端粒与端粒酶的研究进展综述

端粒是存在于真核细胞的染色体末端的特殊结构,其作用是维持染色体末端的遗传稳定性,它的存在避免了染色体被酶降解。端粒酶负责延长端粒的长度,是一种逆转录酶。端粒酶在肿瘤细胞中具有高活性。端粒与端粒酶的存在在细胞的永生化中扮演着重要的角色,是细胞衰老与癌变的重要决定因素。本文综述了端粒与端粒酶目前的研究进展,并对其日后的发展提出展望。     

细胞衰老的研究进展（综述）

细胞衰老的机理不详。综观至目前的各种研究。主要与以下三方面因素有关：（1）基因损伤的积累效应。自由基不断作用导致基因积累的错误信息超出了机体的修复能力,引起细胞衰竭死亡。（2）生命钟基因控制着细胞程序衰老。生物体细胞内存在一系列基因,它们控制着细胞的生长、分化、老化和死亡。（3）染色体端粒的缩短。端粒的长度随细胞的不断分裂而缩短,当DNA丢失到一定程度,细胞随之发生衰老和死亡。端粒酶能延长被缩短的端粒,延迟细胞的衰老,端粒酶的活性受到许多因素影响,其中包括与衰老有关的基因。     

端粒、端粒酶和肿瘤、细胞衰老

端粒和端粒酶是现代生物学研究的热点,端粒的缺失与细胞的衰老,端粒酶的活性与细胞的老化及癌化均有密切的关系.文章综述了端粒和端粒酶的结构和功能及其与细胞衰老及肿瘤的关系,并在此基础之上展望了端粒酶在抗衰老、抑制肿瘤等方面的应用.     

端粒酶与食管癌、胃癌相关性的研究

端粒是染色体DNA端部的特化部分，由高度重复的短序列DNA一蛋白质组成的特殊结构，能维持染色体的稳定和完整．端粒酶是由RNA与蛋白质亚基组成的核糖核蛋白酶，能以自身RNA为模板，合成端粒序列，是一种非常特殊的逆转录酶．端粒的长度和端粒酶的活性与细胞永生化，细胞衰老和癌变密切相关，在肿瘤发生发展中，端粒酶成为一种重要的肿瘤生物学标志物，有望作为诊断和治疗肿瘤的新靶点．本对端粒酶的结构与功能，端粒酶与食管癌、胃癌相关性的研究新进展及端粒酶活性的检测方法做一简要综述．     

是否可以通过延长端粒的长度来减缓衰老?

<正>A:端粒是染色体末端的特殊结构,由许多重复序列和相关蛋白组成,它具有维持染色体结构完整性和稳定性的作用。细胞每进行一次有丝分裂,就有一段端粒序列丢失。而端粒酶能够合成端粒,维持其序列稳定性。1990年,科学家首次将端粒与人类细胞衰老联系在一起,发现成纤维细胞中端粒缩短到一定程度,细胞会停止分裂,变成衰老状态。2010年,科学家以端粒酶缺陷的转基因小鼠为研究对象,通过重新激活端粒酶,成功逆转了衰老过程。这一研究     

Epithalon对人胎肝细胞端粒酶活性和端粒长度的影响

以松果体分泌物,"Epithalamin"缩氨酸为基础,人工合成多肽"Epithalon"。通过用细胞形态学观察用药后细胞的生长情况,MTT法检测Epithalon多肽对人肝细胞株L-02增殖与活力的影响,以及运用端粒酶重复序列扩增——焦磷酸根酶联发光技术检测人肝细胞株L-02端粒酶活性,流式荧光原位杂交法检测端粒长度。研究了多肽作用于人肝细胞L-02后对细胞的生长情况、细胞端粒长度以及细胞端粒酶活性所产生的影响。研究显示Epithalon多肽具有提高端粒酶活性,延缓端粒缩短的作用。     

端粒及端粒酶的研究现状

综述了端粒、端粒酶的结构、功能,以及端粒序列复制问题与端粒酶活性在细胞衰老和癌变中的重要作用。     

外周血白细胞端粒DNA长度与肺癌的关系

外周血白细胞端粒DNA长度与肺癌之间的关系研究有助于肺癌的早期诊断和治疗。本研究采用实时荧光定量PCR法对肺癌患者和健康对照组外周血白细胞端粒DNA的长度进行检测,研究肺癌与外周血白细胞端粒DNA长度的关系。结果表明,肺癌组的端粒长度小于健康对照(normal control,NC)组(P0.05),小细胞肺癌(small cell lung carcinoma,SCLC)组端粒长度短于非小细胞肺癌(non-small cell lung cancer,NSCLC)组(P0.05),Ⅲ+Ⅳ期较Ⅰ+Ⅱ期端粒DNA明显缩短(P0.05)。多元线性回归分析结果显示,SCLC和NSCLC组中年龄与是否吸烟两个因素与端粒的长度具有相关性(P0.05),且前者与端粒长度的关系呈负相关;腺癌组中与端粒长度具有相关性的因素是性别和年龄(P0.05),且后者与端粒长度的关系也呈负相关。     

端粒及端粒酶的研究现状

综述了端粒、端粒酶的结构、功能，以及端粒序列复制问题与端粒酶活性在细胞衰老和癌变中的重要作用。     

端粒、端粒酶与细胞衰老及肿瘤的研究进展(综述)

