is still controversial. Our research supports this argument. In conclusion, our study confirmed that transcription factor KLF14 is an important tumor suppressor, which provides a new idea for the development of tumor drugs.
【学位授予单位】：华东师范大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.2
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