Cmarik J L, Herschman H, Colburn N H
Laboratory of Viral Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702.
Mol Carcinog. 1994 Oct;11(2):115-24. doi: 10.1002/mc.2940110209.
The 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible sequence (TIS) genes are a set of primary response genes induced in Swiss 3T3 cells by TPA. They include three transcription factors, a prostaglandin synthase, and three proteins of unknown function. To ascertain which, if any TIS genes might be involved in tumor promotion, we examined the expression of these genes in response to tumor promoters in transformation promotion-sensitive (P+) and -resistant (P-) JB6 murine epidermal cells, a model used to identify events relevant to promotion. A subset of TIS genes (TIS1, TIS10, and TIS21) was preferentially induced by TPA in P-cells. In addition, TIS1 and TIS21 mRNAs were preferentially induced in P-cells by epidermal growth factor, another transformation promoter that distinguishes P+ from P-cells. TIS1 and TIS21 protein levels were also greater in TPA-treated P-cells than P+ cells. Forskolin, a cAMP-elevating anti-promoter, increased TPA-induced levels of TIS1, TIS10, and TIS21 mRNAs in P+ cells, ruling in potential roles for these genes in modulating tumor promotion. The anti-promoters fluocinolone acetonide, retinoic acid, and superoxide dismutase did not enhance TPA-induced levels of TIS1 and TIS21 mRNAs in P+ cells, suggesting that these inhibitors may act on other promotion-relevant genes. TIS1 encodes a member of the steroid receptor superfamily. TIS1 encodes a protein of unknown function with strong sequence similarity to BTG1, a proposed "anti-proliferative gene" (Rouault JP, Rimokh R, Tessa C, et al., EMBO J 11:1663-1670, 1992). Preferential induction by multiple promoters of these TIS genes in P-cells and enhancement of their induction in P+ cells by the anti-promoter forskolin make TIS1 and TIS21 candidates for promotion suppressor genes.
12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）诱导序列（TIS）基因是一组在瑞士3T3细胞中由TPA诱导的初级反应基因。它们包括三种转录因子、一种前列腺素合酶以及三种功能未知的蛋白质。为了确定哪些（如果有的话）TIS基因可能参与肿瘤促进作用，我们检测了这些基因在转化促进敏感（P +）和抗性（P -）的JB6小鼠表皮细胞中对肿瘤启动子的反应表达情况，JB6小鼠表皮细胞是用于鉴定与促进作用相关事件的模型。一部分TIS基因（TIS1、TIS10和TIS21）在P -细胞中优先被TPA诱导。此外，TIS1和TIS21的mRNA在P -细胞中也优先被表皮生长因子诱导，表皮生长因子是另一种区分P +和P -细胞的转化启动子。在经TPA处理的P -细胞中，TIS1和TIS21的蛋白质水平也高于P +细胞。福斯高林是一种能升高cAMP的抗启动子，它增加了TPA诱导的P +细胞中TIS1、TIS10和TIS21的mRNA水平，这表明这些基因在调节肿瘤促进作用中可能发挥潜在作用。抗启动子氟轻松丙酮化物、视黄酸和超氧化物歧化酶并未增强TPA诱导的P +细胞中TIS1和TIS21的mRNA水平，这表明这些抑制剂可能作用于其他与促进作用相关的基因。TIS1编码类固醇受体超家族的一个成员。TIS21编码一种功能未知的蛋白质，其序列与BTG1有很强的相似性，BTG1是一个被提议的“抗增殖基因”（鲁奥 JP、里莫克 R、泰萨 C等，《欧洲分子生物学组织杂志》11:1663 - 1670，1992）。这些TIS基因在P -细胞中被多种启动子优先诱导，并且抗启动子福斯高林增强了它们在P +细胞中的诱导作用，这使得TIS1和TIS21成为促进作用抑制基因的候选者。
