Affinage

Showing PMAIP1 — NOXA is a alias.

PMAIP1

Phorbol-12-myristate-13-acetate-induced protein 1 · UniProt Q13794

Length
54 aa
Mass
6.0 kDa
Annotated
2026-06-10
100 papers in source corpus 45 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PMAIP1 (NOXA) is a stress-inducible BH3-only proapoptotic Bcl-2 family protein that couples diverse cellular stresses to mitochondrial outer membrane permeabilization (MOMP) and intrinsic apoptosis (PMID:12952892, PMID:14500851). Genetic loss of Noxa in mice and MEFs blunts apoptosis triggered by DNA damage, UV irradiation, and oncogene-driven stress, placing it upstream of BAX/BAK in the intrinsic pathway, with cell-type-specific dominance over PUMA in fibroblasts and transformed cells (PMID:12952892, PMID:14500851, PMID:17283183, PMID:17024184). NOXA acts by selectively binding the labile anti-apoptotic protein MCL-1, with high affinity (Kd ~3.4 nM) and lower affinity for Bcl-xL and Bcl-2 (PMID:21454712); this engagement displaces BAK and BIM from MCL-1 to license BAX/BAK activation, cytochrome c release, and caspase activation (PMID:16782027, PMID:17545623). Beyond sequestration, NOXA recruits cytosolic MCL-1 to mitochondria and drives its destruction: the mitochondria-associated E3 ligase MARCH5, cooperating with the E2 UBE2K and the outer-membrane protein MTCH2, ubiquitinates MCL-1 specifically when it is engaged by NOXA, targeting the complex for proteasomal degradation (PMID:32484436, PMID:32015503, PMID:32094511), a process reinforced by NOXA-dependent disruption of the USP9X–MCL-1 deubiquitinating interaction (PMID:21907705, PMID:24991768). NOXA transcription integrates a broad range of signals through p53 (PMID:12952892), p73 (PMID:15572378), HIF-1α (PMID:14699081), c-MYC (PMID:18042711, PMID:26045051), FoxO3a/FKHRL1 (PMID:16888645), the ATF3/ATF4 integrated stress response (PMID:29352505, PMID:20085765), ERK/CREB and KLF4 (PMID:20802529, PMID:33918002, PMID:25365078), and the MAL/MRTF-A–SRF axis (PMID:22185759), while being epigenetically repressed by Bmi1-directed H3K27 methylation and PHF8-regulated H3K9me2 (PMID:18411339, PMID:26866517). NOXA protein is itself highly labile, degraded by the proteasome via a C-terminal degron and multi-lysine ubiquitination under CUL5/neddylation control (PMID:20378569, PMID:24811167, PMID:33712558), and cleared by p62-dependent autophagy (PMID:29758299); JNK phosphorylation at Ser13 retains it in the cytoplasm and impairs MCL-1 binding (PMID:25404713). NOXA also extends beyond apoptosis to autophagy regulation, displacing MCL-1 from Beclin-1 to enable autophagic responses (PMID:21353614), and serves a physiological role in affinity-based selection of effector T cells (PMID:20620942).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 High

    Established NOXA as a p53-inducible BH3-only effector genetically required for intrinsic apoptosis, defining its place upstream of BAX in stress-induced cell death.

    Evidence Noxa-/- knockout mice and MEFs with DNA-damage and irradiation apoptosis assays, replicated across two labs with cell-type resolution

    PMID:12952892 PMID:14500851

    Open questions at the time
    • Did not define the molecular target NOXA engages to trigger MOMP
    • Cell-type-specific dependence (fibroblasts vs lymphocytes) left mechanistically unexplained
  2. 2003 Medium

    Showed NOXA induction is not exclusively p53-driven, linking hypoxia to NOXA-dependent death and extending its relevance to ischemic injury.

    Evidence HIF-1α promoter reporter assays, antisense knockdown, and in vivo ischemia/infarction model

    PMID:14699081

    Open questions at the time
    • Direct HIF-1α occupancy not confirmed by ChIP
    • Single lab
  3. 2006 High

    Identified MCL-1 as NOXA's key binding partner and framed the NOXA/MCL-1 ratio as an apoptotic rheostat in metabolically stressed cells.

    Evidence Co-immunoprecipitation plus reciprocal siRNA epistasis under glucose deprivation in T cells

    PMID:16782027

    Open questions at the time
    • Binding affinity and selectivity not quantified
    • Mechanism downstream of MCL-1 neutralization not yet resolved
  4. 2007 High

    Demonstrated that NOXA neutralizes MCL-1 by competitive displacement, freeing BAK and BIM to activate the executioner machinery.

