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FLASH GENE
Symbol DDIT4 contributors: mct/npt/pgu - updated : 20-03-2015
HGNC name DNA-damage-inducible transcript 4
HGNC id 24944
PROTEIN
PHYSICAL PROPERTIES acid
STRUCTURE
motifs/domains
  • rich in serine
    • secondary structure a domain characterized by an alpha/beta sandwich consisting of two antiparallel alpha-helices and a mixed beta-sheet encompassing an uncommon psi-loop motif, essential for DDIT4-mediated MTOR inhibition
    HOMOLOGY
    interspecies ortholog to rattus Ddit4
    ortholog to murine Ddit4
    Homologene
    FAMILY
  • DDIT4 family
    • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,cytosolic
    basic FUNCTION
  • might play important roles in Abeta toxicity and the pathogenesis of Alzheimer disease
  • has a crucial role in inhibiting mTORC1 signalling during hypoxic stress
  • involvement in inhibition of MTOR activity
  • conserved stress-response protein that regulates mTORC1, a critical regulator of cell growth and proliferation that is implicated in cancer
  • regulated during neuronal differentiation and functions to influence the timing of both neurogenesis and neuron migration
  • endogenous DDIT4 plays an essential role in temporal control of cortical development and in cortical patterning
  • inhibits the invasive activity of non-small cell lung cancer cells via suppression of the MTOR downstream pathway
  • DDIT4-mediated autophagy promotes cell survival (
  • stress-induced inhibitor of TOR complex 1 (MTOR) activity
  • protective factor in radiation-induced osteoblast cell premature senescence
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    downstream of AKT and upstream of TSC2 in mTOR pathway regulation
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • TXNIP inhibits MTOR activity by binding to and stabilizing DDIT4 protein
  • DDIT4-mediated suppression of MTOR activity exerts feedback control on TP53, thereby limiting the apoptotic response and contributing to cellular survival following DNA damage
  • negative regulator of MTOR and its overexpression delays the onset of replicative senescence
  • induction of DDIT4 gene expression was shown to require the protein kinase EIF2AK3 and enhanced phosphorylation of its substrate EIF2S1
  • in human hematopoietic stem/progenitor cells (HSPCs) DDIT4 is a direct TAL1 target gene
    • cell & other
    REGULATION
    activated by Insulin (insulin stimulates REDD1 expression in adipocytes)
    induced by hypoxia (hypoxia is tissue dependent and hypoxia signals are relayed to MTOR through different pathways in a tissue-specific manner)
    exogenous expression of ATF4 (was sufficient to induce DDIT4 expression)
    Other a transcriptional target of p53 induced following DNA damage
    is subject to ubiquitin-mediated degradation, crucial degradation for the restoration of mTOR signalling as cells recover from hypoxic stress
    regulated by several transcription factors, such as HIF1A, HIF1B
    its elevation contributes to the induction of autophagy
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in prostate cancer
    constitutional     --over  
    during ER stress through a mechanism involving activation of EIF2AK3, phosphorylation of EIF2A, and increased ATF4 expression
    constitutional     --over  
    in Parkinson disease substantia nigral neurons that may mediate their degeneration and death
    constitutional     --over  
    in osteoblast cell line (hFOB) cells after gamma irradiation
    tumoral     --over  
    in breast lesion patients as compared with normal controls
    Susceptibility to Alzheimer's disease
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerlung 
    may thus be a potential therapeutic protein for inhibiting lung metastasis and invasion
    cancerreproductiveprostate
    target for therapeutic intervention in prostate cancer
    cancer  
    apoptotic effect of FAS inhibition in tumor cells to up-regulation of DDIT4), a stress-response gene that negatively regulates the MTOR pathway
    neurologyneurodegenerativeParkinson/dementia Parkinsonism
    with its signaling cascade may be novel potential therapeutic targets for Parkinson disease
    ANIMAL & CELL MODELS