NOVEL PROTEIN REGULATOR OF TUMOR SUPPRESSOR ARF & NF-kB

新型肿瘤抑制蛋白 ARF 调节剂

• 批准号: 7405352
• 负责人: WENDELL G YARBROUGH
• 金额: $ 35.99万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405352
• 关键词: Acetylation; Apoptosis; Binding; Binding Proteins; Biochemical; Biogenesis; Biological; Cell Cycle; Cell Death; Cell Nucleus; Cells; Data; Doctor of Medicine; EP300 gene; Exposure to; Genetic Recombination; Genetic Transcription; Growth; Human; Knock-out; Leucine Zippers; MDM2 gene; MDM2 gene; Molecular; Mus; NF-kappa B; NPM1 gene; Nuclear Export; Oncogene Proteins; Oncogenic; Other Finding; Personal Satisfaction; Phase; Post-Translational Regulation; Process; Protein Binding; Protein Inhibition; Proteins; Reading Frames; Regulation; Resistance; Ribosomal RNA; Role; Stimulus; TP53 gene; Techniques; Testing; Transcriptional Activation; Tumor Suppression; Tumor Suppressor Proteins; Ubiquitination; cancer therapy; chemotherapy; cytokine; embryonic stem cell; homologous recombination; inhibitor/antagonist; irradiation; metaplastic cell transformation; novel; prevent; protein expression; tumor; tumorigenesis; vector

DESCRIPTION (provided by applicant): Utilizing alternative reading frames, the mammalian ARF-INK4a locus encodes two unrelated proteins that both function in tumor suppression, ARF and the cell cycle inhibitor, p16. ARF binds with MDM2 and blocks MDM2-directed ubiquitination of p53 and p53 nuclear export, thus preventing cytoplasmic degradation of p53. Previously, we, and others, found that human ARF binds the MDM2 oncoprotein leading to stabilization and transcriptional activation of p53 with a resultant proliferative arrest. ARF levels are increased through transcription following exposure to oncogenic stimuli, but post-translational regulation of ARF is largely unexplored. Recently, we have found a novel protein, LZAP, (leucine zipper containing ARF-binding protein) that binds ARF in the nucleus and regulates ARF biochemical activity toward MDM2. In addition to its regulation of MDM2 activity, ARF has recently been found to have p53-independent effects including S-phase growth delay, regulation of rRNA processing and inhibition of the nuclear factor kappa B (NF-kB), that may contribute to p53-independent effects of ARF observed in tumorigenesis. In addition to its regulation of ARF, we initially explored the role of LZAP in regulation of NF-kB activity and found that expression of LZAP decreased both basal and cytokine stimulated NF-kB activity, while inhibition of endogenous LZAP expression resulted in increased basal NF-kB activity. Remarkably, LZAP was found to bind directly to NFkB within cells. We have identified a novel protein that regulates ARF activity toward MDM2 and decreases NF-kB activity. Given the importance of ARF and NF-kB in tumorigenesis, the biochemical activities of LZAP suggest that it may serve as a tumor suppressor. We will further evaluate the role of LZAP in regulation of ARF and NF-kB activity and determine if LZAP has tumor suppressor activity.

描述（由申请人提供）：利用替代阅读框架，哺乳动物ARF-INK4A基因座编码两个无关的蛋白质，这些蛋白质在肿瘤抑制，ARF和细胞周期抑制剂P16中均起作用。 ARF与MDM2结合并阻止了p53和p53核输出的MDM2定向的泛素化，从而防止了p53的细胞质降解。 以前，我们和其他人发现，人ARF结合MDM2癌蛋白，从而导致p53的稳定和转录激活，从而产生增生性。 暴露于致癌刺激后的转录中，ARF水平提高，但是ARF的翻译后调节在很大程度上没有探索。 最近，我们发现了一种新型蛋白LZAP（含有ARF结合蛋白的亮氨酸拉链），该蛋白在细胞核中结合ARF并将ARF生化活性调节与MDM2。 除了调节MDM2活性外，最近还发现ARF具有p53独立的效应，包括S期生长延迟，RRNA处理的调节和对核因子KAPPA B（NF-KB）的抑制，这可能会导致肿瘤发生中ARF的P53独立效应。 除了调节ARF外，我们最初探讨了LZAP在调节NF-KB活性中的作用，并发现LZAP的表达降低了基底因子和细胞因子刺激NF-KB活性，而内源性LZAP表达的抑制会导致基础NF-KB活性的增加。 值得注意的是，发现LZAP直接与细胞内的NFKB结合。 我们已经确定了一种新的蛋白质，可调节ARF活性对MDM2的活性并降低NF-KB活性。 鉴于ARF和NF-KB在肿瘤发生中的重要性，LZAP的生化活性表明它可以作为肿瘤抑制剂。 我们将进一步评估LZAP在ARF和NF-KB活性调节中的作用，并确定LZAP是否具有肿瘤抑制活性。