针对p53-鼠双微体基因负反馈环的肿瘤治疗

鼠双微体基因(MDM2)通过抑制p53介导的转录活性和促进p53降解来控制p53的功能.MDM2过度表达引起p53失活,导致p53野生细胞恶性转化.人工合成抑制p53-MDM2蛋白复合体相互作用的小分子可促使p53核内积聚、活化p53,从而诱导肿瘤细胞的死亡.针对p53-MDM2相互作用的抑制剂可成为治疗p53野生型肿瘤系的新型抗癌药物.     

p53基因诱导程序化死亡与肿瘤治疗新战略

ｐ５３基因诱导程序化死亡与肿瘤治疗新战略季代金１张亚历２姜泊２冯福才２周殿元关键词ｐ５３基因细胞凋亡肿瘤治疗中图号Ｒ７３０．２３１Ｒ７３０．４１近年来的研究表明，在肿瘤形成和演化的多步骤过程中，癌基因、抑癌基因与细胞凋亡（Ａｐｏｐｔｏｓｉｓ，ＡＰＯ）...     

p53基因第 72位密码子多态与肿瘤

p53基因突变是人类肿瘤最常见的遗传学改变之一,50% 以上的人类肿瘤有 p53基因的突变或缺失.正常情况下,细胞内 p53蛋白水平很低,当细胞发生 DNA损伤、缺氧、代谢性改变或受到某些细胞因子的刺激时,p53基因被激活,细胞内 p53蛋白水平明显增高,使细胞周期阻滞在 G1期,等待修复或诱导细胞凋亡,若 p53基因功能丧失,可导致细胞异常增生,从而可致肿瘤的形成.p53基因具有多态性,其第 72位密码子的 CGC/CCC是一个常见的多态位点,多态基因可编码或含精氨酸(Arg) 或含脯氨酸(Pro) 的两种 p53蛋白.这两种野生型 p53蛋白具有不同的生物学特性和功能.最近的研究发现,p53基因第 72位密码子 Arg/Pro多态与肿瘤的遗传易感性、癌变的演进及预后有关.本文对这方面的研究作一简要综述.     

肿瘤抑制基因p53的结构与功能保守性的比较分析

目的　比较分析不同物种来源的p5 3蛋白的系统发育规律及其结构与功能的保守性。方法　多序列比较、结构域比对和二级结构预测等生物信息学分析及系统发生树构建。结果　模式生物间p5 3蛋白有较高同源性 ,而且都具有p5 3蛋白的典型结构特征 ;各结构域中维持功能活性必需的氨基酸残基几乎不变 ,二级结构折叠元件的组成和分布也十分类似 ;最大似然法和邻接法两种方法推导出的分子系统进化树基本一致。结论　物种来源不同的p5 3蛋白同属于一个有相似功能作用的蛋白家族。从比较生物学新的角度 ,进一步说明了p5 3蛋白的结构和功能保守性。     

p63基因及其在泌尿系肿瘤中的意义

p63是最新发现的p53同族基因，主要表达于上皮组织的基底层和基底细胞中，是外胚层发育过程中重要的调节基因。近来发现p63基因在很多上皮肿瘤中表达异常，提示该基因可能为肿瘤相关基因，在肿瘤的发生发展过程中具有重要作用。现综述p63基因及其蛋白产物的特点，并详述p63基因表达变化在泌尿系统肿瘤研究中的意义。     

p53基因增加肿瘤放射治疗敏感性的机制

在肿瘤放疗过程中,p53基因的正常功能对肿瘤细胞的凋亡和提高放射敏感性起了关键性作用。野生型p53基因通过激活或抑制一系列基因,使肿瘤细胞周期阻滞,抑制肿瘤细胞放射损伤的修复,促进肿瘤细胞的凋亡,以及在乏氧环境中对促进肿瘤细胞凋亡至关重要,增强了肿瘤细胞对放疗的敏感性。     

