Retinoids exert their biologic effects through two families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which belong to the superfamily of steroid/thyroid hormone nuclear receptors. By using a subtraction hybridization approach, we have identified a cDNA sequence TIG2 (Tazarotene-induced gene 2), whose expression is up-regulated by the treatment of skin raft cultures by an RAR beta/gamma-selective anti-psoriatic synthetic retinoid tazarotene [AGN 190168/ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl] nicotinate]. The retinoid-mediated up-regulation in the expression of TIG2 was confirmed by Northern blot analysis. Upon sequencing, TIG2 was found to be a cDNA whose complete sequence was not in the GenBank and EMBL data bases. The TIG2 cDNA is 830 bp long and encodes a putative protein product of 164 amino acids. TIG2 is neither expressed nor induced by tazarotene in primary keratinocyte and fibroblast cultures. Thus, TIG2 is expressed and induced by tazarotene only when keratinocytes and fibroblasts form a tissue-like 3-dimensional structure. We further demonstrate that RAR-specific retinoids increase TIG2 mRNA levels. In contrast, neither RXR-specific retinoids nor 1,25-dihydroxyvitamin D3 increased TIG2 levels. Finally, we demonstrate that TIG2 is expressed at high levels in nonlesional psoriatic skin but at lower levels in the psoriatic lesion and that its expression is up-regulated in psoriatic lesions after topical application of tazarotene.
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.Retinoic acid (RA) and its synthetic analogs are therapeutically effective in the treatment of hyperproliferative dermatological diseases, such as psoriasis and cutaneous neoplasias, and in certain cancers (1-6). The biological effects of retinoids are mediated through two families of nuclear receptors, retinoic acid receptor (RAR␣, -, and -␥) and retinoid X receptor (receptors ␣, , and ␥) (6, 7). RARs and retinoid X receptors are ligand-dependent transcription factors that, as heterodimers, function by changing the expression of RAresponsive genes (5-8). Tazarotene is an RAR͞␥-selective synthetic retinoid that is used clinically for the treatment of psoriasis, a skin disorder characterized by epidermal hyperproliferation and inflammation (9). Despite the therapeutic efficacy of retinoids in various hyperproliferative dermatological diseases, the molecular basis of their action in skin is largely unknown. Various genes whose expression is induced in cell culture systems by retinoids have been described. Of these, cellular retinoic acid binding protein II and tazaroteneinduced genes (TIG) 1 and 2 are the only markers whose expression is induced in a retinoid-dependent manner in skin (10-12). The increased levels of cellular retinoic acid binding protein II in psoriatic plaques indicate that it may not be a useful efficacy marker of retinoid action in psoriatic lesions. In addition, several lines of evidence suggests that cellular retinoic acid binding p...
-catenin is a component of stable cell adherent complexes whereas its free form functions as a transcription factor that regulate genes involved in oncogenesis and metastasis. Free -catenin is eliminated by two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways regulated by glycogen synthase kinase 3 (GSK3) or p53-inducible Siah-1. Dysregulation of -catenin turnover consequent to mutations in critical genes of the APC-dependent pathways is implicated in cancers such as colorectal cancer. We have identified a novel retinoid X receptor (RXR)-mediated APC-independent pathway in the regulation of -catenin. In this proteasomal pathway, RXR agonists induce degradation of -catenin and RXR␣ and repress -catenin-mediated transcription. In vivo, -catenin interacts with RXR␣ in the absence of ligand, but RXR agonists enhanced the interaction. RXR agonist action was not impaired by GSK3 inhibitors or deletion of the GSK3-targeted sequence from -catenin. In APC-and p53-mutated colorectal cancer cells, RXR agonists still inactivated endogenous -catenin via RXR␣. Interestingly, deletion of the RXR␣ A/B region abolished ligand-induced -catenin degradation but not RXR␣-mediated transactivation. RXR␣-mediated inactivation of oncogenic -catenin paralleled a reduction in cell proliferation. These results suggest a potential role for RXR and its agonists in the regulation of -catenin turnover and related biological events.
The vitreoretinal pharmacokinetic profiles were similar between nonvitrectomized and vitrectomized eyes. These observations are consistent with clinical findings of the DEX implant in patients who have undergone vitrectomy and should reduce concerns about the use of the DEX implant in eyes that have undergone vitrectomy.
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