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DDIT4

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DDIT4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDDIT4, Dig2, REDD-1, REDD1, DNA damage inducible transcript 4
External IDsOMIM: 607729; MGI: 1921997; HomoloGene: 10400; GeneCards: DDIT4; OMA:DDIT4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_019058

NM_029083

RefSeq (protein)

NP_061931

NP_083359

Location (UCSC)Chr 10: 72.27 – 72.28 MbChr 10: 59.79 – 59.79 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6]

Function

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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

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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]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000168209Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020108Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b 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 (April 2002). "Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis". Molecular and Cellular Biology. 22 (7): 2283–93. doi:10.1128/MCB.22.7.2283-2293.2002. PMC 133671. PMID 11884613.
  6. ^ "Entrez Gene: DDIT4 DNA-damage-inducible transcript 4".
  7. ^ Sofer A, Lei K, Johannessen CM, Ellisen LW (July 2005). "Regulation of mTOR and cell growth in response to energy stress by REDD1". Molecular and Cellular Biology. 25 (14): 5834–45. doi:10.1128/MCB.25.14.5834-5845.2005. PMC 1168803. PMID 15988001.
  8. ^ a b Sato T, Nakashima A, Guo L, Coffman K, Tamanoi F (May 2010). "Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer". Oncogene. 29 (18): 2746–52. doi:10.1038/onc.2010.28. PMC 2953941. PMID 20190810.
  9. ^ DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW (January 2008). "Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling". Genes & Development. 22 (2): 239–51. doi:10.1101/gad.1617608. PMC 2192757. PMID 18198340.
  10. ^ Inoki K, Li Y, Xu T, Guan KL (August 2003). "Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling". Genes & Development. 17 (15): 1829–34. doi:10.1101/gad.1110003. PMC 196227. PMID 12869586.
  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. PMID 12453409.
  12. ^ McGhee NK, Jefferson LS, Kimball SR (May 2009). "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. doi:10.3945/jn.108.099846. PMC 2714387. PMID 19297425.
  13. ^ a b Zoncu R, Efeyan A, Sabatini DM (January 2011). "mTOR: from growth signal integration to cancer, diabetes and ageing". Nature Reviews Molecular Cell Biology. 12 (1): 21–35. doi:10.1038/nrm3025. PMC 3390257. PMID 21157483.
  14. ^ 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. PMID 16226444.
  15. ^ 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. PMID 21540236.

Further reading

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