Regulation and Function of C/EBP in UVB Responses

C/EBP 在 UVB 响应中的调节和功能

• 批准号: 7152567
• 负责人: Robert C Smart
• 金额: $ 34.13万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-03 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7152567
• 关键词: Acute Myelocytic Leukemia; Antimitotic Agents; Apoptosis; Apoptotic; Binding; Biological Assay; Biological Process; CCAAT-Enhancer-Binding Proteins; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Cycle Progression; Cells; DNA Damage; DNA Repair; DNA Replication Damage; DNA damage checkpoint; Ensure; Environment; Epidermis; Gene Expression Regulation; Gene Targeting; Genes; Genome; Growth; Human; Mediating; Mitotic; Mus; Nuclear; Process; Protein Overexpression; Regulation; Research Personnel; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Squamous Differentiation; Sunlight; System; TP53 gene; Time; Transcriptional Activation; Translating; Tumor Suppressor Proteins; UVB induced; Ultraviolet B Radiation; Up-Regulation; Work; bZIP Domain; carcinogenesis; cell type; in vivo; insight; involucrin; irradiation; keratinocyte; loricrin; novel; prevent; programs; promoter; repaired; response; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): The basic leucine zipper (bZIP) transcription factor, CCAAT/enhancer binding protein-a/(C/EBPa) is abundantly expressed within keratinocytes of the epidermis, however relatively little is known regarding its function in skin. C/EBPa has been implicated as a human tumor suppressor in acute myeloid leukemia and our results in experimental systems suggest C/EBPa negatively regulates keratinocyte growth and may have a tumor suppressor function in skin tumorigenesis. Sunlight, more specifically the UVB component of sunlight, causes DMA damage and is responsible for the majority of human skin cancers. Keratinocytes can respond to UVB irradiation by undergoing cell cycle arrest, apoptosis and/or altered differentiation. We have discovered that UVB, as well as other DNA damaging agents, are potent inducers of C/EBPa expression in human and mouse keratinocytes and that this induction requires p53, Thus, we have identified C/EBPa as a novel p53-regulated DNA damage-inducible gene in human and mouse keratinocytes. The ability of cells to respond to DNA damage is essential to ensure the integrity of the genome. DNA damage can initiate the activation of cell cycle checkpoints that arrest cell cycle progression preventing replication of damaged DNA and allowing time for DNA repair. We hypothesize that UVB-induced C/EBPa has a DNA damage checkpoint function involving cell cycle arrest and we propose the loss of UVB-induced C/EBPa would enhance UVB carcinogenesis. While p53 is an absolute requirement for UVB-induced C/EBPa, we have observed that catalytically active GSK is also required. We propose that UVB-induction of C/EBPa involves direct binding of p53 to the C/EBPa promoter resulting in increased expression of C/EBPa and that nuclear GSK3 has a regulatory role in this process. Characterization of the biological function of C/EBPa in the UVB-response in keratinocytes as well as how the UVB signal is translated into the transcriptional up-regulation of C/EBPa will provide new insight into mechanisms of UVB-induced gene regulation, cellular responses and skin cancer.

描述（由申请人提供）： 碱性亮氨酸拉链（BZIP）转录因子，CCAAT/增强子结合蛋白-A/（C/EBPA）在表皮的角质细胞中大量表达，但是关于其在皮肤中的功能，知之甚少。 C/EBPA在急性髓样白血病中被认为是人类肿瘤抑制剂，我们在实验系统中的结果表明，C/EBPA对角质形成细胞的生长负面调节，并且可能在皮肤肿瘤发生中具有肿瘤抑制器功能。阳光，更具体地说是阳光的UVB成分，会造成DMA损坏，并导致大多数人皮肤癌。角质形成细胞可以通过经历细胞周期停滞，凋亡和/或改变分化来应对UVB辐射。我们已经发现，UVB以及其他DNA损伤剂都是人和小鼠角质形成细胞中C/EBPA表达的有效诱导剂，并且这种诱导需要p53，因此，我们将C/EBPA鉴定为人类和小鼠Keratinocytes中的新型p53 DNA调节的DNA损伤基因。细胞对DNA损伤做出反应的能力对于确保基因组的完整性至关重要。 DNA损伤可以启动细胞周期检查点的激活，该检查点阻止细胞周期进展，以防止损坏的DNA复制并允许时间进行DNA修复时间。我们假设UVB诱导的C/EBPA具有涉及细胞周期停滞的DNA损伤检查点功能，我们建议UVB诱导的C/EBPA的丧失将增强UVB的癌作用。虽然p53是UVB诱导的C/EBPA的绝对要求，但我们观察到还需要催化活性GSK。我们建议C/EBPA的UVB诱导涉及p53与C/EBPA启动子的直接结合，从而导致C/EBPA的表达增加，并且核GSK3在此过程中具有调节作用。 C/EBPA在角质形成细胞中c/eBPA的生物学功能的表征以及如何将UVB信号转化为C/EBPA的转录上调，将为UVB诱导的基因调控，细胞反应和皮肤癌的机制提供新的见解。