    Evidence Reciprocal Co-IP showing MCL-1/NOXA complex formation and BIM/BAK displacement in bortezomib-treated myeloma

    PMID:17545623

    Open questions at the time
    • Did not establish whether MCL-1 is degraded or only sequestered
    • Contribution of MCL-1 cleavage unresolved
  5. 2011 High

    Quantified NOXA's binding selectivity, showing strong but non-absolute preference for MCL-1 over Bcl-xL and Bcl-2.

    Evidence Surface plasmon resonance with recombinant proteins plus cellular co-pulldown and apoptosis assays

    PMID:21454712

    Open questions at the time
    • Cellular consequences of weaker Bcl-2/Bcl-xL binding context-dependent
    • Did not resolve in vivo target hierarchy
  6. 2011 Medium

    Revealed that NOXA actively promotes MCL-1 degradation, not just sequestration, by disrupting the USP9X–MCL-1 deubiquitinase interaction at mitochondria.

    Evidence Reciprocal Co-IP, ubiquitination assays, and subcellular fractionation with NOXA overexpression

    PMID:21907705

    Open questions at the time
    • E3 ligase responsible not yet identified
    • Single lab
  7. 2014 High

    Established that NOXA recruits cytosolic MCL-1 to mitochondria and that NOXA's degron and ubiquitinated lysines couple NOXA stability to MCL-1 turnover.

    Evidence Structure-function mutagenesis of NOXA BH3, C-terminal targeting domain, and lysines with MCL-1 stability readouts; C-terminal degron transfer experiments

    PMID:24525728 PMID:24811167

    Open questions at the time
    • Mitochondrial E3 ligase for the recruited complex still unidentified
    • Relative roles of ubiquitin-dependent vs degron-mediated turnover incompletely separated
  8. 2020 High

    Identified MARCH5 (with UBE2K and MTCH2) as the E3 machinery that ubiquitinates MCL-1 specifically when engaged by NOXA, completing the NOXA→MCL-1 degradation circuit.

    Evidence Genome-wide CRISPR screen, MARCH5 genetic/pharmacological manipulation, MCL1/NOXA Co-IP and ubiquitination assays, replicated across three simultaneous papers

    PMID:32015503 PMID:32094511 PMID:32484436

    Open questions at the time
    • Structural basis for NOXA-dependent substrate recognition by MARCH5 not defined
    • Tissue-specific dependence on this axis unclear
  9. 2018 High

    Mapped a broad p53-independent transcriptional network (c-MYC, p73, FoxO3a, ATF3/ATF4, ERK/CREB, KLF4, MAL/MRTF-A) that funnels diverse stresses into NOXA induction.

    Evidence ChIP, promoter-reporter assays with element mutants, and gain/loss-of-function across multiple stress and cancer contexts

    PMID:15572378 PMID:16888645 PMID:18042711 PMID:22185759 PMID:26045051 PMID:29352505 PMID:33918002

    Open questions at the time
    • Combinatorial logic among these factors at the promoter not resolved
    • Most validations from single labs in specific cell types
  10. 2021 Medium

    Defined multilayered control of NOXA abundance through proteasomal degradation (CUL5/neddylation, multi-lysine ubiquitination, C-terminal degron), p62-mediated autophagy, JNK Ser13 phosphorylation, and microRNA repression.

    Evidence Ubiquitination and half-life assays, neddylation inhibition, lysine/degron mutants, phospho-mutant localization studies, and 3'UTR luciferase reporters

    PMID:20378569 PMID:22615771 PMID:24524772 PMID:24811167 PMID:25404713 PMID:25429623 PMID:29758299 PMID:33712558

    Open questions at the time
    • Relative quantitative contribution of proteasomal vs autophagic clearance unclear
    • How phosphorylation, ubiquitination, and degron use are coordinated unresolved
  11. 2010 High

    Extended NOXA function beyond apoptosis to physiological T-cell affinity selection and to autophagy regulation via MCL-1/Beclin-1 disruption.

    Evidence Pmaip1-/- mice in influenza infection with TCR affinity analysis; Co-IP and siRNA epistasis linking NOXA to Beclin-1-dependent autophagy

    PMID:20620942 PMID:21353614

    Open questions at the time
    • Molecular switch between pro-apoptotic and pro-autophagic NOXA outputs undefined
    • Physiological non-immune roles of NOXA largely uncharacterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NOXA's binding partner choice, subcellular localization, post-translational state, and degradation route are integrated to dictate apoptosis versus autophagy versus survival outcomes remains unresolved.
  • No structural model of the NOXA–MCL-1–MARCH5 substrate complex
  • Quantitative thresholds governing rheostat behavior in vivo not established
  • Integration of phosphorylation and degradation inputs into functional output undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140313 molecular sequestering activity 3
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 2
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 3
Partners
BCL2BCL2L1BECN1BIMMARCH5MCL1USP9X

