肿瘤抑制基因与衰老的研究进展

衰老是生物界普遍存在的一种自然现象,是多因素错综复杂的过程。衰老相关基因研究成为近年来的热点,目前已发现与细胞衰老过程密切相关的基因包括细胞周期调控基因、端粒酶调控基因、生长抑制基因以及核酸、蛋白质合成与修复基因等。此外,部分反式作用转录因子包括肿瘤抑制基因(P16,P53,P21)、沉默信息调节因子家族、增殖细胞核抗原等的活性变化与衰老也高度有关。P16、P53和P21基因参与肿瘤发生、发展的周期调控,其表达使肿瘤细胞发生不可逆的凋亡,若缺失或突变与肿瘤的发生高相关。同时,作为细胞增生过程中的负调控因子,P16、P53和P21基因表达调控细胞周期进程和细胞凋亡过程,若缺失或突变会使细胞分裂复制、细胞内和细胞间的运输及通讯功能丧失,最后将导致细胞衰老、死亡或被其它细胞清除。本文就P16、P53、P21基因与衰老的相关研究进展作一综述。     

p53与Ras协同及其在肿瘤发生中的作用

肿瘤发生是抑癌基因失活和原癌基因激活共同作用的结果。p53基因被认为是目前最重要的抑癌基因, 50%以上的肿瘤中存在p53基因的点突变现象; 而Ras基因是肿瘤中突变率较高的原癌基因, 其突变率在某些肿瘤中高达30%~90%。研究发现, 肿瘤发生过程中抑癌基因p53与原癌基因Ras之间存在复杂的相互协同作用。根据目前的文献报道, p53与Ras之间的协同作用可以分为3种：第一, p53对Ras的调节作用; 第二, Ras对p53的调节作用; 第三, p53和Ras共同调控某些与肿瘤发生相关的关键基因。了解p53与Ras之间的3种调控作用将有助于我们进一步认识p53失活与Ras激活协同促进肿瘤发生的分子通路和机制, 同时也将为癌症的个性化治疗和药物靶点的选择提供重要依据。因此, 文章将对近年来所发现的p53与Ras的各种协同作用机制及其与肿瘤发生的关系进行概括和综述。     

端粒(酶)调控衰老和肿瘤的相关研究进展

衰老与肿瘤的相互调控是人类研究中重要的课题之一,二者均由细胞损伤造成,且都受细胞损伤应激调节基因的调控。衰老可以作为抑制肿瘤的天然屏障,肿瘤的增殖机制可以作为对抗衰老的重要手段。在二者平衡的寻求中,端粒及端粒酶发挥了不可忽视的作用。端粒酶作为逆转录酶保持了细胞中"分子时钟"——端粒的长度,减少了染色体损伤,从而保证了细胞分裂的持续进行。端粒酶在调控端粒长度的同时,还可以通过影响线粒体功能从而影响细胞代谢水平,在这个过程中,重要的抑癌基因p53起到了重要作用。鉴于端粒及端粒酶的重要调节作用,寻求衰老及肿瘤的平衡从而达到同时对抗衰老及肿瘤变得更加可行。本文探讨同时调节衰老与肿瘤的重要靶点之间的关系,为更好地寻找衰老与肿瘤的平衡打下基础。     

抑癌基因p53与肿瘤研究的最新进展

p53基因是迄今为止已发现的与人类肿瘤发生相关性最高的抑癌基因,其主要生物学功能是通过调控DNA修复、细胞周期停滞和诱导细胞凋亡,维持基因组和细胞稳定,抑制肿瘤生长;肿瘤血管再生、微小RNA（microRNA,miRNA）及肿瘤干细胞是近几年来肿瘤发生机理研究领域的热点,本文综述了p53基因在肿瘤血管再生、miRNA、肿瘤干细胞中作用的最新研究进展及其在肿瘤治疗中的应用。     

MDM2/MDMX异二聚体及MDMX磷酸化调控p53的研究进展

p53作为肿瘤抑制因子在维持机体内稳态和抑制肿瘤发生发展中起到关键作用。超过半数的人类肿瘤中都存在p53的突变。突变的p53具有"获得性功能",反而促进肿瘤的发生、转移和耐药。MDM2和MDMX是两个最主要的p53负调控蛋白,二者是同源蛋白,可以独自或以异二聚体的方式调控p53。在多种刺激信号下,MDM2/MDMX异二聚体对p53的负调控作用被抑制,使得p53活化进而激活下游复杂的信号网络,维持细胞内稳态。磷酸化修饰是MDMX调节的重要方式之一,对其自身的稳定性、核定位以及与MDM2、p53的相互作用均有影响。该文对以上内容进行简要综述,并对现有治疗靶标和小分子化合物进行讨论,为进一步开发新的有效的肿瘤治疗策略提供思路。     

