Identification and characterization of a retinoid-induced class II tumor suppressor growth regulatory gene

Retinoids, synthetic and natural analogs of retinoic acid, exhibit potent g rowth inhibitory and cell differentiation activities that account for their beneficial effects in treating hyperproliferative diseases such as psorias is, actinic keratosis, and certain neoplasias. Tazarotene is a synthetic re tinoid that is used in the clinic for the treatment of psoriasis, To better understand the mechanism of retinoid action in the treatment of hyperproli ferative diseases, me used a long-range differential display-PCR to isolate retinoid-responsive genes from primary human keratinocytes. We have identi fied a cDNA, tazarotene-induced gene 3 (TIG3; Retinoic Acid Receptor Respon der 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 i s correlated with decreased proliferation. TIG3 is expressed in a number of tissues, and expression is reduced in cancer cell lines and some primary t umors. In breast cancer cell lines, retinoid-dependent TIG3 induction is ob served in lines that are growth suppressed by retinoids but not in nonrespo nsive lines. Transient over-expression of TIG3 in T47D or Chinese hamster o vary cells inhibits colony expansion. Finally, studies in 293 cells express ing TIG3 linked to an inducible promoter demonstrated decreased proliferati on with increased TIG3 levels. These studies suggest that TIG3 may be a gro wth regulator that mediates some of the growth suppressive effects of retin oids.