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Noxa is a p53 transcriptional target encoding a BH3-only proapoptotic Bcl-2 family protein required for DNA damage-induced apoptosis; Noxa-deficient mice and MEFs show decreased apoptosis in response to DNA damage and oncogene-dependent stress, and Noxa loss combined with Bax loss further increases resistance, placing Noxa upstream of Bax in the intrinsic apoptotic pathway. Gene-targeted knockout mice (Noxa-/-), MEF apoptosis assays, in vivo irradiation model Genes & development High 12952892
2003 Noxa and Puma are critical BH3-only mediators of p53-dependent apoptosis induced by DNA damage; Noxa deficiency reduces DNA damage-induced apoptosis in fibroblasts but not lymphocytes, while Puma deficiency is broader, also protecting against p53-independent cytotoxic insults. Gene-targeted knockout mice (noxa-/- and puma-/-), apoptosis assays in fibroblasts and lymphocytes Science (New York, N.Y.) High 14500851
2003 The Noxa promoter responds directly to hypoxia via HIF-1alpha transcription factor binding, and Noxa mediates hypoxic cell death involving reactive oxygen species and cytochrome c release; antisense suppression of Noxa rescues cells from hypoxia-induced death and reduces infarction in an ischemia model. Promoter reporter assays, antisense oligonucleotide knockdown, cytochrome c release assay, in vivo ischemia model The Journal of experimental medicine Medium 14699081
2005 Proteasome inhibitors induce p53-independent transcriptional upregulation of NOXA mRNA and protein in melanoma and myeloma cells, and NOXA induction is required for mitochondrial apoptosis (cytochrome c, Smac, AIF release, caspase cascade); antisense knockdown of NOXA reduces apoptotic response by 30–50%. Antisense oligonucleotide knockdown, Western blot, cytochrome c/Smac/AIF release assays, caspase activation assays Cancer research Medium 16024630
2006 Noxa specifically interacts with the labile anti-apoptotic protein Mcl-1, and the Noxa/Mcl-1 axis functions as an apoptosis rheostat in dividing T cells under glucose limitation; Noxa knockdown protects from glucose deprivation-induced apoptosis while Mcl-1 knockdown sensitizes cells. siRNA knockdown, co-immunoprecipitation, apoptosis assays under glucose deprivation Immunity High 16782027
2006 FKHRL1/FoxO3a transcription factor directly induces Noxa (and Bim) expression, and RNAi knockdown of Noxa decreases FKHRL1-induced apoptosis in neuroblastoma cells; Bcl-2 overexpression (but not dominant-negative FADD) blocks this death, establishing Noxa as a downstream effector linking FKHRL1 to the mitochondrial apoptotic pathway. Tamoxifen-regulated transgene, RNAi knockdown, Bcl-2 overexpression, cytochrome c release assay Cell death and differentiation Medium 16888645
2007 In bortezomib-treated myeloma cells, Noxa is induced and forms increased Mcl-1L/Noxa complexes, disrupts Mcl-1/Bak complexes, and displaces Bim from Mcl-1, thereby activating Bax/Bak and inducing apoptosis; Mcl-1 cleavage also occurs alongside Noxa induction. Co-immunoprecipitation, Western blot, siRNA knockdown, caspase activation assays Cancer research High 17545623
2007 Noxa induction by proteasome inhibitors is directly dependent on the oncogene c-MYC; conserved MYC-binding sites in the NOXA promoter were validated by ChIP and reporter assays; c-MYC knockdown abrogated NOXA induction, and forced c-MYC expression in normal cells enabled NOXA accumulation and apoptosis in response to proteasome blockage. ChIP, promoter-reporter assay, siRNA knockdown, c-MYC overexpression Proceedings of the National Academy of Sciences of the United States of America High 18042711
2007 UVR-induced apoptosis in fibroblasts and skin keratinocytes proceeds via the Bcl-2-regulated (mitochondrial) pathway, with Noxa (a p53 target) playing the dominant initiating role; Noxa deficiency suppresses UVR-induced keratinocyte apoptosis in vivo and in primary MEFs, and in transformed cells where Puma is not induced, Noxa is the primary mediator. Noxa-/- knockout MEFs and mice, UV irradiation, TUNEL/apoptosis assays in skin The Journal of cell biology High 17283183
2006 Puma and Noxa differentially participate in dual p53-induced apoptotic pathways: in normal cells, Puma (but not Noxa) induces MOMP via a calcium/ER-dependent pathway; upon E1A oncoprotein expression, cells become susceptible to Noxa-mediated MOMP via an ER-independent pathway. Noxa-/-, Puma-/- MEFs, E1A expression, MOMP/cytochrome c assays, calcium chelation The EMBO journal High 17024184
