REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species.
We identified REDD1 as a novel transcriptional target of p53 induced following DNA damage. During embryogenesis, REDD1 expression mirrors the tissue-specific pattern of the p53 family member p63, and TP63 null embryos show virtually no expression of REDD1, which is restored in mouse embryo fibroblasts following p63 expression. In differentiating primary keratinocytes, TP63 and REDD1 expression are coordinately downregulated, and ectopic expression of either gene inhibits in vitro differentiation. REDD1 appears to function in the regulation of reactive oxygen species (ROS); we show that TP63 null fibroblasts have decreased ROS levels and reduced sensitivity to oxidative stress, which are both increased following ectopic expression of either TP63 or REDD1. Thus, REDD1 encodes a shared transcriptional target that implicates ROS in the p53-dependent DNA damage response and in p63-mediated regulation of epithelial differentiation.
Ellisen
Leif W
LW
Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Ramsayer
Kate D
KD
Johannessen
Cory M
CM
Yang
Annie
A
Beppu
Hideyuki
H
Minda
Karolina
K
Oliner
Jonathan D
JD
McKeon
Frank
F
Haber
Daniel A
DA
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology; D019143:Evolution, Molecular; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D017403:In Situ Hybridization; D015603:Keratinocytes / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D015854:Up-Regulation; D014981:Xenopus; D029867:Xenopus Proteins; D001616:beta-Galactosidase / Q000378:metabolism
C081876:CKAP4 protein, human; C469991:DDIT4 protein, human; D004268:DNA-Binding Proteins; C469992:Ddit4 protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C488640:TP63 protein, Xenopus; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D029867:Xenopus Proteins; D001616:beta-Galactosidase