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

Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Molecular Cell (Impact Factor: 14.46). 12/2002; 10(5):995-1005. DOI: 10.1016/S1097-2765(02)00706-2
Source: PubMed

ABSTRACT 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.

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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.
    Biochemical and Biophysical Research Communications 10/2014; 453(4). DOI:10.1016/j.bbrc.2014.10.032 · 2.28 Impact Factor
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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.
    Frontiers in Cellular Neuroscience 10/2014; 8:313. DOI:10.3389/fncel.2014.00313 · 4.18 Impact Factor
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    • "For example, REDD1 (also known as RTP801/Dig2/DDIT4) is a critical transducer of cellular responses to energy depletion through the TSC-mTOR pathway. Mammalian REDD1 is induced following DNA damage through both p53-dependent and -independent mechanisms [33]. Recently, Jin et al. (2011) found that TXNIP inhibited mTOR activity by binding to and stabilizing the Redd1 protein [34]. "
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    ABSTRACT: Noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists evoke a behavioral and neurobiological syndrome in experimental animals. We previously reported that phencyclidine (PCP), an NMDA receptor antagonist, increased locomotor activity in wildtype (WT) mice but not GluN2D subunit knockout mice. Thus, the aim of the present study was to determine whether the GluN2D subunit is involved in PCP-induced motor impairment. PCP or UBP141 (a GluN2D antagonist) induced potent motor impairment in WT mice but not GluN2D KO mice. By contrast, CIQ, a GluN2C/2D potentiator, induced severe motor impairment in GluN2D KO mice but not WT mice, suggesting that the GluN2D subunit plays an essential role in the effects of PCP and UBP141, and an appropriate balance between GluN2C and GluN2D subunits might be needed for appropriate motor performance. The level of the GluN2D subunit in the mature mouse brain is very low and restricted. GluN2D subunits exist in brainstem structures, the globus pallidus, thalamus, and subthalamic nucleus. We found that the expression of the c-fos gene increased the most among PCP-dependent differentially expressed genes between WT and GluN2D KO mice, and the number of Fos-positive cells increased after PCP administration in the basal ganglia motor circuit in WT mice but not GluN2D KO mice. These results suggest that the GluN2D subunit within the motor circuitry is a key subunit for PCP-induced motor impairment, which requires an intricate balance between GluN2C- and GluN2D-mediated excitatory outputs.
    Molecular Brain 12/2013; 6(1):56. DOI:10.1186/1756-6606-6-56 · 4.35 Impact Factor
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