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

基本信息

批准号：
8272660
负责人：
Jonathan Russell Hall
金额：
$ 5.39万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
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/8272660
关键词：
Ablation Address Apoptosis Basal cell carcinoma Benign Breast CCAAT-Enhancer-Binding Protein-alpha Carcinogens Cells Chromosomal Stability Chromosome abnormality DNA DNA Damage DNA damage checkpoint Development Disease Drug Delivery Systems Endometrial Epigenetic Process Epithelial Esophagus Essential Genes Family Gene Dosage Gene Mutation Genes Genetic Genome Genome Stability Genomic Instability Genomics Head and neck structure Human Human Genome Knockout Mice Laboratory Study Liver Lung Maintenance Malignant - descriptor Malignant Neoplasms Microsatellite Repeats Molecular Mus Mutation Normal Cell Oncogenes Pathway interactions Phenotype Point Mutation Reporting Role S Phase 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 Work bZIP Domain cancer cell cancer therapy insight keratinocyte member neoplastic cell prevent response skin squamous cell carcinoma transcription factor tumor tumor progression tumorigenesis

项目摘要

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 alpha (C/EBPalpha), 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/EBPalpha. 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/EBPalpha. Together these findings suggest a tumor suppressor function of C/EBPalpha in skin cancer through maintenance of the genome. We hypothesize that reduced or ablated expression of C/EBPalpha 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/EBPalpha contributes to an increased rate of malignant tumor progression focusing on the role of C/EBPalpha in the DNA damageinduced G1 checkpoint. To address this objective we aim to 1) delineate the molecular mechanism through which C/EBPalpha functions in the DNA damaged-induced G1 checkpoint and 2) provide molecular evidence for increased genome instability/mutator phenotype in response to C/EBPalpha ablation.

癌症是一种由体细胞基因组改变引起的疾病，基因改变的积累驱动了肿瘤的发生。此外，发育中的肿瘤细胞获得这些基因改变的速度最终决定了癌症的发生。人类皮肤经常遭受太阳辐射引起的 DNA 损伤，角质形成细胞已经形成了复杂的途径来响应 UVB 引起的 DNA 损伤。最近，我们提供了第一个遗传证据，CCAAT/增强子结合蛋白 α (C/EBPα) 是转录因子的基本亮氨酸拉链家族的成员，通过利用小鼠表皮靶向消融 C，发挥上皮肿瘤抑制因子的作用。 /EBPα。这些小鼠对 UVB 和致癌物诱导的鳞状乳头状瘤的发展高度敏感，并且这些良性皮肤肿瘤表现出高度加速的鳞状细胞癌恶性进展速度。人皮肤鳞状细胞癌和基底细胞癌以及小鼠皮肤鳞状细胞癌显示 C/EBPα 表达较弱或消除。这些发现共同表明，C/EBPα 通过维持基因组在皮肤癌中具有抑癌功能。我们假设 C/EBPα 表达的减少或消除会导致 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。该提案的总体目标是了解 C/EBPα 的缺失如何导致恶性肿瘤进展率增加，重点关注 C/EBPα 在 DNA 损伤诱导的 G1 检查点中的作用。为了实现这一目标，我们的目标是 1) 描述 C/EBPα 在 DNA 损伤诱导的 G1 检查点中发挥作用的分子机制，2) 为响应 C/EBPα 消融而增加的基因组不稳定性/突变表型提供分子证据。