DDIT4

DNA-damage-inducible transcript 4
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3LQ9​
Identifiers
Symbols	DDIT4 ; Dig2; REDD-1; REDD1
External IDs	OMIM: 607729 MGI: 1921997 HomoloGene: 10400 GeneCards: DDIT4 Gene
Gene ontology Molecular function • 14-3-3 protein binding Cellular component • intracellular • cytoplasm • mitochondrion • cytosol Biological process • response to hypoxia • neuron migration • transcription initiation from RNA polymerase II promoter • brain development • cell proliferation • gene expression • negative regulation of peptidyl-threonine phosphorylation • neuron differentiation • negative regulation of TOR signaling • negative regulation of peptidyl-serine phosphorylation • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • protein complex disassembly • negative regulation of glycolytic process • neurotrophin TRK receptor signaling pathway • defense response to virus • reactive oxygen species metabolic process • positive regulation of neuron death • negative regulation of intracellular signal transduction Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	54541	74747
Ensembl	ENSG00000168209	ENSMUSG00000020108
UniProt	Q9NX09	Q9D3F7
RefSeq (mRNA)	NM_019058	NM_029083
RefSeq (protein)	NP_061931	NP_083359
Location (UCSC)	Chr 10: 72.27 – 72.28 Mb	Chr 10: 59.95 – 59.95 Mb
PubMed search

DNA-damage-inducible transcript 4 protein is a protein that in humans is encoded by the DDIT4 gene.^[1][2]

Function

DDIT4 acts as a negative regulator of mTOR,^[3] a serine/threonine kinase that regulates a variety of cellular functions such as growth, proliferation and autophagy.^[4] In particular, upregulation of HIF-1 in response to hypoxia upregulates DDIT4,^[5] leading to activation of Tsc1/2 via 14–3–3 shuttling ^[6] and subsequent downregulation of mTOR via Rheb.^[7] In addition to hypoxia, DDRT4 expression has also been shown to be activated by DNA damage ^[8] and energy stress ^[9]

Clinical Significance

Clinical interest in DDIT4 is based primarily on its effect on mTOR, which has been associated with aging ^[10] and linked with diseases such as tuberous sclerosis, lymphangioleiomyomatosis,^[11] diabetes,^[10] and cancer. In particular, the overactivation of mTOR in many cancer types ^[4] has led to the development of mTOR inhibitors for cancer treatment. DDIT4 has begun to receive attention in this regard via the diabetes drug Metformin which has been shown to reduce cancer risk and increase DDIT4 expression.^[12]

See also

• HIF1A
• Tuberous sclerosis protein
• MTOR
• 14-3-3 protein

References

1. Shoshani T, Faerman A, Mett I, Zelin E, Tenne T, Gorodin S, Moshel Y, Elbaz S, Budanov A, Chajut A, Kalinski H, Kamer I, Rozen A, Mor O, Keshet E, Leshkowitz D, Einat P, Skaliter R, Feinstein E (Mar 2002). "Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis". Mol Cell Biol 22 (7): 2283–93. doi:10.1128/MCB.22.7.2283-2293.2002. PMC 133671. PMID 11884613.
2. "Entrez Gene: DDIT4 DNA-damage-inducible transcript 4".
3. Sofer, A.; Lei, K.; Johannessen, C. M.; Ellisen, L. W. (29 June 2005). "Regulation of mTOR and Cell Growth in Response to Energy Stress by REDD1". Molecular and Cellular Biology 25 (14): 5834–5845. doi:10.1128/MCB.25.14.5834-5845.2005.
4. Sato, T; Nakashima, A; Guo, L; Coffman, K; Tamanoi, F (1 March 2010). "Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer". Oncogene 29 (18): 2746–2752. doi:10.1038/onc.2010.28.
5. Shoshani, T.; Faerman, A.; Mett, I.; Zelin, E.; Tenne, T.; Gorodin, S.; Moshel, Y.; Elbaz, S.; Budanov, A.; Chajut, A.; Kalinski, H.; Kamer, I.; Rozen, A.; Mor, O.; Keshet, E.; Leshkowitz, D.; Einat, P.; Skaliter, R.; Feinstein, E. (1 April 2002). "Identification of a Novel Hypoxia-Inducible Factor 1-Responsive Gene, RTP801, Involved in Apoptosis". Molecular and Cellular Biology 22 (7): 2283–2293. doi:10.1128/MCB.22.7.2283-2293.2002.
6. DeYoung, M. P.; Horak, P.; Sofer, A.; Sgroi, D.; Ellisen, L. W. (15 January 2008). "Hypoxia regulates TSC1/2 mTOR signaling and tumor suppression through REDD1-mediated 14 3 3 shuttling". Genes & Development 22 (2): 239–251. doi:10.1101/gad.1617608.
7. Inoki, K. (1 August 2003). "Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling". Genes & Development 17 (15): 1829–1834. doi:10.1101/gad.1110003.
8. Ellisen, Leif W; Ramsayer, Kate D; Johannessen, Cory M; Yang, Annie; Beppu, Hideyuki; Minda, Karolina; Oliner, Jonathan D; McKeon, Frank; Haber, Daniel A (November 2002). "REDD1, a Developmentally Regulated Transcriptional Target of p63 and p53, Links p63 to Regulation of Reactive Oxygen Species". Molecular Cell 10 (5): 995–1005. doi:10.1016/S1097-2765(02)00706-2.
9. McGhee, N. K.; Jefferson, L. S.; Kimball, S. R. (25 March 2009). "Elevated Corticosterone Associated with Food Deprivation Upregulates Expression in Rat Skeletal Muscle of the mTORC1 Repressor, REDD1". Journal of Nutrition 139 (5): 828–834. doi:10.3945/jn.108.099846.
10. Zoncu, Roberto; Efeyan, Alejo; Sabatini, David M. (15 December 2010). "mTOR: from growth signal integration to cancer, diabetes and ageing". Nature Reviews Molecular Cell Biology 12 (1): 21–35. doi:10.1038/nrm3025.
11. Sarbassov, Dos D; Ali, Siraj M; Sabatini, David M (December 2005). "Growing roles for the mTOR pathway". Current Opinion in Cell Biology 17 (6): 596–603. doi:10.1016/j.ceb.2005.09.009.
12. Ben Sahra, I.; Regazzetti, C.; Robert, G.; Laurent, K.; Le Marchand-Brustel, Y.; Auberger, P.; Tanti, J.-F.; Giorgetti-Peraldi, S.; Bost, F. (3 May 2011). "Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1". Cancer Research 71 (13): 4366–4372. doi:10.1158/0008-5472.CAN-10-1769.