p53基因增加肿瘤放射治疗敏感性的机制

在肿瘤放疗过程中,p53基因的正常功能对肿瘤细胞的凋亡和提高放射敏感性起了关键性作用。野生型p53基因通过激活或抑制一系列基因,使肿瘤细胞周期阻滞,抑制肿瘤细胞放射损伤的修复,促进肿瘤细胞的凋亡,以及在乏氧环境中对促进肿瘤细胞凋亡至关重要,增强了肿瘤细胞对放疗的敏感性。     

p53基因与放射敏感性

肿瘤放射敏感性是肿瘤放射治疗成败的关键,如何提高肿瘤细胞的放射敏感性,一直是放射肿瘤学家和放射生物学家关注的问题。传统的预测肿瘤放射敏感性的方法是在整体或细胞水平上进行测算与估计,但未能给临床治疗和评价预后提供足够的信息。近年来,开始在基因水平上研究预测和提高肿瘤放射敏感性及评价预后的方法。目前的研究发现与放射敏感性相关的基因很多,一些癌基因如ras、myc、raf等及抗癌基因RB、p53基因等均与放射敏感相关。p53基因是经广泛研究的抗癌基因,该基因突变与50%人类肿瘤相关。现就p53基因对肿瘤放射敏感性的影响综述如下。…     

Therapeutic opportunities in cancer therapy: targeting the p53-MDM2/MDMX interactions

Ubiquitination is a key enzymatic post-translational modification that influences p53 stability and function. p53 protein regulates the expression of MDM2 (mouse double-minute 2 protein) E3 ligase and MDMX (double-minute 4 protein), through proteasome-based degradation. Exploration of targeting the ubiquitination pathway offers a potentially promising strategy for precision therapy in a variety of cancers. The p53-MDM2-MDMX pathway provides multiple molecular targets for small molecule screening as potential therapies for wild-type p53. As a result of its effect on molecular carcinogenesis, a personalized therapeutic approach based on the wild-type and mutant p53 protein is desirable. We highlighted the implications of p53 mutations in cancer, p53 ubiquitination mechanistic details, targeting p53-MDM2/MDMX interactions, significant discoveries related to MDM2 inhibitor drug development, MDM2 and MDMX dual target inhibitors, and clinical trials with p53-MDM2/MDMX-targeted drugs. We also investigated potential therapeutic repurposing of selective estrogen receptor modulators (SERMs) in targeting p53-MDM2/MDMX interactions. Molecular docking studies of SERMs were performed utilizing the solved structures of the p53/MDM2/MDMX proteins. These studies identified ormeloxifene as a potential dual inhibitor of p53/MDM2/MDMX interaction, suggesting that repurposing SERMs for dual targeting of p53/MDM2 and p53/MDMX interactions is an attractive strategy for targeting wild-type p53 tumors and warrants further preclinical research.     

Mutant p53 as a target for cancer treatment

TP53 (p53) is the single most frequently altered gene in human cancers, with mutations being present in approximately 50% of all invasive tumours. However, in some of the most difficult-to-treat cancers such as high-grade serous ovarian cancers, triple-negative breast cancers, oesophageal cancers, small-cell lung cancers and squamous cell lung cancers, p53 is mutated in at least 80% of samples. Clearly, therefore, mutant p53 protein is an important candidate target against which new anticancer treatments could be developed. Although traditionally regarded as undruggable, several compounds such as p53 reactivation and induction of massive apoptosis-1 (PRIMA-1), a methylated derivative and structural analogue of PRIMA-1, i.e. APR-246, 2-sulfonylpyrimidines such as PK11007, pyrazoles such as PK7088, zinc metallochaperone-1 (ZMC1), a third generation thiosemicarbazone developed by Critical Outcome Techonologies Inc. (COTI-2) as well as specific peptides have recently been reported to reactive mutant p53 protein by converting it to a form exhibiting wild-type properties. Consistent with the reactivation of mutant p53, these compounds have been shown to exhibit anticancer activity in preclinical models expressing mutant p53. To date, two of these compounds, i.e. APR-246 and COTI-2 have progressed to clinical trials. A phase I/IIa clinical trial with APR-246 reported no major adverse effect. Currently, APR-246 is undergoing a phase Ib/II trial in patients with advanced serous ovarian cancer, while COTI-2 is being evaluated in a phase I trial in patients with advanced gynaecological cancers. It remains to be shown however, whether any mutant p53 reactivating compound has efficacy for the treatment of human cancer.     

