Identification and Characterization of a Versatile Retinoid Response Element (Retinoic Acid Receptor Response Element-Retinoid X Receptor Response Element) in the Mouse Tissue Transglutaminase Gene Promoter

Abstract

Tissue transglutaminase (transglutaminase type II) is an intracellular protein cross-linking enzyme that accumulates in connective tissue and in cells undergoing apoptosis. Retinoids regulate the transcription of the mouse tissue transglutaminase gene via activation of regulatory elements contained within 4 kilobases of the 5'-end of the gene. Co-transfection studies with retinoid receptor expression vectors in CV-1 cells demonstrated that the mouse tissue transglutaminase promoter is activated by ligand activation of either retinoic acid receptor-retinoid X receptor (RAR.RXR) heterodimers or RXR homodimers. Optimal induction is achieved with retinoid receptor panagonists; partial activation can also be achieved with either RAR-specific or RXR-specific retinoids. Retinoid-dependent activation of the tissue transglutaminase promoter depends on both a proximal regulatory region containing sequences highly conserved between the human and the mouse tissue transglutaminase promoters and a distal region that includes a 30-base pair retinoid response element (mTGRRE1). mTGRRE1 contains three hexanucleotide half-sites (two canonical and one non-canonical) in a DR7/DR5 motif that bind both RAR*RXR heterodimers and RXR homodimers. These studies suggest that retinoid-dependent expression of the mouse tissue transglutaminase gene is mediated by a versatile tripartite retinoid response element located 1.7 kilobases upstream of the transcription start site.

Retinoid-induced apoptosis in normal and neoplastic tissues

“…(B) the DR5 element is also able to bind RXR homodimers, and confer RXR-dependent transcriptional activation upon ligand stimulation. Two additional elements contribute to retinoid regulation of the mouse tissue transglutaminase gene: the A halfsite, which forms a DR7 with B and a region highly homologous in mouse and human HR-1 (homology region-1) (Nagy et al, 1996a) which is located further downstream from mTGRRE1 and necessary for full retinoid response in the context of the mouse tissue transglutaminase promoter 1996b), ICE (caspase 1) and CPP32 (caspase 3) (Watson et al, 1997) are elevated. It is interesting to note that Bcl-2 down-regulation is RAR-mediated while induction of tissue transglutaminase is predominantly RXR-induced in this myeloid cell line (Nagy et al, 1996b).…”

“…More recently we have isolated and characterized the promoters for both the human and mouse Tgases (Lu et al, 1995;Nagy et al, 1997a). We have identified in the mouse gene a specific tripartite retinoid response element (mTG RRE-1) (Figure 3) whose presence is required for efficient retinoiddependent activation of the promoter (Nagy et al, 1996a). The TGase RRE-1 functions as a ligand-dependent enhancer element capable of activating homologous and heterologous promoters in a position-and orientationindependent manner (Figure 3).…”

Induction of apoptosis by all-trans retinoic acid in the human myeloma cell line RPMI 8226 and negative regulation of some of its typical morphological features by dexamethasone

“…41 Conflicting data have been reported about the type of RA receptors involved in this control. 14,42 Whereas a retinoid response element has been identified within the mouse tTG gene promoter, 43 such a responsive element has not yet been found in the human promoter sequence. 44 Moreover no negative glucocorticoid element has been identified in this promoter to date, and the mechanism of the inhibition of the RA-dependent induction of tTG is still unknown.…”

Apoptosis-linked in vivo regulation of the tissue transglutaminase gene promoter

“…42 In the mouse promoter no consensus glucocorticoid, nur77 or p53 response elements have been found, but the human promoter was shown to contain one potential glucocorticoid response element (TGTACAGCTTGTTCT) and one potential AP1-binding site (TGTGTCAG) within the 1.7 kb upstream DNA segment. 43 By sequence comparison there are three potential AP-1 sites located in the 3.8 kb fragment of the mouse promoter.…”