摘要
QKI是一类RNA结合蛋白,在神经系统中表达含量很高,基因部分缺失小鼠由于神经髓鞘发育障碍,在出生后10天出现严重的震颤表型。尽管关于QKI的研究主要集中于在神经系统领域,但是在神经系统以外的器官,如心,肺,睾丸,也有广泛表达。
在神经系统中的研究发现,QKI-6, 7主要在细胞浆负责目的RNAs的运输及参与稳定性的调控。QKI-5可与目的转录本结合将其滞留在细胞核,但是关于其更多的功能研究却未见报道。
除了在神经系统中对于髓鞘的形成发挥重要功能以外,QKI蛋白在血管发育,凋亡,细胞黏附,细胞生长及形态形成和器官发生等方面具有举足轻重的功能。根据RNA结合蛋白QKI-5对目的基因3’UTR的结合具有特异性以及到目前为止经实验验证的结合位点,我们在通过生物信息学预测的1430个靶基因中选择FoxO1作为我们的研究对象。主要基于以下几方面的原因。
一、对转录因子FoxO1的功能研究发现,FoxO1主要参与细胞的新陈代谢、氧化应激、细胞周期调控、凋亡、衰老以及血管发育等生命过程,与QKI的功能存在某种程度的交叉。如在QKI-5以及FoxO1基因分别敲除的小鼠中,都观察到由于血管发育障碍导致的胚胎致死表型,进一步研究发现这两种敲除小鼠中都存在维甲酸通路功能障碍。
二、对FoxO1的mRNA的3’UTR进行了生物信息学分析,发现在其3’UTR存在三个十分保守的QKI-5结合位点。同时软件预测发现FoxO1的3’UTR在物种间高度保守,且二级结构复杂度非常高,暗示它的3’UTR具有生物学功能,提示可能有转录后调控的存在。
为了验证QKI-5对FoxO1存在转录后调控,我们首先构建含FoxO1的3’UTR的荧光素酶报告系统,发现QKI-5能够明显降低报告系统的活性,提示是一种转录后负性调控。通过RNA免疫共沉淀实验证实QKI-5可与FoxO1的3’UTR特异结合,提示二者之间在细胞内存在相互作用。在此基础上为了进一步验证它们之间的相关性,通过人为升高和降低QKI-5的表达,观察到FoxO1与QKI-5的表达存在负相关。提示QKI-5可能通过转录后水平参与调控FoxO1的表达。那么,QKI-5对FoxO1的这种转录后调控在何种情况下发生且具有什么生理意义呢?
在RA诱导乳腺癌细胞周期阻滞的模型中,我们检测到QKI-5和FoxO1的表达均明显上升。运用siRNA技术特异沉默QKI-5之后,FoxO1及其相关细胞周期蛋白cyclin D1和P27均发生明显改变,使RA诱导后MCF-7细胞周期阻滞进程发展加快。进一步分析QKI对FoxO1的作用机理,特异沉默QKI-5表达组,FoxO1 mRNA稳定性增强。提示QKI-5介导了RA引起FoxO1 mRNA稳定性下降的过程。
由于RA诱导之后,FoxO1的mRNA整体水平是升高的,QKI-5对FoxO1的负性调控具有什么意义呢?结合FoxO1的功能考虑,我们在RA抑制MCF-7细胞增殖模型中,通过SA-gal细胞衰老功能实验发现特异沉默QKI-5表达实验组,RA诱导后,细胞衰老的发生率与未沉默组比较明显增加,提示,正是由于QKI-5对FoxO1的负性调控延缓了FoxO1的快速升高所致的细胞衰老,从而使ATRA对细胞周期的精细调控朝着诱导分化或凋亡的途径进行。
本实验不但证实QKI-5可与FoxO1的3’UTR结合,并且是通过影响了FoxO1的mRNA稳定性发挥转录后负性调控作用;更重要的是,在RA抑制MCF-7细胞增殖中,QKI-5对FoxO1的这种负性调控能够抑制细胞衰老,从而有利于RA更好地发挥调节细胞周期阻滞,诱导分化或凋亡的功能。
维甲酸(All-trans-retinoic acid,ATRA)是一种经典的分化和凋亡诱导剂。在体外一些髓样细胞系中ATRA可以诱导细胞周期阻滞及启动终末分化。并且由于它的这一特性已在临床用于治疗急性早幼粒细胞性白血病,并取得很好的疗效。除了造血系统,RA对许多实体瘤细胞系也具有诱导分化的功能。
尽管研究人员对RA的许多生物学功能了解地非常清楚,但是关于它发挥作用的分子机制却知道的非常有限。我们的前期实验通过基于PCR的消减杂交方法从ATRA诱导人早幼粒白血病HL-60细胞分化过程中,克隆了一系列新基因,Apr3是其中之一。
我们首先通过InterPro和PROSITE这两个蛋白质分析软件对Apr3进行了功能结构域的预测,发现Apr3在其氨基端含有一段信号肽序列,之后紧跟一个EGF domain,在其羧基端分别为跨膜区及氨基酸系列非常短的胞内区,提示Apr3可能是一个膜蛋白。
Apr3是ATRA诱导HL-60细胞分化时差异表达的一个新基因,它是否存在于其他实体瘤呢?RT-PCR分析显示Apr3在多种细胞中有广泛的分布,并且绝大多数细胞经ATRA诱导后,Apr3的表达都有不同程度的升高。通过间接免疫荧光对Apr3的亚细胞定位进行研究发现Apr3沿细胞膜分布,是一个膜蛋白;然而缺失跨膜区及胞内区的截短体Apr3?在细胞浆内呈颗粒样、点状分布,具备分泌蛋白的典型特征。
