Mechanisms of Radioresistance and Cell Cycle Progression

放射抗性和细胞周期进展的机制

• 批准号: 7386915
• 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
• 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/7386915
• 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

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(申请人提供)：当细胞暴露在破坏DNA的物理或化学试剂中时，有害影响可能随之而来，包括突变、癌症或死亡。然而，修复损伤、稳定基因组和中和有害影响的机制是可用的。在前一个供资期间，重点是了解人类HRAD9在促进辐射或化学暴露后存活和基因组完整性的过程中的作用。我们的研究表明，这个进化上保守的基因具有多种细胞应答DNA损伤所需的功能，包括细胞周期检查点、DNA修复和促凋亡活性。最近，我们获得的证据表明，HRAD9还有另一个重要的活性，这是本提案的重点之一。与P53一样，HRAD9也可以作为序列特异性转录因子。HRAD9可与p21启动子中的p53共同序列结合，并在过表达时引起转录。此外，我们还证明了HRAD9可以结合COX-2启动子并反式激活该基因。此外，我们还证明了HRAD9在体内对p21和COX-2的辐射诱导是必不可少的。基于HRAD9的这些和其他功能，我们还假设了编码蛋白在癌症发生中的作用，现在提供了HRAD9与前列腺癌相关的证据。这两个新的HRAD9活性，调节转录的能力和在前列腺癌中的作用，将通过以下两个假设来寻求：1.HRAD9是一个序列特异性转录因子，可以通过反式激活多个下游靶基因网络来调节细胞对DNA损伤的反应，即它控制一个新的损伤反应调节子。实验目标涉及活动的结构要求，以及网络中可诱导基因的鉴定和生物学意义。2.HRAD9与前列腺癌的发生有因果关系。建议通过实验来研究HRAD9在这种类型的癌症中的功能，特别是作为癌基因。这项研究的结果将更好地确定HRAD9作为DNA损伤诱导基因的新调节因子在细胞对DNA损伤的反应中的作用，并阐明HRAD9在肿瘤发生中的作用，特别是在前列腺癌中。因此，专注于HRAD9的发现应该会影响基础研究以及临床领域，在这些领域，DNA损伤剂用于治疗，前列腺癌治疗是一个令人担忧的问题。这项建议侧重于Rad9在调节其他基因表达方面的作用，这些基因涉及控制细胞生长和维持遗传物质的稳定性。此外，还对Rad9在前列腺癌中的作用进行了详细的分析。因此，这个项目很重要，因为结果可能会影响人类健康，并导致新的治疗策略的开发。