Protein: Cyclic AMP-dependent transcription factor ATF-4 (cAMP-dependent transcription factor ATF-4) (Activating transcription factor 4) (C/EBP-related ATF) (C/ATF) (Cyclic AMP-responsive element-binding protein 2) (CREB-2) (cAMP-responsive element-binding protein 2) (Q06507)
Organism: Mus musculus (Mouse)
Function: Transcription factor that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological functions, as regulator of metabolic and redox processes under normal cellular conditions, and as master transcription factor during integrated stress response (ISR). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer. Core effector of the ISR, which is required for adaptation to various stress such as endoplasmic reticulum (ER) stress, amino acid starvation, mitochondrial stress or oxidative stress. During ISR, ATF4 translation is induced via an alternative ribosome translation re-initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation, and stress-induced ATF4 acts as a master transcription factor of stress-responsive genes in order to promote cell recovery. Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation. Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress (By similarity). Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress. However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation (By similarity). Together with DDIT3/CHOP, mediates programmed cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation and the terminal unfolded protein response (terminal UPR), a cellular response that elicits programmed cell death when ER stress is prolonged and unresolved. Together with DDIT3/CHOP, activates the transcription of the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell death by regulating the expression of BBC3/PUMA in response to ER stress. May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress (By similarity). In the absence of stress, ATF4 translation is at low levels and it is required for normal metabolic processes such as embryonic lens formation, fetal liver hematopoiesis, bone development and synaptic plasticity. Acts as a regulator of osteoblast differentiation in response to phosphorylation by RPS6KA3/RSK2: phosphorylation in osteoblasts enhances transactivation activity and promotes expression of osteoblast-specific genes and post-transcriptionally regulates the synthesis of Type I collagen, the main constituent of the bone matrix. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production. Activates transcription of SIRT4. Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4. Binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes. Mainly acts as a transcriptional activator in cellular stress adaptation, but it can also act as a transcriptional repressor: acts as a regulator of synaptic plasticity by repressing transcription, thereby inhibiting induction and maintenance of long-term memory. Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding.
Subcellular location: Nucleus {ECO:0000269|PubMed:15109498, ECO:0000269|PubMed:19232401, ECO:0000269|PubMed:22974638}. Nucleus speckle {ECO:0000250|UniProtKB:P18848}. Cytoplasm {ECO:0000269|PubMed:19232401}. Cell membrane {ECO:0000250|UniProtKB:Q9ES19}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000250|UniProtKB:P18848}. Note=Colocalizes with GABBR1 in hippocampal neuron dendritic membranes. Colocalizes with NEK6 in the centrosome (By similarity). Recruited to nuclear speckles following interaction with EP300/p300 (By similarity). {ECO:0000250|UniProtKB:P18848, ECO:0000250|UniProtKB:Q9ES19}.
Sequence: MTEMSFLNSEVLAGDLMSPFDQSGLGAEESLGLLDDYLEVAKHLKPHGFSSDKAGSSEWPAMDDGLASASDTGKEDAFSGTDWMLEKMDLKEFDFDALFRMDDLETMPDELLTTLDDTCDLFAPLVQETNKEPPQTVNPIGHLPESLIKVDQVAPFTFLQPFPCSPGVLSSTPEHSFSLELGSEVDISEGDRKPDSAAYITLIPPCVKEEDTPSDNDSGICMSPESYLGSPQHSPSTSRAPPDNLPSPGGSRGSPRPKPYDPPGVSLTAKVKTEKLDKKLKKMEQNKTAATRYRQKKRAEQEALTGECKELEKKNEALKEKADSLAKEIQYLKDLIEEVRKARGKKRVP
InterPro domains: - IPR004827: Basic-leucine zipper domain (domain) [274-339]
- IPR046347: Basic-leucine zipper domain superfamily (homologous_superfamily) [284-337]
Interaction partners: - DNA damage-inducible transcript 3 protein
- CCAAT/enhancer-binding protein gamma
- Eukaryotic translation initiation factor 2-alpha kinase 3
- CCAAT/enhancer-binding protein beta
- Protein phosphatase 1 regulatory subunit 15A
- Eukaryotic translation initiation factor 2 subunit 1
- Cyclic AMP-responsive element-binding protein 1
- Cyclic AMP-dependent transcription factor ATF-6 beta
- Cyclic AMP-dependent transcription factor ATF-3
- Histone lysine acetyltransferase CREBBP
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:1901363 (heterocyclic compound binding), GO:0003682 (chromatin binding), GO:0097159 (organic cyclic compound binding), GO:0005515 (protein binding), GO:0003676 (nucleic acid binding), GO:0001067 (transcription regulatory region nucleic acid binding), GO:0003677 (DNA binding), GO:0003690 (double-stranded DNA binding), GO:0043565 (sequence-specific DNA binding), GO:0000976 (transcription cis-regulatory region binding), GO:1990837 (sequence-specific double-stranded DNA binding), GO:0000987 (cis-regulatory region sequence-specific DNA binding), GO:0000977 (RNA polymerase II transcription regulatory region sequence-specific DNA binding), GO:0000978 (RNA polymerase II cis-regulatory region sequence-specific DNA binding)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0023052 (signaling), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0048519 (negative regulation