The Role of C/EBPa in Genome Stability and Tumor Progression

C/EBPa 在基因组稳定性和肿瘤进展中的作用

• 批准号: 7914552
• 负责人: Jonathan Russell Hall
• 金额: $ 4.76万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914552
• 关键词: Ablation; Address; Basal cell carcinoma; Benign; CCAAT-Enhancer-Binding Proteins; Carcinogens; DNA Damage; Development; Disease; Drug Delivery Systems; Epithelial; Essential Genes; Family; Genes; Genetic; Genome; Genome Stability; Genomic Instability; Genomics; Human; Human Genome; Maintenance; Malignant - descriptor; Malignant Neoplasms; Molecular; Mus; Mutation; Oncogenes; Pathway interactions; Phenotype; Point Mutation; Role; Skin; Skin Cancer; Skin Neoplasms; Solar Energy; Somatic Cell; Somatic Mutation; Squamous Cell Papillomas; Squamous cell carcinoma; Tumor Suppressor Proteins; UVB induced; Ultraviolet B Radiation; bZIP Domain; cancer therapy; insight; keratinocyte; member; neoplastic cell; prevent; public health relevance; response; skin squamous cell carcinoma; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Cancer is a disease that arises from genomic alterations in somatic cells and it is the accumulation of genetic alterations that drives tumorigenesis. Moreover, it is the rate at which a developing tumor cell acquires these genetic alterations that ultimately determines the onset of cancer. Human skin is routinely subjected to DNA damage induced by solar radiation and keratinocytes have developed intricate pathways to response to UVB-induced DNA damage. Recently, we provided the first genetic evidence CCAAT/enhancer binding protein 1 (C/EBP1), a member of the basic leucine zipper family of transcription factors, functions as an epithelial tumor suppressor through utilization of mice with an epidermal-targeted ablation of C/EBP1. These mice are highly susceptible to UVB- and carcinogen-induced squamous papilloma development and these benign skin tumors display a highly accelerated rate of malignant progression to squamous cell carcinomas. Human skin squamous cell carcinomas and basal cell carcinomas as well as mouse skin squamous carcinomas display weak or ablated expression of C/EBP1. Together these findings suggest a tumor suppressor function of C/EBP1 in skin cancer through maintenance of the genome. We hypothesize that reduced or ablated expression of C/EBP1 results in an impaired DNA damage-induced G1 checkpoint, resulting in the accumulation of somatic mutations and promoting skin cancer progression. The overall objective of this proposal is to understand how the loss of C/EBP1 contributes to an increased rate of malignant tumor progression focusing on the role of C/EBP1 in the DNA damage- induced G1 checkpoint. To address this objective we aim to 1) delineate the molecular mechanism through which C/EBP1 functions in the DNA damaged-induced G1 checkpoint and 2) provide molecular evidence for increased genome instability/mutator phenotype in response to C/EBP1 ablation. . PUBLIC HEALTH RELEVANCE: Understanding how C/EBP1 influences the rate of cancer progression and the acquisition of mutations will provide further insights to the mechanisms of carcinogen- and UVB-induced skin cancer as well as numerous cancers where C/EBP1 expression is diminished. Recent analysis of the genomes from human cancers discovered that mutations in specific cancer associated genes can vary dramatically within a give tumor type and suggest the identification of the origin of genomic point mutations may be a more effective strategy for cancer treatment than targeting a specific cancer gene as mutations in other essential genes will be enhanced and selected by the mutator phenotype. Drugs that target point mutation genetic instability may delay the accumulation of mutations and subsequently prevent cancer onset.

描述（由申请人提供）：癌症是一种疾病，是由体细胞中的基因组改变引起的，是遗传改变的积累导致肿瘤发生。此外，正是发育中的肿瘤细胞获得这些遗传改变的速度最终决定了癌症的发作。通常，人体皮肤受到太阳辐射诱导的DNA损伤，角质形成细胞已发展为对UVB诱导的DNA损伤的反应的复杂途径。最近，我们提供了第一个遗传证据CCAAT/增强剂结合蛋白1（C/EBP1），这是转录因子基本拉链家族的成员，它通过用表皮靶向C/EBP1的表皮靶向消融而充当上皮肿瘤抑制器。这些小鼠非常容易受到UVB和致癌物诱导的鳞状乳头瘤发育的影响，这些良性的皮肤肿瘤表现出高度加速的恶性肿瘤向鳞状细胞癌。人皮肤鳞状细胞癌和基底细胞癌以及小鼠皮肤鳞状癌显示C/EBP1的弱或消融表达。这些发现共同表明，通过维持基因组，C/EBP1在皮肤癌中具有肿瘤抑制剂的功能。我们假设C/EBP1的降低或消融表达导致DNA损伤诱导的G1检查点受损，从而导致体细胞突变的积累并促进皮肤癌的进展。该提案的总体目的是了解C/EBP1的损失如何导致致害性肿瘤进展的率提高，重点是C/EBP1在DNA损伤诱导的G1检查点中的作用。为了解决这一目标，我们旨在1）描述C/EBP1在DNA损坏诱导的G1检查点中功能的分子机制，2）提供分子证据，以响应C/EBP1消融而增加基因组不稳定性/突变型表型。 。 公共卫生相关性：了解C/EBP1如何影响癌症进展的速率和突变的获取将为致癌物和UVB诱导的皮肤癌以及C/EBP1表达降低的众多癌症提供进一步的见解。对人类癌症的基因组的最新分析发现，特定癌症相关的基因的突变在给出肿瘤类型的情况下可能会发生巨大变化，并暗示鉴定基因组点突变的起源可能是针对癌症治疗的更有效策略，而不是将特定的癌症基因作为其他必要基因中的突变，将得到突变器现象的增强和选择。靶向点突变遗传不稳定性的药物可能会延迟突变的积累，并随后预防癌症发作。