DiSepio D, Ghosn C, Eckert R L, Deucher A, Robinson N, Duvic M, Chandraratna R A, Nagpal S
Retinoid Research, Departments of Biology and Chemistry, Allergan, Inc., Irvine, CA 92623, USA.
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14811-5. doi: 10.1073/pnas.95.25.14811.
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, we 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.
类视黄醇是视黄酸的合成及天然类似物，具有强大的生长抑制和细胞分化活性，这解释了它们在治疗银屑病、光化性角化病和某些肿瘤等过度增殖性疾病中的有益作用。他扎罗汀是一种用于临床治疗银屑病的合成类视黄醇。为了更好地理解类视黄醇在治疗过度增殖性疾病中的作用机制，我们使用长距离差异显示聚合酶链反应从原代人角质形成细胞中分离类视黄醇反应基因。我们鉴定出一种与II类肿瘤抑制基因H-rev 107具有显著同源性的cDNA，他扎罗汀诱导基因3（TIG3；视黄酸受体反应基因3）。他扎罗汀处理可增加原代人角质形成细胞和银屑病皮损体内的TIG3表达。TIG3表达增加与增殖减少相关。TIG3在多种组织中表达，在癌细胞系和一些原发性肿瘤中表达降低。在乳腺癌细胞系中，在被类视黄醇抑制生长的细胞系中观察到类视黄醇依赖性TIG3诱导，而在无反应的细胞系中未观察到。在T47D或中国仓鼠卵巢细胞中瞬时过表达TIG3可抑制集落形成。最后，在表达与可诱导启动子相连的TIG3的293细胞中的研究表明，随着TIG3水平升高，细胞增殖减少。这些研究表明，TIG3可能是一种生长调节因子，介导类视黄醇的一些生长抑制作用。