of biological process), GO:0009605 (response to external stimulus), GO:0048869 (cellular developmental process), GO:0009628 (response to abiotic stimulus), GO:0048856 (anatomical structure development), GO:0007275 (multicellular organism development), GO:0051051 (negative regulation of transport), GO:0042221 (response to chemical), GO:0019222 (regulation of metabolic process), GO:0032879 (regulation of localization), GO:0007267 (cell-cell signaling), GO:0048522 (positive regulation of cellular process), GO:0050794 (regulation of cellular process), GO:0009893 (positive regulation of metabolic process), GO:0051716 (cellular response to stimulus), GO:0048583 (regulation of response to stimulus), GO:0006950 (response to stress), GO:0048523 (negative regulation of cellular process), GO:0007154 (cell communication), GO:0051049 (regulation of transport), GO:0060548 (negative regulation of cell death), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0006979 (response to oxidative stress), GO:0030154 (cell differentiation), GO:0080134 (regulation of response to stress), GO:0048731 (system development), GO:0070482 (response to oxygen levels), GO:0080135 (regulation of cellular response to stress), GO:0009636 (response to toxic substance), GO:0060255 (regulation of macromolecule metabolic process), GO:0009891 (positive regulation of biosynthetic process), GO:0009991 (response to extracellular stimulus), GO:0010035 (response to inorganic substance), GO:0010941 (regulation of cell death), GO:0007214 (gamma-aminobutyric acid signaling pathway), GO:0031325 (positive regulation of cellular metabolic process), GO:0070887 (cellular response to chemical stimulus), GO:0033554 (cellular response to stress), GO:0009889 (regulation of biosynthetic process), GO:0043271 (negative regulation of monoatomic ion transport), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0031323 (regulation of cellular metabolic process), GO:0031668 (cellular response to extracellular stimulus), GO:0080090 (regulation of primary metabolic process), GO:0071496 (cellular response to external stimulus), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0034599 (cellular response to oxidative stress), GO:0010038 (response to metal ion), GO:1901215 (negative regulation of neuron death), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0071453 (cellular response to oxygen levels), GO:0062197 (cellular response to chemical stress), GO:1901214 (regulation of neuron death), GO:1903202 (negative regulation of oxidative stress-induced cell death), GO:0043267 (negative regulation of potassium ion transport), GO:0010468 (regulation of gene expression), GO:1901522 (positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus), GO:1900407 (regulation of cellular response to oxidative stress), GO:0034976 (response to endoplasmic reticulum stress), GO:0010557 (positive regulation of macromolecule biosynthetic process), GO:0022008 (neurogenesis), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0051254 (positive regulation of RNA metabolic process), GO:0007399 (nervous system development), GO:1903201 (regulation of oxidative stress-induced cell death), GO:0071241 (cellular response to inorganic substance), GO:0031667 (response to nutrient levels), GO:0036293 (response to decreased oxygen levels), GO:0043620 (regulation of DNA-templated transcription in response to stress), GO:1902882 (regulation of response to oxidative stress), GO:0031326 (regulation of cellular biosynthetic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0051252 (regulation of RNA metabolic process), GO:0043269 (regulation of monoatomic ion transport), GO:0031669 (cellular response to nutrient levels), GO:0030182 (neuron differentiation), GO:0031328 (positive regulation of cellular biosynthetic process), GO:0090649 (response to oxygen-glucose deprivation), GO:1903203 (regulation of oxidative stress-induced neuron death), GO:2001141 (regulation of RNA biosynthetic process), GO:0006355 (regulation of DNA-templated transcription), GO:0010959 (regulation of metal ion transport), GO:0010042 (response to manganese ion), GO:1903204 (negative regulation of oxidative stress-induced neuron death), GO:0071248 (cellular response to metal ion), GO:0036294 (cellular response to decreased oxygen levels), GO:1902680 (positive regulation of RNA biosynthetic process), GO:0048699 (generation of neurons), GO:0043618 (regulation of transcription from RNA polymerase II promoter in response to stress), GO:0043619 (regulation of transcription from RNA polymerase II promoter in response to oxidative stress), GO:0090650 (cellular response to oxygen-glucose deprivation), GO:0006357 (regulation of transcription by RNA polymerase II), GO:0045893 (positive regulation of DNA-templated transcription), GO:0071287 (cellular response to manganese ion), GO:0036003 (positive regulation of transcription from RNA polymerase II promoter in response to stress), GO:0043266 (regulation of potassium ion transport), GO:1903508 (positive regulation of nucleic acid-templated transcription), GO:1903506 (regulation of nucleic acid-templated transcription), GO:0045944 (positive regulation of transcription by RNA polymerase II)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0031974 (membrane-enclosed lumen), GO:0005654 (nucleoplasm), GO:0043229 (intracellular organelle), GO:0043233 (organelle lumen), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle), GO:0070013 (intracellular organelle lumen), GO:0031981 (nuclear lumen), GO:0005634 (nucleus)