pRb2/p130: from the mechanisms to gene therapy

pRb2/p130：从机制到基因治疗

基本信息

批准号：
7225910
负责人：
Antonio Giordano
金额：
$ 32.11万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7225910
关键词：
Acetylation Adenocarcinoma Cell Adult Apoptosis Apoptotic Binding Biochemical Cell Cycle Cell Cycle Progression Cell Death Cell Line Cell Proliferation Cells Chromatin Chromatin Structure Complex DNA Damage Data Development Down-Regulation E2F transcription factors E2F1 gene EP300 gene Ectopic Expression Enzymes Epigenetic Process Equilibrium Event Evolution Exhibits Failure Family Family member Gene Silencing Genes Genetic Transcription Goals Growth HDAC1 gene Hand Histone Deacetylase Histone Deacetylation Histones Human Hypermethylation In Vitro KRAS2 gene Link Literature Lung Lung Adenocarcinoma Lung Neoplasms MDM2 gene MDM2 gene Malignant neoplasm of lung Mediating Messenger RNA Methylation Modification Modification Type Molecular Mutation Non-Small-Cell Lung Carcinoma Northern Blotting Nucleosomes Numbers Oncogene Proteins Oncogenic Oncornaviruses Pathway interactions Pattern Phase Phosphorylation Physiological Point Mutation Positioning Attribute Post-Translational Protein Processing Primary Neoplasm Probability Process Prognostic Factor Property Protein Binding Protein Family Protein Overexpression Proteins Proto-Oncogenes Purpose RBL2 gene Range Recruitment Activity Regulation Reporting Repression Research Resistance Resources Rest Retinoblastoma Retinoblastoma Protein Role Series Signal Transduction Site Specimen TP53 gene Tail Technology Therapeutic Thinking Time Tissues Transcriptional Regulation Transfection Translating Tumor Suppressor Proteins Ubiquitin Vascular Endothelial Growth Factors Work angiogenesis base cDNA Arrays cancer therapy cdc Genes cell growth cell transformation design expectation experience gene therapy in vivo innovation insight member mouse model neoplastic neoplastic cell novel therapeutics prevent promoter protein protein interaction research study response tool transcription factor tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): pRb2/pl30: from the mechanisms to therapy. The retinoblastoma (RB) family proteins are negative cell-cycle regulators normally expressed in a number of adult tissues. Each RB protein binds to and modulates the activity of the E2F transcription factors that stimulate the transcription of genes needed to progress through the S phase. The RBs-E2Fs repressive complexes function in association with histone deacetylase (HDAC 1) which essentially repress transcription probably through deacetylation of histone tail that protrudes from nucleosome. The protein stability and the functional activity of each RB family protein can be hampered by gene silencing due to their promoter hypermethylation and/or by their post-translational modifications such as acetylation and phosphorylation. Although some indications are available about the role of epigenetic or post-translational control of pRb/pl05 functional activity, there are very few data about the other members of RB family. However, acetylation and phosphorylation may be not completely independent processes. Phosphorylation and acetylation status can influence also the protein stability by determining the probability of ubiquitin-mediated degradation, which it is though to be an early event in programmed cell death, possibly related to cell commitment to apoptosis. As a consequence, it has been shown that failure to the interior cleavage of pRb/p105 is associates with resistance to induction of apoptotic response. Up to now no similar data has been reported for pRb2/pl30. Deregulated cell proliferation together with suppressed apoptosis, constitute the minimal common platform upon which all neoplastic evolution occurs. The rationale for these studies is that the identification of significance of the epigenetic or post-translational modification on the function, stability, biochemical interactions and degradation of pRb2/pl30. We will pursue the following aims:/) Rb2/p130 negatively regulates the transcription of cell-cycle genes to exert its growth suppressive function. 2) Epigenetic events for pRb2/p130 gene silencing promoting tumor progression. 3) pRb2/pl30 post-translational modification during the induction of growth arrest and apoptotic response. 4) The cross talk between the pRb2/pl 30 growth suppressive and apoptotic function and the activated KRas oncogenic signals in the LSL-K-Ras G12D mouse model. These experiments will provide further insight into the post-translational modifications necessary to induce pRb2/p 130- dependent growth suppression and apoptosis. Finally, our results will be significant in that they will give us clues to the mechanisms underlying pRb2/p 130 activity and to characterize its role in tumorigenesis providing useful tools for design novel therapeutic strategies.

描述（由申请人提供）：pRb2/pl30：从机制到治疗。视网膜母细胞瘤 (RB) 家族蛋白是负细胞周期调节因子，通常在许多成体组织中表达。每个 RB 蛋白都与 E2F 转录因子结合并调节其活性，这些转录因子刺激 S 期所需基因的转录。 RBs-E2Fs 抑制复合物与组蛋白脱乙酰酶 (HDAC 1) 相关，其本质上可能是通过从核小体突出的组蛋白尾部脱乙酰化来抑制转录。每个 RB 家族蛋白的蛋白稳定性和功能活性可能会因启动子高甲基化和/或翻译后修饰（如乙酰化和磷酸化）而受到基因沉默的阻碍。尽管关于pRb/p105功能活性的表观遗传或翻译后控制的作用已有一些迹象，但关于RB家族其他成员的数据很少。然而，乙酰化和磷酸化可能不是完全独立的过程。磷酸化和乙酰化状态还可以通过确定泛素介导的降解概率来影响蛋白质稳定性，这被认为是程序性细胞死亡的早期事件，可能与细胞凋亡相关。因此，已表明 pRb/p105 内部裂解的失败与对诱导凋亡反应的抵抗有关。迄今为止，尚未报道pRb2/pl30的类似数据。细胞增殖失调和细胞凋亡受到抑制，构成了所有肿瘤进化发生的最小公共平台。这些研究的基本原理是鉴定表观遗传或翻译后修饰对 pRb2/pl30 的功能、稳定性、生化相互作用和降解的重要性。我们将追求以下目标：/) Rb2/p130负向调节细胞周期基因的转录，以发挥其生长抑制功能。 2) pRb2/p130基因沉默促进肿瘤进展的表观遗传事件。 3) pRb2/p130在诱导生长停滞和凋亡反应期间的翻译后修饰。 4) LSL-K-Ras G12D 小鼠模型中 pRb2/pl 30 生长抑制和凋亡功能与激活的 KRas 致癌信号之间的串扰。这些实验将进一步深入了解诱导 pRb2/p 130 依赖性生长抑制和细胞凋亡所需的翻译后修饰。最后，我们的结果将具有重要意义，因为它们将为我们提供 pRb2/p 130 活性潜在机制的线索，并表征其在肿瘤发生中的作用，为设计新的治疗策略提供有用的工具。