2004 E1A expression induces Noxa in p53-deficient cancer cells in a TAp73-dependent manner; E1A activates the TAp73 promoter via E2F1-binding sites, and TAp73 then transcriptionally activates Noxa, establishing p73 as a p53-independent transcriptional activator of Noxa. Promoter-reporter assay, E1A mutant analysis, endogenous mRNA/protein detection, p53-deficient cell lines The Journal of biological chemistry Medium 15572378
2008 Bmi1 polycomb group protein directly binds the Noxa gene locus with accompanying H3K27 methylation, recruits other PcG products and Dnmt1, and promotes CpG methylation of the Noxa gene; Bmi1 loss increases Noxa expression leading to enhanced memory T cell death, and Noxa deletion rescues memory Th2 cell generation in Bmi1-/- mice. ChIP, CpG methylation analysis, Bmi1-/- and Noxa-/- genetic crosses, T cell survival assays The Journal of experimental medicine High 18411339
2010 Cisplatin-induced Noxa expression is ERK-dependent and p53-independent; ERK inhibition or siRNA-mediated Noxa ablation both attenuate cisplatin-induced cell death and permit clonogenic survival, establishing an ERK→Noxa axis as critical for platinum drug cytotoxicity. siRNA knockdown, ERK inhibitors, clonogenic survival assay, Western blot Oncogene Medium 20802529
2010 NOXA protein is ubiquitinated on at least three primary lysine residues and has a short half-life (~1–2 h) subject to proteasomal degradation; in CLL cells, bortezomib causes a rapid, transcription-independent increase in NOXA protein that precedes cytochrome c release and caspase activation. Western blot, siRNA knockdown, ubiquitination analysis, protein half-life measurement Haematologica Medium 20378569
2011 Noxa controls Mcl-1 ubiquitination and proteasomal degradation at the mitochondria by disrupting the USP9X/Mcl-1 interaction: Noxa overexpression decreases USP9X–Mcl-1 binding, increases Mcl-1 polyubiquitination, increases Mule–Mcl-1 interaction, and decreases Mule–USP9X complex, resulting in proteasomal Mcl-1 degradation. Noxa's degradative effect requires its exclusive mitochondrial localization. Co-immunoprecipitation, ubiquitination assay, subcellular fractionation, Noxa overexpression Biochemical and biophysical research communications Medium 21907705
2011 Full-length Noxa binds Mcl-1 with Kd ~3.4 nM, Bcl-xL with ~70 nM, and wild-type Bcl-2 with ~250 nM by surface plasmon resonance, demonstrating selectivity but not absolute specificity for Mcl-1; Noxa–Bcl-2 interaction is confirmed by co-pulldown from cells, and Bcl-2 overexpression reduces bortezomib-induced apoptosis. Surface plasmon resonance with recombinant proteins, co-immunoprecipitation, Bcl-2 overexpression/knockdown, apoptosis assays The Journal of biological chemistry High 21454712
2011 Oncogenic H-Ras induces Noxa expression, and Noxa displaces Mcl-1 from Beclin-1, enabling Beclin-1-dependent autophagy and autophagic cell death; Noxa or Beclin-1 silencing reduces Ras-induced autophagy and increases clonogenic survival. siRNA knockdown, co-immunoprecipitation (Noxa–Mcl-1, Mcl-1–Beclin-1), autophagy assays, clonogenic survival Molecular cell Medium 21353614
2011 In neuroblastoma cells, endogenous Noxa associates (by immunoprecipitation) with both Bcl-xL and Mcl-1; shRNA knockdown of Noxa significantly reduces bortezomib-induced apoptosis, while Bcl-xL (but not Mcl-1) overexpression prevents apoptosis, establishing that Noxa neutralizes Bcl-xL in neuronal cells. Co-immunoprecipitation, shRNA knockdown, overexpression of Bcl-xL vs Mcl-1, apoptosis assays The Journal of biological chemistry Medium 20051518
2010 During T cell activation, Noxa is induced and acts as a competitive selector during immune responses: Pmaip1-/- effector T cells display decreased antigen affinity and persistence of subdominant clones; Mcl-1 protein stability is controlled by TCR affinity-dependent IL-2 signaling, defining a Noxa/Mcl-1 axis that enforces affinity-based selection. Pmaip1-/- mice, influenza infection model, TCR affinity measurement, IL-2 signaling analysis Immunity High 20620942
2014 Noxa recruits MCL-1 from the cytosol to the mitochondria; Noxa mutations in the BH3 domain, C-terminal mitochondrial targeting domain, or ubiquitinated lysines alter both Noxa localization/stability and MCL-1 mitochondrial localization, phosphorylation, and ubiquitination, triggering proteasome-mediated MCL-1 degradation. Noxa mutant expression, subcellular fractionation, phosphorylation/ubiquitination analysis, MCL-1 stability assays Cell death & disease Medium 24525728
2014 The C-terminal tail of Noxa contains a degron mediating ubiquitylation-independent proteasomal degradation; this degron does not require Mcl-1 interaction for Noxa degradation, but mutation of the C-terminal tail stabilizes both Noxa and endogenous Mcl-1 through BH3-mediated direct interaction. Noxa C-terminal deletion/mutation constructs, proteasome inhibition, co-immunoprecipitation, protein half-life assays The Journal of biological chemistry High 24811167
