Regulation and Function of C/EBP in UVB Responses

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)在表皮角质形成细胞中大量表达，但对其在皮肤中的功能知之甚少。C/EBPA被认为是人类急性髓系白血病的肿瘤抑制因子，我们在实验系统中的结果表明，C/EBPA负向调节角质形成细胞的生长，可能在皮肤肿瘤的发生中具有肿瘤抑制功能。阳光，更具体地说是阳光中的UVB成分，会导致DMA损伤，并导致大多数人类皮肤癌。角质形成细胞可以通过细胞周期停滞、细胞凋亡和/或分化改变来响应UVB辐射。我们发现UVB和其他DNA损伤剂都是人和小鼠角质形成细胞表达C/EBPA的有效诱导剂，而这种诱导需要P53，因此，我们确定C/EBPA是人和小鼠角质形成细胞中受P53调控的DNA损伤诱导基因。细胞对DNA损伤的反应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，阻止细胞周期进程，阻止受损DNA的复制，并为DNA修复留出时间。我们假设UVB诱导的C/EBPA具有细胞周期停滞的DNA损伤检查点功能，我们认为UVB诱导的C/EBPA的缺失可能会促进UVB的致癌作用。虽然P53是UVB诱导的C/EBPA的绝对必需，但我们观察到催化活性的GSK也是必需的。我们认为，UVB诱导的C/EBPA涉及P53与C/EBPA启动子的直接结合，导致C/EBPA表达增加，核GSK3在这一过程中具有调节作用。研究角质形成细胞中C/EBPA在UVB反应中的生物学功能，以及UVB信号如何被转化为C/EBPA转录上调，将为研究UVB诱导的基因调控、细胞反应和皮肤癌的机制提供新的视角。

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.