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REGULATION OF CALCITRIOL ON TPA INDUCED TUMORIGENESIS

骨化三醇对TPA诱导肿瘤发生的调节作用

基本信息

批准号：
2895477
负责人：
PI-LING CHANG
金额：
$ 10.67万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-01 至 2001-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2895477
关键词：
1,25 dihydroxycholecalciferol antisense nucleic acid chemical carcinogenesis drug interactions gene induction /repression hormone regulation /control mechanism isozymes nutrition related tag osteopontin phorbols phosphorylation protein kinase C protooncogene tissue /cell culture vitamin analog vitamin receptor

项目摘要

DESCRIPTION: The Applicant has observed that calcitriol could enhance 2-O-tetradecanoylphorbol-13-acetate (TPA) - induced tumorigenic transformation of the pre-neoplastic mouse epidermal JB6 line. Treatment of these cells with calcitriol by itself didnot induce cell transformation nor did it lead to phosphorylation of osteopontin (POPN). In contrast she observed that induction of POPN and its secretion correlated with tumorigenesis when the cells were stimulated with TPA or TPA and calcitriol. The Applicant proposes to pursue the mechanisms by which calcitriol enhances TPA induced tumorigenesis. She conjectures that calcitriol enhances TPA-induced tumorigenesis by regulating transcription of a combination of genes including the gene for POPN which confers upon these cells a transformed phenotype. The Applicant proposes four specific aims. These include: the employment of calcitriol analogs with defined functions (i.e., binding to the vitamin D receptor or mediating cellular calcium fluxes) to determine if synergism of calcitriol with TPA arises from genomic and/or nongenomic effects of calcitriol. 2) She plans to determine if calcitriol treatment of her cell line affects TPA induced expression of members of the fos and jun families of protooncogenes as well as enhances the expression of protein kinase C. 3) She plans to develop antisense constructs to the OPN gene to determine whether expression of OPN is necessary for TPA-induced tumorigenic transformation. 4) Finally, she plans to use differential display of MRNA to investigate possible unique gene expression in the cell line treated with TPA and/or calcitriol.

描述：申请人已经观察到骨化三醇可以增强 2-O-十四酰佛波醇-13-乙酸酯（TPA）诱导的致瘤性肿瘤前小鼠表皮JB 6系的转化。治疗这些细胞与骨化三醇本身并不诱导细胞转化也不导致骨桥蛋白（POPN）的磷酸化。相反，她观察到POPN的诱导及其分泌当细胞被TPA刺激时，或TPA和骨化三醇。申请人建议继续采用这些机制，骨化三醇通过其增强TPA诱导的肿瘤发生。她承认骨化三醇通过调节TPA诱导的肿瘤发生，包括POPN基因的基因组合的转录其赋予这些细胞转化的表型。申请人提出了四个具体目标。这些措施包括：具有确定功能的骨化三醇类似物（即，与维生素结合 D受体或介导细胞钙流），以确定是否骨化三醇与TPA协同作用来自基因组和/或非基因组骨化三醇的作用 2)她计划确定骨化三醇治疗影响TPA诱导的fos基因成员的表达和jun家族的原癌基因，并增强表达蛋白激酶C 3)她计划开发反义结构， OPN基因，以确定OPN的表达是否是必要的， TPA诱导的致瘤性转化。 4)最后，她计划利用 mRNA差异显示研究可能的独特基因在用TPA和/或骨化三醇处理的细胞系中表达。