2010 NF-κB is required for p53-mediated Noxa induction at the protein level (without affecting Noxa mRNA) and for p73-mediated induction of Noxa mRNA; in NF-κB-deficient MEFs, genotoxin treatment fails to induce p73 activation and Noxa mRNA, and cytochrome c release is compromised. p65-/- knockout MEFs, microarray, cytochrome c release assay, NF-κB inhibition Cell cycle (Georgetown, Tex.) / Aging Medium 20160496 20195489
2012 miR-200c directly represses Noxa expression by binding a target site in the Noxa 3'UTR, as validated by luciferase reporter assay; miR-200c overexpression reduces basal and proteasome-inhibitor-induced Noxa levels. Luciferase reporter assay with 3'UTR, miR-200c overexpression, RT-PCR, Western blot PloS one Medium 22615771
2014 miR-23a negatively regulates NOXA by binding its 3'UTR; heat shock reduces miR-23a levels, leading to NOXA mRNA accumulation and apoptosis; HSP70 protects cells by maintaining miR-23a stability, thereby suppressing NOXA expression. RT-qPCR, stable miR-23a overexpression/knockdown, apoptosis assays, miR-23a stability measurement Cell death & disease Medium 25429623
2014 NOXA protein is degraded by autophagy: p62 acts as autophagic cargo receptor for NOXA, and three C-terminal lysine residues of NOXA are required for its lysosomal degradation; autophagy inhibition increases NOXA protein levels and promotes apoptosis. Autophagy inhibitors, p62 knockdown, NOXA lysine mutants, protein half-life assays, apoptosis assays Biochimica et biophysica acta. Molecular cell research Medium 29758299
2015 Sall2 transcription factor directly binds conserved sites in the NOXA promoter (validated by EMSA and ChIP) and positively regulates Noxa expression; Sall2-/- MEFs show decreased Noxa induction and reduced apoptosis in response to doxorubicin even in the presence of functional p53. EMSA, ChIP, Sall2-/- MEFs, promoter-reporter assay, apoptosis assays Cell death & disease Medium 26181197
2015 MLN4924 (NAE inhibitor) causes c-Myc accumulation (as a CRL substrate), which transactivates the PMAIP1 gene encoding Noxa; c-Myc knockdown diminishes Noxa induction, and Noxa siRNA diminishes MLN4924-induced killing in AML; Noxa also neutralizes Mcl-1 to synergize with BCL2 inhibitors. siRNA knockdown of c-Myc and Noxa, Western blot, apoptosis assays, Bax/Bak activation Cell death and differentiation Medium 26045051
2018 ATF3 and ATF4 cooperatively bind the CRE element in the NOXA promoter and transcriptionally activate Noxa in a p53-independent manner; ERK1 is involved in cisplatin-induced ATF4 and Noxa induction; ATF3 or ATF4 knockdown reduces cisplatin-induced Noxa expression. Promoter-luciferase reporter assays, siRNA knockdown of ATF3/ATF4, Western blot, ChIP-like binding assays Molecular oncology Medium 29352505
2020 MARCH5 (mitochondria-associated E3 ubiquitin ligase) is the primary mediator of NOXA-dependent MCL1 degradation in prostate cancer cells; MARCH5 loss prevents Noxa-driven MCL1 ubiquitination and degradation, and MARCH5 inhibition sensitizes cells to BCLXL-targeting BH3 mimetics. MARCH5 knockdown/inhibition, ubiquitination assays, apoptosis assays, MCL1 stability measurement eLife High 32484436
2020 MARCH5 controls MCL1/NOXA complex levels during steady state and mitotic arrest; MARCH5 inhibition causes NOXA accumulation, sensitizes cancer cells to microtubule-targeting agents, and primes cells that undergo mitotic slippage to die in G1. The E2 enzyme UBE2K and mitochondrial outer membrane protein MTCH2 cooperate with MARCH5 to degrade MCL1 specifically when engaged by NOXA. Genome-wide CRISPR-Cas9 screen, MARCH5 inhibition, MCL1/NOXA co-IP, ubiquitination assays, mitotic arrest experiments Cell death and differentiation / Cell death and differentiation High 32015503 32094511
2021 Cullin-5 (CUL5) neddylation-mediated ubiquitination is responsible for NOXA proteasomal degradation in colorectal cancer; PRDX1 oligomers promote this by bridging UBE2F and CUL5 to enhance CUL5 neddylation; PRDX1 silencing reduces CUL5 neddylation and extends NOXA protein half-life. Ubiquitination assays, neddylation inhibition, PRDX1 knockdown, Co-IP of UBE2F/CUL5/PRDX1 tricomplex, NOXA half-life measurement Cell death & disease Medium 33712558
2020 5-Azacitidine induces NOXA transcription via the integrated stress response (ISR) pathway within hours, independent of DNA methylation; NOXA complexes with anti-apoptotic proteins to 'prime' AML cells for venetoclax-induced apoptosis; PMAIP1 CRISPR knockout abolishes venetoclax/5-Aza synergy. CRISPR-Cas9 PMAIP1 knockout, Western blot, qPCR, Co-IP, in vivo xenograft models Clinical cancer research High 32054729
