EVIDENCE FOR THE INVOLVEMENT OF RETINOIC ACID RECEPTOR RAR-ALPHA-DEPENDENT SIGNALING PATHWAY IN THE INDUCTION OF TISSUE TRANSGLUTAMINASE AND APOPTOSIS BY RETINOIDS

In this study, we show that all-trans-retinoic acid (RA) is a potent i nducer of tissue transglutaminase (TGase II) and apoptosis in the rat tracheobronchial epithelial cell line SPOC-1. We demonstrate that thes e cells express the retinoid receptors RAR alpha, RAR gamma, and RXR b eta. To identify which of these receptors are involved in regulating t hese processes, we analyzed the effects of several receptor-selective agonists, an antagonist, and a dominant-negative RAR alpha. We show th at the RAR-selective retinoid SRI-6751-84 strongly increased TGase II expression at both the protein and mRNA levels, whereas the RXR-select ive retinoid SR11217 had little effect. The RAR alpha-selective retino id Ro40-6055 was also able to induce TGase II, whereas the RAR gamma-s elective retinoid CD437 was inactive. The induction of TGase II by the RAR-selective retinoid was completely inhibited by the RAR alpha-anta gonist Ro41-5253. Overexpression of a truncated RAR alpha gene with do minant-negative activity also inhibited the induction of TGase II expr ession. The increase in TGase II is associated with an induction of ap optosis as revealed by DNA fragmentation and the generation of apoptot ic cells. We demonstrate that apoptosis is affected by retinoids in a manner similar to TGase II. Our results suggest that the induction of TGase II expression and apoptosis in SPOC-1 cells are mediated through an RAR alpha-dependent signaling pathway.