DDIT4 explained

DNA-damage-inducible transcript 4 (DDIT4) protein also known as protein regulated in development and DNA damage response 1 (REDD1) 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, leading to activation of Tsc1/2 via 14–3–3 shuttling^[5] and subsequent downregulation of mTOR via Rheb.^[6] In addition to hypoxia, DDIT4 expression has also been shown to be activated by DNA damage^[7] and energy stress.^[8]

Clinical significance

Clinical interest in DDIT4 is based primarily on its effect on mTOR, which has been associated with aging^[9] and linked with diseases such as tuberous sclerosis, lymphangioleiomyomatosis,^[10] diabetes, 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.^[11]

See also

• HIF1A
• Tuberous sclerosis protein
• MTOR
• 14-3-3 protein
• DDIT4L/ REDD2

Further reading

• Ellisen LW . Growth control under stress: mTOR regulation through the REDD1-TSC pathway . Cell Cycle . 4 . 11 . 1500–02 . November 2005 . 16258273 . 10.4161/cc.4.11.2139 . free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A . Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs . Genome Research . 11 . 3 . 422–35 . March 2001 . 11230166 . 311072 . 10.1101/gr.GR1547R .
• Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S . Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing . EMBO Reports . 1 . 3 . 287–92 . September 2000 . 11256614 . 1083732 . 10.1093/embo-reports/kvd058 .
• Kim JR, Lee SR, Chung HJ, Kim S, Baek SH, Kim JH, Kim YS . Identification of amyloid beta-peptide responsive genes by cDNA microarray technology: involvement of RTP801 in amyloid beta-peptide toxicity . Experimental & Molecular Medicine . 35 . 5 . 403–11 . October 2003 . 14646594 . 10.1038/emm.2003.53 . free .
• Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW . Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation . Nature Biotechnology . 22 . 6 . 707–16 . June 2004 . 15146197 . 10.1038/nbt971 . 27764390 .
• Lee M, Bikram M, Oh S, Bull DA, Kim SW . Sp1-dependent regulation of the RTP801 promoter and its application to hypoxia-inducible VEGF plasmid for ischemic disease . Pharmaceutical Research . 21 . 5 . 736–41 . May 2004 . 15180327 . 10.1023/B:PHAM.0000026421.09367.b3 . 21039750 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–44 . October 2004 . 15489336 . 528930 . 10.1101/gr.2576704 .
• Schwarzer R, Tondera D, Arnold W, Giese K, Klippel A, Kaufmann J . REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase . Oncogene . 24 . 7 . 1138–49 . February 2005 . 15592522 . 10.1038/sj.onc.1208236 . free .
• Corradetti MN, Inoki K, Guan KL . The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway . The Journal of Biological Chemistry . 280 . 11 . 9769–72 . March 2005 . 15632201 . 10.1074/jbc.C400557200 . free .
• Sofer A, Lei K, Johannessen CM, Ellisen LW . Regulation of mTOR and cell growth in response to energy stress by REDD1 . Molecular and Cellular Biology . 25 . 14 . 5834–45 . July 2005 . 15988001 . 1168803 . 10.1128/MCB.25.14.5834-5845.2005 .
• Oh JH, Yang JO, Hahn Y, Kim MR, Byun SS, Jeon YJ, Kim JM, Song KS, Noh SM, Kim S, Yoo HS, Kim YS, Kim NS . Transcriptome analysis of human gastric cancer . Mammalian Genome . 16 . 12 . 942–54 . December 2005 . 16341674 . 10.1007/s00335-005-0075-2 . 69278 .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–8 . January 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration . Cell . 125 . 4 . 801–14 . May 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .
• Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA . 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 . The Journal of Neuroscience . 26 . 39 . 9996–10005 . September 2006 . 17005863 . 6674487 . 10.1523/JNEUROSCI.3292-06.2006 .
• Jin HO, An S, Lee HC, Woo SH, Seo SK, Choe TB, Yoo DH, Lee SB, Um HD, Lee SJ, Park MJ, Kim JI, Hong SI, Rhee CH, Park IC . 6 . 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 . Cellular Signalling . 19 . 7 . 1393–403 . July 2007 . 17307335 . 10.1016/j.cellsig.2006.12.014 .

Notes and 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 . Eli Keshet . Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis . Molecular and Cellular Biology . 22 . 7 . 2283–93 . April 2002 . 11884613 . 133671 . 10.1128/MCB.22.7.2283-2293.2002 .
2. Web site: Entrez Gene: DDIT4 DNA-damage-inducible transcript 4.
3. Sofer A, Lei K, Johannessen CM, Ellisen LW . Regulation of mTOR and cell growth in response to energy stress by REDD1 . Molecular and Cellular Biology . 25 . 14 . 5834–45 . July 2005 . 15988001 . 10.1128/MCB.25.14.5834-5845.2005 . 1168803.
4. Sato T, Nakashima A, Guo L, Coffman K, Tamanoi F . Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer . Oncogene . 29 . 18 . 2746–52 . May 2010 . 20190810 . 10.1038/onc.2010.28 . 2953941.
5. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW . Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling . Genes & Development . 22 . 2 . 239–51 . January 2008 . 18198340 . 10.1101/gad.1617608 . 2192757.
6. Inoki K, Li Y, Xu T, Guan KL . Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling . Genes & Development . 17 . 15 . 1829–34 . August 2003 . 12869586 . 10.1101/gad.1110003 . 196227.
7. Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, Oliner JD, McKeon F, Haber DA . REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species . Molecular Cell . 10 . 5 . 995–1005 . November 2002 . 12453409 . 10.1016/S1097-2765(02)00706-2 . free .
8. McGhee NK, Jefferson LS, Kimball SR . Elevated corticosterone associated with food deprivation upregulates expression in rat skeletal muscle of the mTORC1 repressor, REDD1 . The Journal of Nutrition . 139 . 5 . 828–834 . May 2009 . 19297425 . 10.3945/jn.108.099846 . 2714387.
9. Zoncu R, Efeyan A, Sabatini DM . mTOR: from growth signal integration to cancer, diabetes and ageing . Nature Reviews Molecular Cell Biology . 12 . 1 . 21–35 . January 2011 . 21157483 . 10.1038/nrm3025 . 3390257.
10. Sarbassov DD, Ali SM, Sabatini DM . Growing roles for the mTOR pathway . Current Opinion in Cell Biology . 17 . 6 . 596–603 . December 2005 . 16226444 . 10.1016/j.ceb.2005.09.009 .
11. Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F . Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1 . Cancer Research . 71 . 13 . 4366–72 . July 2011 . 21540236 . 10.1158/0008-5472.CAN-10-1769 . free .