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.[5][6]
Function
DDIT4 acts as a negative regulator of mTOR,[7] a serine/threonine kinase that regulates a variety of cellular functions such as growth, proliferation and autophagy.[8] In particular, upregulation of HIF-1 in response to hypoxia upregulates DDIT4,[5] leading to activation of Tsc1/2 via 14–3–3 shuttling[9] and subsequent downregulation of mTOR via Rheb.[10] In addition to hypoxia, DDIT4 expression has also been shown to be activated by DNA damage[11] and energy stress.[12]
Clinical significance
Clinical interest in DDIT4 is based primarily on its effect on mTOR, which has been associated with aging[13] and linked with diseases such as tuberous sclerosis, lymphangioleiomyomatosis,[14]diabetes,[13] and cancer. In particular, the overactivation of mTOR in many cancer types[8] 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.[15]
^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.
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. S2CID27764390.
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. S2CID21039750.
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. S2CID69278.
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.
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.