端粒是真核生物线形染色体末端的一种特殊的异质化结构,在稳定染色体及防止染色体在复制时缩短方面有重要作用。其行为的异常被认为同细胞衰老及肿瘤的发生发展有密切关系。端粒酶是一个特殊的具有反转录活性的核糖核蛋白。近来的研究表明,端粒酶已不仅仅能维持端粒的长度,它更有助于肿瘤的形成。笔者综述了端粒的缩短所扮演的双重角色,以及端粒酶的激活与肿瘤之间的关系。     

Telomeres shorten during ageing of human fibroblasts

The terminus of a DNA helix has been called its Achilles' heel. Thus to prevent possible incomplete replication and instability of the termini of linear DNA, eukaryotic chromosomes end in characteristic repetitive DNA sequences within specialized structures called telomeres. In immortal cells, loss of telomeric DNA due to degradation or incomplete replication is apparently balanced by telomere elongation, which may involve de novo synthesis of additional repeats by novel DNA polymerase called telomerase. Such a polymerase has been recently detected in HeLa cells. It has been proposed that the finite doubling capacity of normal mammalian cells is due to a loss of telomeric DNA and eventual deletion of essential sequences. In yeast, the est1 mutation causes gradual loss of telomeric DNA and eventual cell death mimicking senescence in higher eukaryotic cells. Here, we show that the amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo. It is not known whether this loss of DNA has a causal role in senescence.     

POT1 as a terminal transducer of TRF1 telomere length control

Human telomere maintenance is essential for the protection of chromosome ends, and changes in telomere length have been implicated in ageing and cancer. Human telomere length is regulated by the TTAGGG-repeat-binding protein TRF1 and its interacting partners tankyrase 1, TIN2 and PINX1 (refs 5-9). As the TRF1 complex binds to the duplex DNA of the telomere, it is unclear how it can affect telomerase, which acts on the single-stranded 3' telomeric overhang. Here we show that the TRF1 complex interacts with a single-stranded telomeric DNA-binding protein--protection of telomeres 1 (POT1)--and that human POT1 controls telomerase-mediated telomere elongation. The presence of POT1 on telomeres was diminished when the amount of single-stranded DNA was reduced. Furthermore, POT1 binding was regulated by the TRF1 complex in response to telomere length. A mutant form of POT1 lacking the DNA-binding domain abrogated TRF1-mediated control of telomere length, and induced rapid and extensive telomere elongation. We propose that the interaction between the TRF1 complex and POT1 affects the loading of POT1 on the single-stranded telomeric DNA, thus transmitting information about telomere length to the telomere terminus, where telomerase is regulated.     

BRAFE600-associated senescence-like cell cycle arrest of human naevi

Most normal mammalian cells have a finite lifespan, thought to constitute a protective mechanism against unlimited proliferation. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16(INK4a) (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes; however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi (moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations (predominantly V600E, where valine is substituted for glutamic acid) in BRAF, a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma). This raises the question of whether naevi undergo BRAF(V600E)-induced senescence. Here we show that sustained BRAF(V600E) expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16(INK4a) and senescence-associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-beta-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)-driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.     

In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymena telomerase RNAs.

Mutating the CAACCCCAA sequence in the RNA component of telomerase causes the synthesis in vivo of new telomere sequences corresponding to the mutated RNA sequence, demonstrating that the telomerase contains the template for telomere synthesis. These mutations also lead to nuclear and cell division defects, and senescence, establishing an essential role for telomerase in vivo.     

The changes in telomerase activity and telomere length in HeLa cells undergoing apoptosis induced by sodium butyrate

The changes in telomerase activity and telomere length during apoptosis in HeLa cells as induced by sodium butyrate (SB) have been studied. After a 48 h SB treatment, HeLa cells demonstrated characteristic apoptotic hallmarks including chromatin condensation, formation of apoptotic bodies and DNA Laddering which were caused by the cleavage and degradation of DNA between nucleosomes. There were no significant changes in telomerase activity of apoptotic cells, while the telomere length shortened markedly. In the meanwhile, cells became more susceptible to apoptotic stimuli and telomere became more vulnerable to degradation after telomerase activity was inhibited. All the results suggest that the apoptosis induced by SB is closely related to telomere shortening, while telomerase enhances resistance of HeLa cells to apoptotic stimuli by protecting telomere.     

Defects in mismatch repair promote telomerase-independent proliferation

Mismatch repair has a central role in maintaining genomic stability by repairing DNA replication errors and inhibiting recombination between non-identical (homeologous) sequences. Defects in mismatch repair have been linked to certain human cancers, including hereditary non-polyposis colorectal cancer (HNPCC) and sporadic tumours. A crucial requirement for tumour cell proliferation is the maintenance of telomere length, and most tumours achieve this by reactivating telomerase. In both yeast and human cells, however, telomerase-independent telomere maintenance can occur as a result of recombination-dependent exchanges between often imperfectly matched telomeric sequences. Here we show that loss of mismatch-repair function promotes cellular proliferation in the absence of telomerase. Defects in mismatch repair, including mutations that correspond to the same amino-acid changes recovered from HNPCC tumours, enhance telomerase-independent survival in both Saccharomyces cerevisiae and a related budding yeast with a degree of telomere sequence homology that is similar to human telomeres. These results indicate that enhanced telomeric recombination in human cells with mismatch-repair defects may contribute to cell immortalization and hence tumorigenesis.     

网络计划资源均衡优化方法研究

通过示例分析，对网络计划资源均衡优化中缩方差法的工序调整计算公式进行了修正，提出了比较完善的计算公式，使优化过程的工作量大大减小。