RA作为分化诱导剂,它可以抑制细胞的增殖,同时促进细胞的分化。相关的机理研究表明,ATRA可诱导细胞周期阻滞于G1期,Apr3是受到RA诱导表达的分子,它是否参与对细胞周期的调控是我们首先关注的内容。流式细胞仪检测发现Apr3能将细胞周期阻滞于G1/S期,而Apr3?使S期细胞增多,提示它可以促进细胞的增殖。在细胞周期进程中,cyclin D1是发挥作用最关键的调节因子。为此通过荧光素酶报告系统观察Apr3是否影响cyclin D1启动子的活性,结果表明Apr3过表达能显著抑制cyclin D1的启动子活性,而Apr3?则具有完全相反的作用,高度提示膜蛋白Apr3可能是调控细胞周期的关键分子。进一步检测细胞周期调控的关键分子cyclin D1的mRNA和蛋白水平,与报告系统结果一致。
本课题研究结果提示Apr3在多种肿瘤细胞中广泛表达,并且受到RA信号通路的上调。它分布在细胞膜表面,主要可能通过识别相关配体直接参与对细胞周期的调控,特别是通过抑制cyclin D1的表达,引起细胞周期的阻滞。说明此分子在ATRA信号通路的重要作用。
QKI is an RNA binding protein essential for normal myelination, and are abundantly expressed in the central nervous system. QKI viable mice exhibit extensive body tremors detectable by postnatal day 10 resulting from a severe deficit in myelination. Although the most extensive study about QKI are foused on nervous system, profound and abundant distribution of QKI-5, was observed in various other tissues of adult, such as heart, lung or testis.
Analyzing the functions of QKI isoform in nervous system disclosed that QKI-6, 7 are mainly responsible for transport and stability of target RNAs. Whereas, QKI-5 binds target transcripts to retain them in the nucleus., Specific role of QKI-5 has been largly unknown
In addition to its fundamental role in myelination, QKI also participated in vascular development, apoptosis, cell adhesion, cell growth, morphogenesis and organogenesis. In light of the validated target motif and RNA binding specificity of QKI with its targets, we select FoxO1 as a candidate gene from 1430 new putative mRNA targets predicted by other researcher.
1. As we known, FoxO proteins have an important role in the regulation of metabolism, resistance to oxidative stress, cell cycle progression, apoptosis, longevity, senescence and vascular development. Interestingly, there is a common embryonic lethal phenotype shared by QKI or FoxO1 knockout mice due to vascular development disturbance, hinting the functional overlap between them. The underlying mechanism are both related with dysregulation of retinoic acid (RA) signaling pathways.
2. One the basis of bioinformatics analysis on FoxO1 3’UTR., it contains 3 predicted QRE and may be a QKI target transcript, its mRNA sequence is evolutionarily conserved among organisms, and secondary structure is highly complicated. These features highly suggested that 3’UTR of FoxO1 is functionally important in vivo.
