Use p105(sr) to study p50 homodimer in skin tumor/cancer

使用 p105(sr) 研究皮肤肿瘤/癌症中的 p50 同二聚体

• 批准号: 7088616
• 负责人: LI LIN
• 金额: $ 18.65万
• 依托单位: MEDSTAR HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088616
• 关键词: antineoplastics; apoptosis; carcinogenesis; cell growth regulation; cell line; chemical carcinogenesis; dimer; neoplastic transformation; nuclear factor kappa beta; protein structure function; skin neoplasms; squamous cell carcinoma

DESCRIPTION (provided by applicant): NF-kappaB plays a significant role in tumori- and carcinogenesis. Constitutively active NF-kappaB has been detected in several types of tumors and cancers. However, unlike other types of cancers where NF-kappaB heterodimer p50/RelA activity is elevated, chemical-induced skin papillomas and squamous cell carcinomas (SCC), exhibit significantly elevated p50 homodimer activity. The cause of this elevation in skin tumors and cancers, what are the genes regulated by p50 homodimer, and how these genes contribute to tumorigenesis and malignancy are unknown. SCCs are also known for their resistance to cancer therapies. Introduction of kappa-B-alpha-based NF-kappaB super represser (sr) into cancer cells has led to successful dissection of the NF-kappaB target genes via DNA microarray analysis. Repression of NF-kappaB activities by this method also facilitates tumor necrosis factor alpha (TNFalpha)-, or chemotherapy reagents-induced apoptosis in cancer cells. Since p50 homodimer activities are not regulated by prototypic kappaBs, such approach cannot be applied to skin tumors and cancers. We have developed an NF-kappaB super represser based on NF-kappaB inhibitor p105, and demonstrated that p105(sr) broadly and effectively inhibits all NF-kappaB species. Overexpression of p105(sr) generates p105(sr)/p50 heterodimers and therefore, prevents formation of p50 homodimers. Formation of p105(sr)/Rel protein complexes should broadly inhibit NF-kappaB activities. Our long-term goal is to understand the role of NF-kappaB in tumorigenesis. We hypothesize that carcinogen TPA treatment of skin leads to enhanced turnover of p50 precursor p105, releasing p50 to form homodimers. The p50 homodimer, in synergy with constitutively activated Ha-ras in skin tumors, plays a role in tumorigenesis. Introduction of p105(sr) into skin tumor cells will lead to systematic dissection of NF-kappaB-regulated genes including those controlled by p50 homodimers. Such approach will also aid to facilitate apoptosis of the tumor cells mediated by TNFalpha, and chemotherapy reagents. We will study the mechanism of how p50 homodimer activity is elevated in skin tumor cells. We will also test whether introducing p105(sr) into skin tumor cells facilitates apoptosis, and whether this approach significantly affects physiologic functions of normal keratinocytes.

描述（由申请人提供）：NF-κ B在肿瘤和癌发生中起重要作用。在几种类型的肿瘤和癌症中检测到组成型活性NF-κ B。然而，与其中NF-κ B异二聚体p50/RelA活性升高的其他类型的癌症不同，化学诱导的皮肤乳头状瘤和鳞状细胞癌（SCC）表现出显著升高的p50同二聚体活性。皮肤肿瘤和癌症中这种升高的原因，p50同源二聚体调控的基因是什么，以及这些基因如何促进肿瘤发生和恶性肿瘤尚不清楚。SCC还因其对癌症疗法的抗性而闻名。将基于kappa-B-alpha的NF-κ B超级阻遏物（sr）引入癌细胞中已经通过DNA微阵列分析成功地解剖了NF-κ B靶基因。通过这种方法抑制NF-κ B活性也促进肿瘤坏死因子α（TNF α）或化疗试剂诱导的癌细胞凋亡。由于p50同二聚体活性不受原型kappaB调节，因此这种方法不能应用于皮肤肿瘤和癌症。我们已经开发了一种基于NF-κ B抑制剂p105的NF-κ B超级阻遏物，并证明p105（sr）广泛有效地抑制所有NF-κ B种类。p105（sr）的过表达产生p105（sr）/p50异源二聚体，因此阻止了p50同源二聚体的形成。p105（sr）/Rel蛋白复合物的形成应广泛抑制NF-κ B活性。我们的长期目标是了解NF-κ B在肿瘤发生中的作用。我们假设皮肤的致癌物TPA处理导致p50前体p105的周转增强，释放p50形成同源二聚体。p50同二聚体与皮肤肿瘤中组成性激活的Ha-ras协同作用，在肿瘤发生中发挥作用。将p105（sr）导入皮肤肿瘤细胞将导致NF-κ B调控基因的系统解剖，包括由p50同源二聚体控制的基因。这种方法还有助于促进TNF α和化疗试剂介导的肿瘤细胞凋亡。我们将研究皮肤肿瘤细胞中p50同源二聚体活性升高的机制。我们也将测试是否将p105（sr）导入皮肤肿瘤细胞促进凋亡，以及这种方法是否显著影响正常角质形成细胞的生理功能。