p53家族成员在细胞生长、组织发育及肿瘤形成等方面都具有十分重要的生物学功能,其自身受到严格调控,泛素化修饰就是其中非常重要的方式之一,作为泛素化过程中决定底物特异性的泛素连接酶E3作用则更加突出.泛素连接酶E3可以分为两类:RING(really interesting new gene)类和HECT(homologous to E6AP C-terminus)类E3.近年来,HECT类E3对p53家族的调控效应不断得到揭示.本文综述了HECT类E3在调控p53家族转录活性、稳定性方面的重要作用、分子机制以及其作用对生物体肿瘤形成和生长发育等产生的影响,为进一步完善p53家族调控网络,揭示HECT类E3在肿瘤发生发展及防治中的作用提供参考.
An increasing data indicates that altered microRNAs(miRNAs)participate in the radiation-induced DNA damage response.However,a correlation of mRNA and miRNA profiles across the entire genome and in response to irradiation has not been thoroughly assessed.We analyzed miRNA microarray data collected from HeLa cells after ionizing radiation(IR),quantified the expression profiles of mRNAs and performed comparative analysis of the data sets using target prediction algorithms,Gene Ontology(GO)analysis,pathway analysis,and gene network construction.The results showed that the altered miRNAs were involved in regulation of various cellular functions.miRNA-gene network analyses revealed that miR-186,miR-106b,miR-15a/b,CCND1and CDK6 played vital role in the cellular radiation response.Using qRT-PCR,we confirmed that twenty-two miRNAs showed differential expression in HeLa cells treated with IR and some of these miRNAs affected cell cycle progression.This study demonstrated that miRNAs influence gene expression in the entire genome during the cellular radiation response and suggested vital pathways for further research.
HU ZhengTIE YiLü GuiXiangFU HanJiangXING RuiYunZHU JieSUN ZhiXianZHENG XiaoFei
The tumor suppressor p53 locates at the key point of cell growth or apoptosis balance, and the expression level of p53 is tightly controlled by ubiquitin ligases including MDM2. Upon DNA damage stresses, p53 was accumulated and activated, leading to cell cycle arrest or apoptosis. We previously showed that Smad ubiquitylation regulatory factor 1/2 (Smurf1/2) promotes p53 degradation by interacting with and stabilizing MDM2, and consequently enhancing MDM2-mediated ubiquitylation of p53. However, it is unclear how the Smurf1-MDM2 interaction is regulated in response to DNA damage stress. Here, we show that in response to etoposide treatment Smurf1 dissociates from MDM2, resulting in MDM2 destabilization and p53 accumulation. The negative regulation of Smurf1 on apoptosis is released. Notably, this dissociation is a slow process rather than a rapid response, implicating high expression of Smurf1 might confer the resistance against p53 activation. Consistent with this notion, we observed that Smurf1/2 ligases are highly expressed in colon cancer, esophageal squamous cell carcinoma and pancreatic cancer tissues, suggesting the oncogenic tendency of Smurf1/2.
Ionizing radiation (IR) causes severe cellular damage both directly and indirectly and disrupts RNA integrity. RNA strand breaks are the most frequent type of damage caused by IR. RNA damage is involved in the development of degenerative diseases, including Alzheimer’s disease and Parkinson’s disease. However, the mechanism of mRNA damage and any resulting pathophysiological outcomes are poorly understood. This is partly because there is a lack of sensitive tools to monitor damage randomly occurring in RNA, especially RNA strand break damage in a given RNA. In this work, a method using the reverse transcription polymerase chain reaction (RT-PCR) after poly(A) addition to 3′-end of RNA to determine RNA strand break damage in a specific RNA by poly(A) polymerase has been developed. The levels of damage in specific mRNAs, including ABL1, TP53, GADD45A and ATR from IR-treated HeLa cells were examined. Strand breaks were detected in all mRNAs examined. The study provides a novel and sensitive method based on 3 -end poly(A)-tailing RT-PCR to monitor RNA strand break damage.
TIE YiHU ZhengLU GuiXiangFU HanJiangXING RuiYunZHU JieSUN ZhiXianHENG XiaoFei