p53在肿瘤发生过程中的功能研究及进展

p53是迄今为止细胞中最为重要的肿瘤抑制因子之一.p53能够响应细胞内外众多的信号刺激,通过抑制细胞生长、诱导细胞凋亡、促进DNA损伤修复等过程抑制肿瘤的发生发展.近年来发现p53在细胞自噬、细胞代谢,尤其在葡萄糖代谢中也发挥重要作用.p53在超过1/2的人类肿瘤中,发生缺失或突变,提示p53突变和肿瘤发生是紧密相关的.本文将主要结合本研究组近十年来围绕p53所开展的相关研究,从p53自身稳定性的调控机制、p53与肿瘤发生、p53与细胞代谢以及p53调控非编码RNA方面进行简要综述,并展望p53研究的新方向.     

靶向p53信号通路在癌症治疗中的作用

作为一种肿瘤抑制因子,p53可协调多种反应,包括细胞周期阻滞、DNA修复、抗氧化作用、抗血管生成作用、自噬、衰老和凋亡等。p53主要通过调节其靶基因的转录发挥其肿瘤抑制功能,但p53是癌症中最常见的突变基因之一,当p53发生突变时,就会导致其功能丧失进而导致肿瘤细胞生长。p53已成为癌症治疗中最重要和最有吸引力的药物靶点之一,因此以p53为靶点产生了许多癌症治疗方式。本文回顾了靶向p53信号通路在基因治疗、靶向治疗以及免疫治疗中的研究,以期为了解靶向p53的研究提供新思路。     

多糖调控p53信号网络研究进展

肿瘤抑制基因p53是目前研究最广泛和系统的抑癌基因之一。p53与其上、下游基因形成复杂的信号网络来发挥功能。p53基因的突变或缺失与多种人类恶性肿瘤的发生、发展密切相关,所以p53基因是目前多种抗肿瘤药物开发的靶点。多糖由于其低毒和抗肿瘤效果成为生物大分子抗肿瘤的研究热点。目前认为,多糖在体内外抗肿瘤机制有两方面:一是通过增强机体免疫力以抑制肿瘤增殖,另一则是激活胞内信号通路,调控肿瘤相关基因表达,诱导肿瘤细胞衰老、细胞周期阻滞与凋亡达到对肿瘤细胞的抑制作用。该文综述了近些年多糖通过调控p53信号网络来发挥其抗肿瘤及抗衰老等作用,为多糖的开发与利用提供参考依据。     

p53在乳腺癌中的作用

乳腺癌是一种世界范围内女性发病率较高的肿瘤之一,至今为止对其的诊断、病理机制、治疗及预后已有一定的了解.一部分科学家的对乳腺癌的研究主要集中在p53在其发病机理、治疗、预后中的作用的探讨.p53是目前被广泛关注的肿瘤抑制基因,它所编码的转录蛋白因子主要调节一系列与细胞周期抑制、衰老、凋亡、DNA的修复、新血管生成的反应相关的基因.主要就近几年对乳腺癌的研究中,p53基因在乳腺癌中的作用机制的进一步研究,p53做为分子标记在诊断和预后的意义,它的突变和等位基因的性质,以及以p53为基础的各种治疗手段中其与药物及其他基因最新的作用机制进行初步的阐述.     

突变型p53与其合成致死基因的研究进展

恶性肿瘤的靶向治疗已经成为现阶段肿瘤治疗的热点。随着人们对癌基因认知的加深,借助合成致死的方法靶向治疗肿瘤已成为针对肿瘤特异性治疗的新策略。p53基因突变在肿瘤的形成和发展过程中具有重要作用。因此,了解肿瘤中与突变型p53基因有合成致死关系的靶基因的作用方式,有助于指导由突变型p53基因诱发肿瘤的个性化治疗。与突变型p53基因具有合成致死关系的靶基因可分为细胞周期调控基因和细胞非周期调控基因,文章综述了这两类靶基因与突变型p53基因如何构成合成致死作用以及此作用的现实意义。     

Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation

Telomeres protect chromosome ends from fusion, degradation and recombination. Loss of telomere function has opposite effects on tumorigenesis: apoptosis, which inhibits tumour growth, and genomic instability, which accelerates tumour formation. Here we describe a new mechanism by which short telomeres inhibit tumorigenesis through interference with oncogenic translocations. In mice that are null for both ataxia-telangiectasia-mutated (Atm) and telomerase RNA (mTR), the first generation (G1) Atm-/- mTR-/- mice have a lower rate of tumour formation than Atm-/- mTR+/+ mice. These Atm-/- mTR-/- G1 tumours show no increase in either apoptosis or overall genomic instability. Strikingly, the tumours show a high fraction of translocations containing telomere signals at the translocation junctions. Translocations of the T-cell receptors on chromosome 14, which initiate tumorigenesis, were interrupted by fusion with telomeres. Telomere repeats were also detected at the translocation junctions in pre-malignant thymocytes. We propose that telomere fusion to DNA double-strand breaks competes with the generation of oncogenic translocations and thus reduces tumour formation.     

Disease states associated with telomerase deficiency appear earlier in mice with short telomeres.

Mice deficient for the mouse telomerase RNA (mTR-/-) and lacking telomerase activity can only be bred for approximately six generations due to decreased male and female fertility and to an increased embryonic lethality associated with a neural tube closure defect. Although late generation mTR-/- mice show defects in the hematopoietic system, they are viable to adulthood, only showing a decrease in viability in old age. To assess the contribution of genetic background to the effect of telomerase deficiency on viability, we generated mTR-/- mutants on a C57BL6 background, which showed shorter telomeres than the original mixed genetic background C57BL6/129Sv. Interestingly, these mice could be bred for only four generations and the survival of late generation mTR-/- mice decreased dramatically with age as compared with their wild-type counterparts. Fifty percent of the generation 4 mice die at only 5 months of age. This decreased viability with age in the late generation mice is coincident with telomere shortening, sterility, splenic atrophy, reduced proliferative capacity of B and T cells, abnormal hematology and atrophy of the small intestine. These results indicate that telomere shortening in mTR-/- mice leads to progressive loss of organismal viability.     

Cooperation between p53 mutation and high telomerase transgenic expression in spontaneous cancer development

Telomerase reintroduction in adult somatic tissues is envisioned as a way to extend their proliferative capacity. It is still a question, however, whether constitutive telomerase expression in adult tissues impacts the normal aging and spontaneous cancer incidence of an organism. Here, we studied the aging and spontaneous cancer incidence of mice with transgenic telomerase expression in a wide range of adult tissues, K5-Tert mice. For this, we maintained large colonies of K5-Tert mice for more than 2 years. K5-Tert mice showed a decreased life span compared to wild-type cohorts associated with a higher incidence of preneoplastic and neoplastic lesions in various tissue types. Neoplasias in K5-Tert mice were coincident with transgene expression in the affected tissues. These observations suggest that high telomerase activity may cooperate with genetic alterations that occur with age to promote tumorigenesis. Indeed, we demonstrate here that increased cancer incidence and the reduced viability of K5-Tert mice are aggravated in a p53(+/-) genetic background, indicating that telomerase cooperates with loss of p53 function in inducing tumorigenesis. Altogether, these results demonstrate that constitutive high levels of telomerase activity result in a decreased life span associated with an increased incidence of neoplasias as the organism ages.     

Telomere shortening in mTR-/- embryos is associated with failure to close the neural tube

Mice genetically deficient for the telomerase RNA (mTR) can be propagated for only a limited number of generations. In particular, mTR-/- mice of a mixed C57BL6/129Sv genetic background are infertile at the sixth generation and show serious hematopoietic defects. Here, we show that a percentage of mTR-/- embryos do not develop normally and fail to close the neural tube, preferentially at the forebrain and midbrain. The penetrance of this defect increases with the generation number, with 30% of the mTR-/- embryos from the fifth generation showing the phenotype. Moreover, mTR-/- kindreds in a pure C57BL6 background are only viable up to the fourth generation and also show defects in the closing of the neural tube. Cells derived from mTR-/- embryos that fail to close the neural tube have significantly shorter telomeres and decreased viability than their mTR-/- littermates with a closed neural tube, suggesting that the neural tube defect is a consequence of the loss of telomere function. The fact that the main defect detected in mTR-/- embryos is in the closing of the neural tube, suggests that this developmental process is among the most sensitive to telomere loss and chromosomal instability.     

Telomerase activation in mouse mammary tumors: lack of detectable telomere shortening and evidence for regulation of telomerase RNA with cell proliferation.