2014 Pemetrexed increases Noxa expression through ATF4 and ATF3 upregulation; Noxa upregulation reduces USP9X availability to Mcl-1, promoting Mcl-1 ubiquitination and degradation, leading to apoptosis (Noxa-Usp9x-Mcl-1 axis); Noxa siRNA promotes Usp9x expression. siRNA knockdown of Noxa/ATF4/ATF3/Usp9x, Western blot, Co-IP, apoptosis assays Cell death & disease Medium 24991768
2014 NOXA mRNA is highly expressed but protein is rapidly degraded (T½ ~15–30 min) via ubiquitination and proteasomal degradation in mantle cell lymphoma cells; B-cell receptor signaling and cyclin D1 overexpression contribute to NOXA mRNA expression via PI3K/AKT/mTOR pathway. Protein half-life measurement, ubiquitination analysis, BCR signaling inhibitors, Western blot, mRNA analysis Cell death & disease Medium 24457957
2013 Noxa is phosphorylated at Ser13 by JNK in H. pylori-infected gastric epithelial cells, causing cytoplasmic retention of Noxa and impaired Mcl-1–Noxa interaction; JNK inhibition restores Mcl-1–Noxa interaction at mitochondria, and overexpression of non-phosphorylatable Noxa enhances mitochondrial apoptosis. In vitro binding assay, immunoprecipitation, confocal microscopy (subcellular localization), phospho-specific analysis, JNK inhibition, Noxa mutant expression FASEB journal Medium 25404713
2012 Myocardin-related transcription factor A (MAL/MRTF-A) directly transcriptionally induces Noxa/Pmaip1 expression via a CArG-like box in its promoter; MAL and SRF are recruited to the Noxa promoter upon G-actin-MAL-SRF pathway activation, and this is sensitive to latrunculin but p53-independent. ChIP, promoter-reporter assay with CArG-box mutants, latrunculin treatment, p53-depletion Cell cycle (Georgetown, Tex.) Medium 22185759
2010 Hydrogen peroxide induces Noxa protein accumulation via ATF4-dependent Noxa mRNA increase and simultaneous inhibition of Noxa protein degradation; Noxa silencing strongly suppresses H2O2-induced apoptosis, establishing Noxa as a crucial mediator of oxidative stress-induced mitochondrial apoptosis. siRNA knockdown, Western blot, mRNA analysis, Bcl-2 overexpression, Bax/Bak DKO cells FEBS letters Medium 20085765
2021 KLF4 transcription factor binds a specific UV-inducible CRE-like element in the NOXA promoter and mediates ERK-dependent, p53-independent NOXA transcriptional induction; KLF4 knockdown reduces NOXA expression in p53-mutated TNBC cells, and KLF4-inducing compound APTO-253 induces NOXA-mediated apoptosis. Promoter-reporter assay with defined element, KLF4 siRNA knockdown, ERK inhibition, APTO-253 compound treatment Genes Medium 33918002
2016 PHF8 histone demethylase promotes loss of repressive H3K9me2 mark from the PMAIP1 transcription start site and activates its transcription; PHF8 loss reduces apoptosis during early ESC differentiation; Pmaip1 knockdown mimics the PHF8-deficient phenotype (decreased apoptosis, promoted mesodermal/cardiac differentiation). PHF8 knockout, ChIP (H3K9me2 at PMAIP1 TSS), pmaip1 knockdown/overexpression, apoptosis and differentiation assays Stem cells (Dayton, Ohio) Medium 26866517
2022 RUNX1 inhibition reshapes the epigenetic landscape at the NOXA promoter with H3K27ac enrichment, leading to NOXA upregulation and NOXA-dependent cell death in PDAC; NOXA expression in PDAC marks a subtype with synthetic lethality to RUNX1 inhibition. Genome-wide CRISPR drug screen, NOXA isogenic KO cell lines, ChIP-seq for H3K27ac, RUNX1 gain/loss-of-function, patient-derived organoids Proceedings of the National Academy of Sciences of the United States of America Medium 35197278
2013 During oxidative stress, lysosomal membrane permeabilization (LMP) acts upstream of MOMP; LMP induces p53-dependent Noxa expression, and Noxa expression is required for MOMP and subsequent apoptosis; MOMP but not LMP is Noxa-dependent. Noxa siRNA, iron chelation, LMP assays, MOMP assay, p53 pathway analysis Free radical biology & medicine Medium 23770082
2008 Noxa (along with Bmf and Bim) is induced by arsenic trioxide in myeloma and shown by co-immunoprecipitation to bind Mcl-1, displacing Bak and Bim; Noxa silencing significantly protects myeloma cells from ATO-induced apoptosis; Noxa induction is enhanced by GSH depletion and inhibited by GSH elevation. Gene expression profiling, co-immunoprecipitation, siRNA knockdown, GSH manipulation Blood Medium 18354037
2014 Noxa upregulation in melanoma is driven by oncogenic BRAFV600E/MEK/ERK signaling via CREB transcription factor; Noxa promotes constitutive low-level autophagy via MEK/ERK and is required for autophagy-mediated delay of apoptosis under nutrient deprivation. BRAFV600E/MEK inhibitors, CREB reporter assay, Noxa siRNA, autophagy assays Oncotarget Medium 25365078

