Mechanisms of Radioresistance and Cell Cycle Progression

放射抗性和细胞周期进展的机制

基本信息

批准号：
7502577
负责人：
HOWARD B. LIEBERMAN
金额：
$ 36.08万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-28 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7502577
关键词：
Address Adenocarcinoma Androgen Receptor Animals Antibodies Apoptotic Appearance Basic Science Binding Binding Sites Bioinformatics Biological Biological Models Biopsy Specimen Bypass Bystander Effect CDKN1A gene Cancerous Carcinogenicity Tests Cell Cycle Checkpoint Cell Cycle Progression Cell Death Cell Line Cell Maintenance Cell physiology Cells Cessation of life Chemical Agents Chemical Exposure Chemicals Choristoma Clinical Complement Complex Computer software Condition Consensus Consensus Sequence Coupled DNA Damage DNA Repair DNA lesion DU145 Data Defect Deoxycytidine Dependence Development EMSA Ectopic Expression Fission Yeast Funding Funding Mechanisms Gamma Rays Gene Dosage Gene Expression Gene Expression Microarray Analysis Gene Expression Regulation Gene Targeting Genes Genetic Materials Genetic Recombination Genetic Transcription Genome Genome Stability Genomics Grant H1299 Health Human Human Cloning Immunohistochemistry In Vitro Investigation Ionizing radiation Lead Light Link Luciferases Maintenance Malignant Neoplasms Malignant neoplasm of prostate Mediating Methods Methylation Methyltransferase Microtomy Molecular Monitor Mus Mutagenesis Mutation Nude Mice Numbers Oncogenes PC3 cell line Pathway interactions Pattern Phenotype Primary Neoplasm Procedures Process Promega Promoter Regions Prostate Protein Overexpression Proteins RNA Radiation Radiation therapy Radiation, Other Regulon Reporter Research Resistance Resources Rest Role Sampling Selection Criteria Site Small Interfering RNA Standards of Weights and Measures Stress System TP53 gene Testing Testosterone Time Tissue Sample Tissues Trans-Activators Transactivation Transcriptional Activation Transcriptional Regulation Translations Up-Regulation Western Blotting Work base biological adaptation to stress cancer cell cancer therapy cancer type carcinogenesis cell growth data modeling follow-up gene function gene induction hrad9 protein hydroxyurea in vivo inhibitor/antagonist irradiation knock-down novel novel therapeutics oncoprotein p21 programs promoter repaired research study response small molecule transcription factor tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): When cells are exposed to physical or chemical agents that damage DNA, deleterious effects can ensue, including mutation, cancer or death. However, mechanisms are available to repair the damage, stabilize the genome and neutralize harmful effects. During the previous funding period, focus was placed on understanding the role of human HRAD9 in processes that promote survival and genomic integrity after radiation or chemical exposure. Our studies indicate that this evolutionarily conserved gene has multiple functions needed for the cellular response to DNA damage, including cell cycle checkpoints, DNA repair and pro-apoptotic activities. Recently, we obtained evidence that HRAD9 has another important activity, which is one focus of this proposal. HRAD9 can, like p53, act as a sequence specific transcription factor. HRAD9 can bind p53 consensus sequences in the p21 promoter and cause transcription when overexpressed. In addition, we demonstrated that HRAD9 can bind the Cox-2 promoter and transactivate that gene as well. Furthermore, we show that HRAD9 is essential for the radiation induction in vivo of both p21 and Cox-2. Based on these and other functions of HRAD9, we also hypothesized a role for the encoded protein in carcinogenesis, and now provide evidence for a relationship between HRAD9 and specifically prostate cancer. These two novel HRAD9 activities, ability to regulate transcription and a role in prostate cancer, will be pursued by addressing the following two hypotheses: 1. HRAD9 is a sequence specific transcription factor that can regulate the cellular response to DNA damage by transactivation of a network of multiple downstream target genes, i.e., it controls a novel damage response regulon. Experimental aims concern structural requirements of the activity, and the identification and biological significance of inducible genes in the network. 2. HRAD9 is causally related to prostate cancer. Experiments are proposed to examine the function of HRAD9 in this type of cancer, in particular as an oncogene. The results of this study should better define the role of HRAD9 in the cellular response to DNA damage, as a novel regulator of DNA damage-inducible genes, and also elucidate the role of HRAD9 in carcinogenesis, specifically in prostate. As such, the findings focused on HRAD9 should impact on basic research as well as clinical arenas where DNA damaging agents are used for therapy and prostate cancer treatment is a concern. This proposal focuses on the role of Rad9 in regulating expression of other genes involved in controlling cell growth and maintaining stability of the genetic material. In addition, it concerns a detailed analysis of the function of Rad9 in prostate cancer. As such, this project is important since the results could impact on human health and lead to the development of novel therapeutic strategies.

描述（由申请人提供）：当细胞暴露于损害DNA的物理或化学药物时，可能随之而来的有害作用，包括突变，癌症或死亡。但是，可以使用机制来修复损害，稳定基因组并中和有害影响。在上一个资金期间，将重点放在理解人HRAD9在促进辐射或化学暴露后促进生存和基因组完整性的过程中的作用。我们的研究表明，该进化保守的基因具有对DNA损伤的细胞反应所需的多个功能，包括细胞周期检查点，DNA修复和促凋亡活性。最近，我们获得了HRAD9有另一个重要活动的证据，这是该提案的重点。 HRAD9可以像p53一样充当序列特异性转录因子。 HRAD9可以在P21启动子中结合p53共有序列，并在过表达时引起转录。此外，我们证明了HRAD9可以结合COX-2启动子并反式激活该基因。此外，我们表明HRAD9对于P21和COX-2的体内辐射诱导至关重要。基于HRAD9的这些和其他功能，我们还假设编码蛋白在癌变中的作用，现在为HRAD9或特别是前列腺癌之间的关系提供了证据。通过解决以下两个假设来追求这两种新型的HRAD9活性，调节转录的能力和在前列腺癌中的作用，可以追求：1。HRAD9是一个序列特异性转录因子，可以通过对多个下游靶基因的网络的反式激活来调节细胞对DNA损伤的反应。实验目的涉及活动的结构要求，以及网络中诱导基因的鉴定和生物学意义。 2。HRAD9与前列腺癌有因果关系。提出了实验来检查HRAD9在这种类型的癌症中的功能，特别是作为癌基因。这项研究的结果应更好地定义HRAD9在细胞对DNA损伤反应中的作用，作为DNA损伤诱导基因的新调节剂，还阐明了HRAD9在癌变中的作用，特别是在前列腺中。因此，关注HRAD9的发现应影响基础研究以及使用DNA损害剂进行治疗和前列腺癌治疗的临床领域。该建议的重点是RAD9在调节控制细胞生长和维持遗传物质稳定性中涉及的其他基因表达中的作用。此外，它涉及对Rad9在前列腺癌中的功能的详细分析。因此，该项目很重要，因为结果可能会影响人类健康，并导致新型治疗策略的发展。