Activation of telomerase in human cancers is thought to be necessary to overcome the progressive loss of telomeric DNA that accompanies proliferation of normal somatic cells. According to this model, telomerase provides a growth advantage to cells in which extensive terminal sequence loss threatens viability. To test these ideas, we have examined telomere dynamics and telomerase activation during mammary tumorigenesis in mice carrying a mouse mammary tumor virus long terminal repeat-driven Wnt-1 transgene. We also analyzed Wnt-1-induced mammary tumors in mice lacking p53 function. Normal mammary glands, hyperplastic mammary glands, and mammary carcinomas all had the long telomeres (20 to 50 kb) typical of Mus musculus and did not show telomere shortening during tumor development. Nevertheless, telomerase activity and the RNA component of the enzyme were consistently upregulated in Wnt-1-induced mammary tumors compared with normal and hyperplastic tissues. The upregulation of telomerase activity and RNA also occurred during tumorigenesis in p53-deficient mice. The expression of telomerase RNA correlated strongly with histone H4 mRNA in all normal tissues and tumors, indicating that the RNA component of telomerase is regulated with cell proliferation. Telomerase activity in the tumors was elevated to a greater extent than telomerase RNA, implying that the enzymatic activity of telomerase is regulated at additional levels. Our data suggest that the mechanism of telomerase activation in mouse mammary tumors is not linked to global loss of telomere function but involves multiple regulatory events including upregulation of telomerase RNA in proliferating cells.     

Decreased Mdm2 Expression Inhibits Tumor Development and Extends Survival Independent of Arf and Dependent on p53

Inactivation of the Arf-Mdm2-p53 tumor suppressor pathway is a necessary event for tumorigenesis. Arf controls Mdm2, which in turn regulates p53, but Arf and Mdm2 also have p53-independent functions that affect tumor development. Moreover, inhibition of oncogene-induced tumorigenesis relies on Arf and p53, but the requirements of Arf and p53 in tumor development initiated in the absence of overt oncogene overexpression and the role of Mdm2 in this process remain unclear. In a series of genetic experiments in mice with defined deficiencies in Arf, Mdm2 and/or p53, we show Mdm2 haploinsufficiency significantly delayed tumorigenesis in mice deficient in Arf and p53. Mdm2 heterozygosity significantly inhibited tumor development in the absence of Arf, and in contrast to Myc oncogene-driven cancer, this delay in tumorigenesis could not be rescued with the presence of one allele of Arf. Notably, Mdm2 haploinsufficieny blocked the accelerated tumor development in Arf deficient mice caused by p53 heterozygosity. However, tumorigenesis was not inhibited in Mdm2 heterozygous mice lacking both alleles of p53 regardless of Arf status. Surprisingly, loss of Arf accelerated tumor development in p53-null mice. Tumor spectrum was largely dictated by Arf and p53 status with Mdm2 haploinsufficiency only modestly altering the tumor type in some of the genotypes and not the number of primary tumors that arose. Therefore, the significant effects of Mdm2 haploinsufficiency on tumor latency were independent of Arf and required at least one allele of p53, and an Mdm2 deficiency had minor effects on the types of tumors that developed. These data also demonstrate that decreased levels of Mdm2 are protective in the presence of multiple genetic events in Arf and p53 genes that normally accelerate tumorigenesis.     

Telomere shortening and cell fates in mouse models of neoplasia.

Cell division in the absence of telomerase leads to telomere shortening that can activate checkpoint responses and impair chromosomal stability. The absence of telomerase in primary human cells and its near universal reactivation in human cancers has highlighted the importance of telomere shortening and telomerase reactivation during tumor development. Data from telomerase-deficient mouse models of cancer have indicated that telomere shortening can exert profoundly different influences on cell fates in developing cancers, limiting tumorigenesis by enhancing cell death or facilitating carcinogenesis by compromising chromosomal stability. These alternate fates depend on the integrity of the p53 pathway and on cell type.     

Longevity, stress response, and cancer in aging telomerase-deficient mice

Telomere maintenance is thought to play a role in signaling cellular senescence; however, a link with organismal aging processes has not been established. The telomerase null mouse provides an opportunity to understand the effects associated with critical telomere shortening at the organismal level. We studied a variety of physiological processes in an aging cohort of mTR-/- mice. Loss of telomere function did not elicit a full spectrum of classical pathophysiological symptoms of aging. However, age-dependent telomere shortening and accompanying genetic instability were associated with shortened life span as well as a reduced capacity to respond to stresses such as wound healing and hematopoietic ablation. In addition, we found an increased incidence of spontaneous malignancies. These findings demonstrate a critical role for telomere length in the overall fitness, reserve, and well being of the aging organism.