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science (New York, N.Y.) 1090 14500851
2011 Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival. Molecular cell 350 21353614
2003 Integral role of Noxa in p53-mediated apoptotic response. Genes & development 285 12952892
2005 Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer research 275 16024630
2008 Noxa: at the tip of the balance between life and death. Oncogene 234 19641509
2003 BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha. The Journal of experimental medicine 234 14699081
2007 Noxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple myeloma. Cancer research 212 17545623
2020 5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis. Clinical cancer research : an official journal of the American Association for Cancer Research 163 32054729
2006 The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells. Immunity 157 16782027
2007 Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition. Proceedings of the National Academy of Sciences of the United States of America 150 18042711
2006 FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells. Cell death and differentiation 142 16888645
2019 Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells. Cancer letters 131 30660647
2004 BOK and NOXA are essential mediators of p53-dependent apoptosis. The Journal of biological chemistry 123 15102863
2011 Modulation of NOXA and MCL-1 as a strategy for sensitizing melanoma cells to the BH3-mimetic ABT-737. Clinical cancer research : an official journal of the American Association for Cancer Research 95 22173547
2007 Ultraviolet radiation triggers apoptosis of fibroblasts and skin keratinocytes mainly via the BH3-only protein Noxa. The Journal of cell biology 93 17283183
2008 Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene. The Journal of experimental medicine 88 18411339
2014 Parthenolide induces apoptosis via TNFRSF10B and PMAIP1 pathways in human lung cancer cells. Journal of experimental & clinical cancer research : CR 87 24387758
2012 TRAIL and Noxa are selectively upregulated in prostate cancer cells downstream of the RIG-I/MAVS signaling pathway by nonreplicating Sendai virus particles. Clinical cancer research : an official journal of the American Association for Cancer Research 83 23014529
2011 Noxa controls Mule-dependent Mcl-1 ubiquitination through the regulation of the Mcl-1/USP9X interaction. Biochemical and biophysical research communications 83 21907705
2011 2-deoxyglucose induces Noxa-dependent apoptosis in alveolar rhabdomyosarcoma. Cancer research 83 21911456
2006 Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways. The EMBO journal 83 17024184
2015 MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors. Cell death and differentiation 82 26045051
2010 Apoptosis threshold set by Noxa and Mcl-1 after T cell activation regulates competitive selection of high-affinity clones. Immunity 81 20620942
2021 Puma, noxa, p53, and p63 differentially mediate stress pathway induced apoptosis. Cell death & disease 79 34193827
2011 Noxa/Bcl-2 protein interactions contribute to bortezomib resistance in human lymphoid cells. The Journal of biological chemistry 79 21454712
2010 Role of NOXA and its ubiquitination in proteasome inhibitor-induced apoptosis in chronic lymphocytic leukemia cells. Haematologica 73 20378569
2010 An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs. Oncogene 73 20802529
2017 Exploiting the pro-apoptotic function of NOXA as a therapeutic modality in cancer. Expert opinion on therapeutic targets 72 28670929
2004 E1A activates transcription of p73 and Noxa to induce apoptosis. The Journal of biological chemistry 72 15572378
2022 BH3-Only Proteins Noxa and Puma Are Key Regulators of Induced Apoptosis. Life (Basel, Switzerland) 68 35207544
2014 Noxa determines localization and stability of MCL-1 and consequently ABT-737 sensitivity in small cell lung cancer. Cell death & disease 67 24525728
2012 A review of the role of Puma, Noxa and Bim in the tumorigenesis, therapy and drug resistance of chronic lymphocytic leukemia. Cancer gene therapy 66 23175245
2014 Usp9x- and Noxa-mediated Mcl-1 downregulation contributes to pemetrexed-induced apoptosis in human non-small-cell lung cancer cells. Cell death & disease 65 24991768
2008 BH3-only proteins Noxa, Bmf, and Bim are necessary for arsenic trioxide-induced cell death in myeloma. Blood 65 18354037