Targeting p73 in cancer

p73 is a member of the p53 family of tumor suppressors. Transactivating isoforms of p73 (TAp73) have p53-like, anti-proliferative and pro-apoptotic activities that are crucial for an efficient chemotherapy response. In line with this, genetic studies in mice have confirmed that TAp73 acts as a tumor suppressor. However, in contrast to p53, which is commonly inactivated in human cancer by point mutations, the TP73 gene is almost never mutated. Instead, the tumor suppressor activity of TAp73 is inhibited through a variety of mechanisms including epigenetic silencing and complex formation with inhibitory proteins. All these mechanisms have in common that they are in principle reversible and therefore amenable to therapeutic intervention. Here, we will review how tumor cells control the tumor suppressor activity of TAp73 and discuss possible strategies targeting p73 for reactivation.     

p53 Mutations are present in colorectal cancer with cytoplasmic p53 accumulation

Previous studies have shown that nuclear p53 over-expression is an indicator of p53 mutations whereas cytoplasmic p53 accumulation is related to wild-type p53 in several kinds of tumors. Cytoplasmic p53 accumulation has been demonstrated to be an independent prognostic factor in colorectal adenocarcinomas. The purpose was to examine whether mutations occur in cases with p53 accumulated in the cytoplasm and whether there are any differences in the frequency and characteristics of p53 mutations in different staining patterns. In the present study, we identified p53 mutations using PCR single-strand conformation polymorphism (SSCP) and DNA sequencing in 75 primary colorectal adenocarcinomas with different staining patterns (negative, nucleus, cytoplasm, nucleus and cytoplasm). The results show that the frequency and nature of mutations in tumors with cytoplasmic p53 accumulation were similar to those with nuclear p53 expression. However, the tumors with accumulation in both the nucleus and cytoplasm demonstrated a higher mutation rate. We suppose that the role of cytoplasmic p53 accumulation in predicting prognosis in patients with colorectal cancer may be dependent on both mutational and non-mutational mechanisms.     

Regulation of p53R2 and its role as potential target for cancer therapy

p53R2, a recently discovered small subunit of human ribonucleotide reductase, is believed to play essential roles in DNA repair, mtDNA synthesis, and protection against oxidative stress. Because of the positive correlation between the level of this protein and drug sensitivity and tumor invasiveness, it constitutes a potential target for anticancer drugs as well as a diagnostic marker in cancer.     

同时针对VEGF和p53腺病毒干扰载体的构建及干扰作用

目的:构建能同时干扰VEGF和p53基因表达的RNAi腺病毒干扰载体,观察其对肿瘤细胞VEGF和p53的干扰作用.方法:先分别构建能干扰p53和VEGF的质粒载体,依次将构建干扰载体的干扰序列和H1启动子序列切下并连接到pAdTrack上,构建成pAdTrack/VEGF/p53,将构建的质粒转染含有pAdEasy-1的BJ5183工程菌中,回收并酶切鉴定重组腺病毒载体,将阳性腺病毒载体感染293细胞并收集病毒,采用荧光定量PCR检测腺病毒干扰载体同时降低VEGF和p53表达的作用.结果:经过酶切鉴定,pAd/VEGF/p53载体中含有插入的2个启动子和干扰序列.转染腺病毒干扰载体后,肿瘤细胞中的VEGF和p53 mRNA表达量显著降低.结论:构建能同时干扰VEGF和p53基因的腺病毒干扰载体可以显著降低MCF-7细胞中VEGF和p53 mRNA的表达.