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Modulation of p53 induction by targeting cap-dependent translation in cancer

通过靶向癌症中帽依赖性翻译来调节 p53 诱导

基本信息

批准号：
8640123
负责人：
Da-Qing Yang
金额：
$ 7.4万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8640123
关键词：
5&apos Untranslated Regions 8-methylguanosine Apoptosis Breast Breast Cancer Cell Cell Cycle Arrest Cell Death Cells Chemicals Code DNA Damage Gene Mutation Genes Genotoxic Stress Goals Growth Growth Inhibitors Induction of Apoptosis Internal Ribosome Entry Site Lead Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mammary Neoplasms Mediating Messenger RNA Mutate Mutation Neoplasm Metastasis Nude Mice Peptide Initiation Factors Preventive Prostate Protein Binding Protein p53 Proteins Recruitment Activity Research Solid Neoplasm Structure Testing Therapeutic Therapeutic Agents Translation Initiation Translations Tumor Suppressor Proteins cancer cell cancer type cell growth cytotoxic genetic regulatory protein inhibitor/antagonist insight malignant breast neoplasm neoplastic cell novel therapeutics overexpression public health relevance response treatment strategy tumor tumor growth tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The p53 tumor suppressor protein protects cells against malignant transformation through induction of either cell cycle arrest or apoptosis. Since p53 is the most commonly mutated gene in cancer, the vast majority of research examining the link between p53 and cancer has been aimed at characterizing the genetic mutations that alter the p53 protein and lead to the loss of its transcriptional activity in cancer cells. However, mutations in the p53 coding region occur at a significantly lower rate in breast (20%) and prostate (18%) cancers than in other solid tumors, such as lung cancer (70%). Our results provide convincing evidence that defective p53 synthesis following DNA damage can lead to malignant transformation of breast tumor cells even though they retain the wild-type p53 coding region. Since defective p53 synthesis may be one of the key underlying mechanisms for tumorigenesis in these cancer cells, chemical compounds that can restore p53's tumor suppressive function in these cells may become highly effective preventive or therapeutic agents against cancer. Cap-dependent initiation of protein translation is used by the majority of eukaryotic mRNAs, since most of them have an N7-methylguanosine cap structure at their 5'-ends. eIF-4E is a translation initiation protein that binds to the cap structure and drives cap-dependent translation. It is known that the activity of eIF- 4E is elevated in cancer cells and its overexpression and hyperactivation cause malignant transformation and metastasis in various types of cancers, including breast and prostate cancer. Recent results have shown that inhibition of eIF-4E induces apoptosis in cancer cells. However, the underlying mechanism for induction of apoptosis by blocking cap-dependent translation is unclear. We discovered that an internal ribosome entry site (IRES) sequence is present at the 5'-untranslated region (UTR) of p53 mRNA. This is an alternate form of cap-dependent translation in which ribosomal subunits are recruited to an IRES sequence by a subset of initiation factors without the participation of eIF-4E. Multiple lines of recent evidence have revealed a new mechanism by which cap-dependent translation switches to cap-independent translation, including IRES- mediated p53 synthesis, following cyto- or genotoxic stress. Since cap-dependent translation is usually compromised by stressful conditions such as DNA damage, we hypothesize that treatment of cancer cells with inhibitors of cap-dependent translation may cause a similar transition from cap-dependent translation to IRES-mediated translation of p53, leading to apoptosis. The goal of this project is to test this hypothesis by treating cancer cells with several newly discovered cap-dependent translation inhibitors and to examine whether these inhibitors can restore p53's tumor suppressive function in non-p53 responsive cancer cells. Findings from this project will provide new insights into the functional link between suppression of cap- dependent translation and p53 induction and may lead to new therapeutic agents against cancer.

描述（由申请人提供）：p53肿瘤抑制蛋白通过诱导细胞周期停滞或细胞凋亡保护细胞免于恶性转化。由于p53是癌症中最常见的突变基因，因此绝大多数研究p53与癌症之间联系的研究都旨在表征改变p53蛋白并导致其在癌细胞中转录活性丧失的基因突变。然而，p53编码区的突变在乳腺癌（20%）和前列腺癌（18%）中的发生率明显低于其他实体瘤，如肺癌（70%）。我们的研究结果提供了令人信服的证据表明，DNA损伤后有缺陷的p53合成可导致乳腺肿瘤细胞的恶性转化，即使它们保留野生型p53编码区。由于缺陷性p53合成可能是这些癌细胞中肿瘤发生的关键潜在机制之一，因此可以在这些细胞中恢复p53的肿瘤抑制功能的化合物可能成为针对癌症的高效预防或治疗剂。蛋白质翻译的帽依赖性起始被大多数真核mRNA使用，因为它们中的大多数在其5 '端具有N7-甲基鸟苷帽结构。eIF-4 E是一种翻译起始蛋白，它与帽结构结合并驱动帽依赖性翻译。已知eIF-4 E的活性在癌细胞中升高，并且其表达与癌细胞的增殖密切相关。过表达和过度活化导致各种类型癌症（包括乳腺癌和前列腺癌）的恶性转化和转移。最近的结果表明，抑制eIF-4 E诱导癌细胞凋亡。然而，通过阻断帽依赖性翻译诱导细胞凋亡的潜在机制尚不清楚。我们发现在p53 mRNA的5 '非翻译区（UTR）存在一个内部核糖体进入位点（IRES）序列。这是帽依赖性翻译的另一种形式，其中核糖体亚基在没有eIF-4 E参与的情况下通过起始因子的子集募集到IRES序列。最近的多条证据揭示了一种新的机制，通过该机制，在细胞毒性或基因毒性应激后，帽依赖性翻译转换为帽非依赖性翻译，包括IRES介导的p53合成。由于帽依赖性翻译通常受到应激条件如DNA损伤的影响，我们假设用帽依赖性翻译抑制剂治疗癌细胞可能会导致从帽依赖性翻译到IRES介导的p53翻译的类似转变，从而导致细胞凋亡。该项目的目标是通过用几种新发现的帽依赖性翻译抑制剂治疗癌细胞来验证这一假设，并检查这些抑制剂是否可以在非p53反应性癌细胞中恢复p53的肿瘤抑制功能。该项目的发现将为抑制帽依赖性翻译和p53诱导之间的功能联系提供新的见解，并可能导致新的抗癌治疗药物。