REDD1, a Developmentally Regulated Transcriptional Target of p63 and p53, Links p63 to Regulation of Reactive Oxygen Species

Department of Molecular and Cell Biology, Harvard University, Cambridge, Massachusetts, United States
Molecular Cell (Impact Factor: 14.02). 12/2002; 10(5):995-1005. DOI: 10.1016/S1097-2765(02)00706-2
Source: PubMed


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.

    • "Hypoxia has been identified as a stimulus for regulated in development and DNA damage response 1 (REDD1, also referred to as Rtp801) (Ellisen et al., 2002), which inhibits mammalian target of rapamycin (mTOR) a central regulator of protein synthesis (Brugarolas et al., 2004). REDD1 is thought to contribute to skeletal muscle wasting associated with more severe chronic obstructive pulmonary disease (Favier et al., 2010; Langen et al., 2013), a disease state characterized by upper respiratory airflow limitation and lung inflammation that can result in chronic systemic hypoxemia (Pauwels et al., 2001), ergo one theory is that highaltitude associated skeletal muscle atrophy may be induced by an upregulation of REDD1 "
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    ABSTRACT: The role of hypoxia on skeletal muscle mitochondria is controversial. Studies superimposing exercise training with hypoxic exposure demonstrate an increase in skeletal muscle mitochondrial volume density (MitoVD ) over equivalent normoxic training. In contrast, a reduction in both skeletal muscle mass and MitoVD have been reported following mountaineering expeditions. These observations may however be confounded by negative energy balance, which may obscure the results. Accordingly we sought to examine the effects of high altitude hypoxic exposure on mitochondrial characteristics, with emphasis on MitoVD , while minimizing changes in energy balance. For this purpose, skeletal muscle biopsies were obtained from 9 lowlanders at sea level (Pre) and following 7 (7 Days) and 28 (28 Days) days of exposure to 3454 m. Maximal ergometer power output, whole-body weight and composition, leg lean mass, and skeletal muscle fibre area all remained unchanged following the altitude exposure. Transmission electron microscopy determined intermyofibrillar (IMF) MitoVD was augmented (P = 0.028) by 11.5 ± 9.2% from Pre (5.05 ± 0.9%) to Day 28 (5.61 ± 0.04%). On the contrary, there was no change in subsarcolemmal (SS) MitoVD . As a result total MitoVD (IMF + SS) was increased (P = 0.031) from 6.20 ± 1.5% at Pre to 6.62 ± 1.4% on Day 28 (7.8 ± 9.3%). At the same time no changes in mass-specific respiratory capacities, mitochondrial protein or antioxidant content were found. This study demonstrates that skeletal muscle MitoVD may increase with 28 days acclimation to 3454 m. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Sep 2015 · The Journal of Physiology
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    • "Hyperactive mTORC1 negatively feeds back to inhibit the insulin receptor substrate-1 (IRS-1) by reducing tyrosine phosphorylation and promoting serine phosphorylation [9] [12], downregulating insulin signaling. A repressor of mTORC1, the protein regulated in development and DNA damage responses 1 (REDD1; also known as DDIT4 and RTP801) was initially reported as a stress-regulated protein [13] (e.g. hypoxia [14], glucocorticoids [15], DNA damage [16], endoplasmic reticulum (ER) stress [17]). "
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    ABSTRACT: A lack of the REDD1 promotes dysregulated growth signaling, though little has been established with respect to the metabolic role of REDD1. Therefore, the goal of this study was to determine the role of REDD1 on glucose and insulin tolerance, as well as insulin stimulated growth signaling pathway activation in skeletal muscle. First, intraperitoneal (IP) injection of glucose or insulin were administered to REDD1 wildtype (WT) versus knockout (KO) mice to examine changes in blood glucose over time. Next, alterations in skeletal muscle insulin (IRS-1, Akt, ERK 1/2) and growth (4E-BP1, S6K1, REDD1) signaling intermediates were determined before and after IP insulin treatment (10 min). REDD1 KO mice were both glucose and insulin intolerant when compared to WT mice, evident by higher circulating blood glucose concentrations and a greater area under the curve following IP injections of glucose or insulin. While the REDD1 KO exhibited significant though blunted insulin-stimulated increases (p<0.05) in Akt S473 and T308 phosphorylation versus the WT mice, acute insulin treatment has no effect (p<0.05) on REDD1 KO skeletal muscle 4E-BP1 T37/46, S6K1 T389, IRS-1 Y1222, and ERK 1/2 T202/Y204 phosphorylation versus the WT mice. Collectively, these novel data suggest that REDD1 has a more distinct role in whole body and skeletal muscle metabolism and insulin action than previously thought.
    Full-text · Article · Oct 2014 · Biochemical and Biophysical Research Communications
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    • "Deoxyribonucleic acid (DNA) damaging agents, including ionizing radiation and the DNA alkylating agent methyl methane sulfonate (MMS) also boosted RTP801 expression (Ellisen et al., 2002; Lin et al., 2005a). Ionizing radiation induced RTP801 in a p53-dependent manner in mouse embryonic fibroblasts (MEFs; Ellisen et al., 2002). DNA-damage-inducible transcript 4 transcription was also enhanced by MMS in human keratinocytes via Elk-1 and CCAAT/enhancer-binding protein (C/EBP) in a p53-independent manner (Lin et al., 2005a). "
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    ABSTRACT: Mechanistic target of Rapamycin (mTOR) pathway regulates essential processes directed to preserve cellular homeostasis, such as cell growth, proliferation, survival, protein synthesis and autophagy. Importantly, mTOR pathway deregulation has been related to many diseases. Indeed, it has become a hallmark in neurodegenerative disorders, since a fine-tuned regulation of mTOR activities is crucial for neuron function and survival. RTP801/REDD1/Dig2 has become one of the most puzzling regulators of mTOR. Although the mechanism is not completely understood, RTP801 inactivates mTOR and Akt via the tuberous sclerosis complex (TSC1/TSC2) in many cellular contexts. Intriguingly, RTP801 protects dividing cells from hypoxia or H2O2-induced apoptosis, while it sensitizes differentiated cells to stress. Based on experimental models of Parkinson's disease (PD), it has been proposed that at early stages of the disease, stress-induced RTP801 upregulation contributes to mTOR repression, in an attempt to maintain cell function and viability. However, if RTP801 elevation is sustained, it leads to neuron cell death by a sequential inhibition of mTOR and Akt. Here, we will review RTP801 deregulation of mTOR in a context of PD and other neurodegenerative disorders.
    Full-text · Article · Oct 2014 · Frontiers in Cellular Neuroscience
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