Molecule Information

General Information of the Molecule (ID: Mol04091)

• Name: Activating transcription factor 4 (ATF4) ,Homo sapiens
• Synonyms: Activating transcription factor 4; Cyclic AMP-responsive element-binding protein 2; Tax-responsive enhancer element-binding protein 67
• Molecule Type: Protein
• Gene Name: ATF4
• Gene ID: 468
• Location: chr22:39519695-39522686[+]
• Sequence:
  MTEMSFLSSEVLVGDLMSPFDQSGLGAEESLGLLDDYLEVAKHFKPHGFSSDKAKAGSSE
  WLAVDGLVSPSNNSKEDAFSGTDWMLEKMDLKEFDLDALLGIDDLETMPDDLLTTLDDTC
  DLFAPLVQETNKQPPQTVNPIGHLPESLTKPDQVAPFTFLQPLPLSPGVLSSTPDHSFSL
  ELGSEVDITEGDRKPDYTAYVAMIPQCIKEEDTPSDNDSGICMSPESYLGSPQHSPSTRG
  SPNRSLPSPGVLCGSARPKPYDPPGEKMVAAKVKGEKLDKKLKKMEQNKTAATRYRQKKR
  AEQEALTGECKELEKKNEALKERADSLAKEIQYLKDLIEEVRKARGKKRVP
• 3D-structure: PDB ID: 1CI6; Classification: Transcription; Method: X-ray diffraction; Resolution: 2.60 Å
• 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) (PubMed:16682973, PubMed:17684156, PubMed:31023583, PubMed:31444471, PubMed:32132707). Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer (By similarity). 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 (PubMed:31023583, PubMed:32132707). 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 (PubMed:31023583, PubMed:32132706, PubMed:32132707). Promotes the transcription of genes linked to amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation (By similarity). Activates the transcription of NLRP1, possibly in concert with other factors in response to ER stress (PubMed:26086088). Activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress (PubMed:11960987). However, when associated with DDIT3/CHOP, the transcriptional activation of the ASNS gene is inhibited in response to amino acid deprivation (PubMed:18940792). 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 (By similarity). Activates the expression of COX7A2L/SCAF1 downstream of the EIF2AK3/PERK-mediated unfolded protein response, thereby promoting formation of respiratory chain supercomplexes and increasing mitochondrial oxidative phosphorylation (PubMed:31023583). 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 (PubMed:15775988). May cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis which is critical for cell viability in response to ER stress (PubMed:33384352). 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 (By similarity). 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 (PubMed:15109498). Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production (By similarity). Activates transcription of SIRT4 (By similarity). Regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4 (By similarity). 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 (By similarity). 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 (By similarity). Regulates synaptic functions via interaction with DISC1 in neurons, which inhibits ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding (PubMed:31444471). .; (Microbial infection) Binds to a Tax-responsive enhancer element in the long terminal repeat of HTLV-I. .
• Uniprot ID: ATF4_HUMAN
• Ensembl ID: ENSG00000128272
• HGNC ID: HGNC:786

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Temozolomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Glioblastoma [ICD-11: 2A00.02] [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Temozolomide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNT-22 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.

YN-968D1

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Non-small cell lung carcinoma [ICD-11: 2C25.Y] [2]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Resistant Drug: YN-968D1
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2alpha/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells.

PD-166866

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: T-cell acute lymphoblastic leukemia [ICD-11: 2A90.5] [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: T-cell acute lymphoblastic leukemia [ICD-11: 2A90.5]
• Resistant Drug: PD-166866
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: The 6 to 8-week-old NCG mice, with Jurkat-luciferase cell; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cd7 antibody assay
• Mechanism Description: Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2alpha pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells.

Clinical Trial Drug(s) 1 drug(s) in total

AZD-4547

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: T-cell acute lymphoblastic leukemia [ICD-11: 2A90.5] [3]

• Metabolic Type: Glucose metabolism
• Resistant Disease: T-cell acute lymphoblastic leukemia [ICD-11: 2A90.5]
• Resistant Drug: AZD-4547
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: The 6 to 8-week-old NCG mice, with Jurkat-luciferase cell; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cd7 antibody assay
• Mechanism Description: Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2alpha pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells.

References

• Ref 1: Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide. Sci Rep. 2021 Jul 8;11(1):14161.
• Ref 2: Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer. Cell Death Dis. 2022 Jul 21;13(7):636.
• Ref 3: ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming. Acta Pharmacol Sin. 2023 Nov;44(11):2282-2295.