In order to assess whether QKI-5 could regulate FoxO1 expression at post-transcriptional level, we made a reporter constructs containing 3”UTR of FoxO1 at the downstream of luc reporter gene. Upon QKI-5 overexpression, the luciferase activity were gradually decreased, implying that QKI-5 could negatively regulate FoxO1 expression at post-transcriptional level. Furthermore we performed RNA co-immprecipitation assay, and verified that QKI-5 could associate specifically with 3’UTR of FoxO1 in vivo. Is this type of regulation functionally important in vivo?
In model of RA-induced cell cycle arrest of mammary cancer cells, the expression of QKI-5 and FoxO1 were both up-regulated. we analyzed the effect of QKI-5 on cell cycle regulation following RA induction by specifically silencing the expression of QKI-5. As expected, the FoxO1 and related cell cycle regulators were moderately altered, implying that the effects of RA is partially mediated by QKI-5. Besides the stability of FoxO1 mRNA was greatly enhanced upon RA induction in QKI-5-silenced cells compared with that of controls, confirming the effects of RA on the stability of FoxO1 mRNA was mediated by QKI-5.
It was known that ATRA is able to induce the differentiation of breast epithelium normally. In MCF-7 breast cancer line, ATRA induced cell cycle arrest, Under the condition of lacking QKI-5 , or at very low level, mimicked by qki-5 RNAi treatment, we found the incidence of senescence was dramatically enhanced determined by SA-gal detection assay. Our results have disclosed an underlying importance of QKI-5 in the posttranscriptional regulation of FoxO1 during ATRA induced cell cycle and differentiation process, without QKI-5, the cell tends to be more susceptible to become senescent under the ATRA treatment.
All-trans-retinoic acid (ATRA) is a classic differentiation and apoptosos agent. ATRA treatment induce terminal differentiation and growth arrest of several established human myeloid cell lines in vitro and has also proven to be effective in the clinical treatment of acute promyelocytic leukemia (APL) by inducing differentiation and apoptosis of the immature blasts. Besides, ATRA is capable of directing the differentiation of several solid tumor cell lines.
Although the biologic effects of ATRA are well characterized, the molecular mechanisms involved are largely unknown. Our previous experiment identified a series of differentially expressed genes in HL-60 cells upon treatment with ATRA by use of PCR-based subtractive hybridization method. Apr3 was one of the novel genes among them.
The structural analysis by use of InterPro and PROSITE predicted that Apr3 contains several putative functional domains, including a signal sequence at N-terminus, following with one EGF-domain, one transmembrane region and the extremely short intracellular region at C-terminus. Our specific interest is to characterize if Apr3 was a membrane protein and participate in RA signal pathway in vivo.
Since Apr3 was a differentially expressed genes in HL-60 cells upon ATRA treatment, In order to define its expression pattern in other cell line, RT-PCR analyses was employed to observe that Apr3 has a wide distribution among several cell lines, and be obviously up-regulated upon ATRA treatment. Indirect immunofluorescence assay disclosed that Apr3 was localized on the cell membrane, but its truncated mutant, lacking the transmembrane region and intracellular domain, was shown to be dotted and be likely a secreted one. Previous studies have indicated that retinoic acids could inhibit cell proliferation by inducing G1 arrest in many different cell types. In order to study the effects of Apr3 on cell cycle progression, FACS showed a higher ratio of cells arrest at G1 cell cycle phase after transient Apr3 transfection, while its mutant form overexpression showed the opposite effects with higher number of cells at S phase, denoting the high rate of cell proliferation. Cyclin D1 is one of the most important marker in G1 phase. we first performed cyclin D1 promoter reporter assay. Apr3 overexpression strongly inhibited the cyclin D1 promoter activities, in contrast, its mutant showed an opposite enhancing effects on cyclin D1. Both RT-PCR and Western Blot analyses confirmed the above results.
Our data provide the first evidence to show that Apr3 is a membrane protein and plays a critical role in inducing cell cycle arrest at G1 phase by inhibiting Cyclin D1 expression. Its mutant form Apr3? showed opposite effects, suggesting that Apr3 is functionally important to regulate the cell proliferative status in vivo.
引文
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