Departments of Internal Medicine, Developmental Biology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Apart from HIF1 and 2, other transcription factors have been implicated in REDD1 induction:
- ATF4 (activating transcription factor 4): REDD1 is induced under ER stress conditions in an ATF4-dependent manner (Whitney et al., 2009). Experiments performed in HepG2 cells showed REDD1 induction with the ER stress inducers Thapsigargin and Tunicamycin. This induction was shown to be protein kinase RNA-like ER kinase (PERK) and ATF4-dependent based on studies on PERK or ATF4-deficient MEFs. In addition, ectopically overexpressed ATF4 was sufficient to induce REDD1 expression in HEK293.
- CREBP (CCAAT/enhancer-binding protein): DNA-damaging agent MMS induces REDD1 mRNA in HaCaT cells in a CREBP-dependent manner (Lin et al., 2005a). Luciferase reporter assays identified a MMS-responsive region within -1057/-981 (Lin et al., 2005a) which included a putative CREBP site at -1009/-999, and CREBP was found to bind to this sequence in EMSA.
- Elk1: REDD1 mRNA is induced in HaCaT cells exposed to arsenite, in a Elk1 and CCAAT/enhancer-binding protein (CREBP)-dependent manner (Lin et al., 2005b). Luciferase reporter assays in HaCaT cells mapped the arsenite-responsive region to the -1057/-981 (Lin et al., 2005b), and EMSA assays showed CREBP binding to that region.
- NFATc3 (nuclear factor of activated T-cell): in intestinal cells REDD1 is induced by the NFAT activators PMA and A23187, and siRNA knockdown of NFATc3 but not other family members compromised PMA/A23187-induced REDD1 expression (Zhou et al., 2012). Luciferase-reporter assays showed that NFATc3 was sufficient to activate expression of REDD1 promoter sequences and ChIP assays in HT29 cells showed binding of NFATc3 (-2931/-97) (Zhou et al., 2012).
- p53: MEFs treated with ionizing radiation induced REDD1 in a p53-dependent manner, and overexpression of p53 in SAOS and U2OS cells induced REDD1 (Ellisen et al., 2002). Luciferase reporter assays in U2OS cells identified a p53-responsive element at -600 bp (Ellisen et al., 2002).
- Sp1: REDD1 levels are increased in high cell densities in a Sp-1 dependent manner (Jin et al., 2007). Sp1 siRNA in HeLa cells abolished REDD1 induction by high cell density. Sp1 can also contribute to REDD1 induction in hypoxia or in response to hypoxia mymetics (Jin et al., 2007), and siRNA experiments compromised CoCl2-dependent REDD1 induction. The putative Sp1 binding site was mapped to -476/-446 of the REDD1 promoter by luciferase-reporter assays in HeLa cells (Jin et al., 2007).
The REDD1 promoter region contains putative target sequences for other transcription factors, including NFkB and hepatocyte-nuclear factor 4 (HNF4) (Lin et al., 2005b).
Silvia Vega-Rubin-de-Celis ; James Brugarolas
DDIT4 (DNA-damage-inducible transcript 4)
Atlas Genet Cytogenet Oncol Haematol. 2012-12-01
Online version: http://atlasgeneticsoncology.org/gene/45802/ddit4-(dna-damage-inducible-transcript-4)