Further reading

• Ellisen LW (2007). "Growth control under stress: mTOR regulation through the REDD1-TSC pathway.". Cell Cycle 4 (11): 1500–02. doi:10.4161/cc.4.11.2139. PMID 16258273.
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination.". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Wiemann S, Weil B, Wellenreuther R; et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs.". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
• Simpson JC, Wellenreuther R, Poustka A; et al. (2001). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing.". EMBO Rep. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
• Ellisen LW, Ramsayer KD, Johannessen CM; et al. (2003). "REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species.". Mol. Cell 10 (5): 995–1005. doi:10.1016/S1097-2765(02)00706-2. PMID 12453409.
• Strausberg RL, Feingold EA, Grouse LH; et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Kim JR, Lee SR, Chung HJ; et al. (2004). "Identification of amyloid beta-peptide responsive genes by cDNA microarray technology: involvement of RTP801 in amyloid beta-peptide toxicity.". Exp. Mol. Med. 35 (5): 403–11. doi:10.1038/emm.2003.53. PMID 14646594.
• Brandenberger R, Wei H, Zhang S; et al. (2005). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.". Nat. Biotechnol. 22 (6): 707–16. doi:10.1038/nbt971. PMID 15146197.
• Lee M, Bikram M, Oh S; et al. (2004). "Sp1-dependent regulation of the RTP801 promoter and its application to hypoxia-inducible VEGF plasmid for ischemic disease.". Pharm. Res. 21 (5): 736–41. doi:10.1023/B:PHAM.0000026421.09367.b3. PMID 15180327.
• Wiemann S, Arlt D, Huber W; et al. (2004). "From ORFeome to biology: a functional genomics pipeline.". Genome Res. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
• Schwarzer R, Tondera D, Arnold W; et al. (2005). "REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase.". Oncogene 24 (7): 1138–49. doi:10.1038/sj.onc.1208236. PMID 15592522.
• Corradetti MN, Inoki K, Guan KL (2005). "The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway.". J. Biol. Chem. 280 (11): 9769–72. doi:10.1074/jbc.C400557200. PMID 15632201.
• Sofer A, Lei K, Johannessen CM, Ellisen LW (2005). "Regulation of mTOR and cell growth in response to energy stress by REDD1.". Mol. Cell. Biol. 25 (14): 5834–45. doi:10.1128/MCB.25.14.5834-5845.2005. PMC 1168803. PMID 15988001.
• Oh JH, Yang JO, Hahn Y; et al. (2006). "Transcriptome analysis of human gastric cancer.". Mamm. Genome 16 (12): 942–54. doi:10.1007/s00335-005-0075-2. PMID 16341674.
• Mehrle A, Rosenfelder H, Schupp I; et al. (2006). "The LIFEdb database in 2006.". Nucleic Acids Res. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
• Lim J, Hao T, Shaw C; et al. (2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.". Cell 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID 16713569.
• Malagelada C, Ryu EJ, Biswas SC; et al. (2006). "RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation.". J. Neurosci. 26 (39): 9996–10005. doi:10.1523/JNEUROSCI.3292-06.2006. PMID 17005863.
• Jin HO, An S, Lee HC; et al. (2007). "Hypoxic condition- and high cell density-induced expression of Redd1 is regulated by activation of hypoxia-inducible factor-1alpha and Sp1 through the phosphatidylinositol 3-kinase/Akt signaling pathway.". Cell. Signal. 19 (7): 1393–403. doi:10.1016/j.cellsig.2006.12.014. PMID 17307335.