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 DDIT4gene.[1][2]
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,[1] 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,[9] 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]
↑Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, Oliner JD, McKeon F, Haber DA (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. PMID12453409.
↑Sarbassov DD, Ali SM, Sabatini DM (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. PMID16226444.
↑Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F (July 2011). "Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1". Cancer Research. 71 (13): 4366–72. doi:10.1158/0008-5472.CAN-10-1769. PMID21540236.
Further reading
Ellisen LW (November 2005). "Growth control under stress: mTOR regulation through the REDD1-TSC pathway". Cell Cycle. 4 (11): 1500–02. doi:10.4161/cc.4.11.2139. PMID16258273.
Kim JR, Lee SR, Chung HJ, Kim S, Baek SH, Kim JH, Kim YS (October 2003). "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. doi:10.1038/emm.2003.53. PMID14646594.
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 (June 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology. 22 (6): 707–16. doi:10.1038/nbt971. PMID15146197.
Lee M, Bikram M, Oh S, Bull DA, Kim SW (May 2004). "Sp1-dependent regulation of the RTP801 promoter and its application to hypoxia-inducible VEGF plasmid for ischemic disease". Pharmaceutical Research. 21 (5): 736–41. doi:10.1023/B:PHAM.0000026421.09367.b3. PMID15180327.
Schwarzer R, Tondera D, Arnold W, Giese K, Klippel A, Kaufmann J (February 2005). "REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase". Oncogene. 24 (7): 1138–49. doi:10.1038/sj.onc.1208236. PMID15592522.
Corradetti MN, Inoki K, Guan KL (March 2005). "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. doi:10.1074/jbc.C400557200. PMID15632201.
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 (December 2005). "Transcriptome analysis of human gastric cancer". Mammalian Genome. 16 (12): 942–54. doi:10.1007/s00335-005-0075-2. PMID16341674.
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 (January 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC1347501. PMID16381901.
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 (May 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. PMID16713569.
Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA (September 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". The Journal of Neuroscience. 26 (39): 9996–10005. doi:10.1523/JNEUROSCI.3292-06.2006. PMID17005863.
Jin HO, An S, Lee HC, Woo SH, Seo SK, Choe TB, et al. (July 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". Cellular Signalling. 19 (7): 1393–403. doi:10.1016/j.cellsig.2006.12.014. PMID17307335.