Identification and characterization of a retinoid-induced class II tumor suppressor growth regulatory gene
Identification and characterization of a retinoid-induced class II tumor suppressor growth regulatory gene
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DOI：
10.1073/pnas.95.25.14811
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发表时间：
1998-12-08
影响因子：
11.1
通讯作者：
Nagpal, S
中科院分区：
文献类型：
--
作者：
DiSepio, D;Ghosn, C;Nagpal, S
维甲酸是合成的和天然的维甲酸类似物，具有强大的生长抑制和细胞分化活性，这是它们在治疗牛皮癣、光化性角化病和某些肿瘤等增殖性疾病方面的有益效果的原因。他扎罗汀是一种人工合成的维甲酸，用于临床治疗银屑病，为了更好地了解维甲酸在治疗增生性疾病中的作用机制，我使用远程差异显示-聚合酶链式反应从原代人角质形成细胞中分离了维甲酸反应基因。我们已经确定了一个与II类肿瘤抑制基因H-rev 107有显著同源性的基因，即他扎罗汀诱导基因3(TIG3；维甲酸受体响应器3)，他扎罗汀治疗增加了原代人角质形成细胞和银屑病皮损中TIG3的表达。TIG3的表达增加与增殖减少相关。TIG3在许多组织中表达，在癌细胞系和一些原发肿瘤中表达降低。在乳腺癌细胞系中，维甲酸依赖的TIG3在被维甲酸抑制生长的细胞系中被观察到，但在无反应的细胞系中没有观察到。TIG3在T47D或中国仓鼠卵巢细胞中的瞬时过表达抑制集落扩张。最后，对表达TIG3的293细胞的研究表明，随着TIG3水平的升高，细胞的增殖减少。这些研究表明，TIG3可能是一种生长调节剂，介导了维甲酸的某些生长抑制效应。
Retinoids, synthetic and natural analogs of retinoic acid, exhibit potent growth inhibitory and cell differentiation activities that account for their beneficial effects in treating hyperproliferative diseases such as psoriasis, actinic keratosis, and certain neoplasias. Tazarotene is a synthetic retinoid that is used in the clinic for the treatment of psoriasis, To better understand the mechanism of retinoid action in the treatment of hyperproliferative diseases, me used a long-range differential display-PCR to isolate retinoid-responsive genes from primary human keratinocytes. We have identified a cDNA, tazarotene-induced gene 3 (TIG3; Retinoic Acid Receptor Responder 3) showing significant homology to the class II tumor suppressor gene, H-rev 107, Tazarotene treatment increases TIG3 expression in primary human keratinocytes and in vivo in psoriatic lesions. Increased TIG3 expression is correlated with decreased proliferation. TIG3 is expressed in a number of tissues, and expression is reduced in cancer cell lines and some primary tumors. In breast cancer cell lines, retinoid-dependent TIG3 induction is observed in lines that are growth suppressed by retinoids but not in nonresponsive lines. Transient over-expression of TIG3 in T47D or Chinese hamster ovary cells inhibits colony expansion. Finally, studies in 293 cells expressing TIG3 linked to an inducible promoter demonstrated decreased proliferation with increased TIG3 levels. These studies suggest that TIG3 may be a growth regulator that mediates some of the growth suppressive effects of retinoids.