2010 The anti-apoptotic protein BCL2L1/Bcl-xL is neutralized by pro-apoptotic PMAIP1/Noxa in neuroblastoma, thereby determining bortezomib sensitivity independent of prosurvival MCL1 expression. The Journal of biological chemistry 63 20051518
2018 p53-independent Noxa induction by cisplatin is regulated by ATF3/ATF4 in head and neck squamous cell carcinoma cells. Molecular oncology 56 29352505
2009 ABT-737 synergizes with chemotherapy to kill head and neck squamous cell carcinoma cells via a Noxa-mediated pathway. Molecular pharmacology 55 19246337
2022 Identification of NOXA as a pivotal regulator of resistance to CAR T-cell therapy in B-cell malignancies. Signal transduction and targeted therapy 53 35370290
2006 BH3-only proapoptotic Bcl-2 family members Noxa and Puma mediate neural precursor cell death. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 16822983
2018 Noxa: Role in Cancer Pathogenesis and Treatment. Current cancer drug targets 50 29521234
2005 Notch and NOXA-related pathways in melanoma cells. The journal of investigative dermatology. Symposium proceedings 50 16363061
2020 MARCH5 mediates NOXA-dependent MCL1 degradation driven by kinase inhibitors and integrated stress response activation. eLife 49 32484436
2018 Testosterone-Dependent miR-26a-5p and let-7g-5p Act as Signaling Mediators to Regulate Sperm Apoptosis via Targeting PTEN and PMAIP1. International journal of molecular sciences 48 29670053
2019 TFAP2C increases cell proliferation by downregulating GADD45B and PMAIP1 in non-small cell lung cancer cells. Biological research 47 31296259
2007 Role of Noxa in p53-independent fenretinide-induced apoptosis of neuroectodermal tumours. Apoptosis : an international journal on programmed cell death 46 17216584
2014 Discrepant NOXA (PMAIP1) transcript and NOXA protein levels: a potential Achilles' heel in mantle cell lymphoma. Cell death & disease 45 24457957
2018 NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death. Proceedings of the National Academy of Sciences of the United States of America 43 30404918
2020 Gambogenic acid induces Noxa-mediated apoptosis in colorectal cancer through ROS-dependent activation of IRE1α/JNK. Phytomedicine : international journal of phytotherapy and phytopharmacology 42 32854039
2010 ROS-mediated upregulation of Noxa overcomes chemoresistance in chronic lymphocytic leukemia. Oncogene 42 20935673
2014 Noxa and cancer therapy: Tuning up the mitochondrial death machinery in response to chemotherapy. Molecular & cellular oncology 41 27308315
2020 MARCH5-dependent degradation of MCL1/NOXA complexes defines susceptibility to antimitotic drug treatment. Cell death and differentiation 40 32015503
2020 Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression. Clinical cancer research : an official journal of the American Association for Cancer Research 40 33310890
2021 Cullin-5 neddylation-mediated NOXA degradation is enhanced by PRDX1 oligomers in colorectal cancer. Cell death & disease 39 33712558
2014 The carboxyl-terminal tail of Noxa protein regulates the stability of Noxa and Mcl-1. The Journal of biological chemistry 39 24811167
2014 Noxa upregulation by oncogenic activation of MEK/ERK through CREB promotes autophagy in human melanoma cells. Oncotarget 37 25365078
2020 MARCH5 requires MTCH2 to coordinate proteasomal turnover of the MCL1:NOXA complex. Cell death and differentiation 36 32094511
2020 Bim, Puma and Noxa upregulation by Naftopidil sensitizes ovarian cancer to the BH3-mimetic ABT-737 and the MEK inhibitor Trametinib. Cell death & disease 35 32424251
2010 p53-mediated induction of Noxa and p53AIP1 requires NFkappaB. Cell cycle (Georgetown, Tex.) 35 20160496
2022 Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia. Haematologica 34 33853293
2013 Noxa couples lysosomal membrane permeabilization and apoptosis during oxidative stress. Free radical biology & medicine 34 23770082
2009 Activation of p73 and induction of Noxa by DNA damage requires NF-kappa B. Aging 33 20195489
2009 Proapoptotic Noxa is required for particulate matter-induced cell death and lung inflammation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 19237507
2011 BH3-only protein Noxa regulates apoptosis in activated B cells and controls high-affinity antibody formation. Blood 31 22144184
2007 NOXA and PUMA expression add to clinical markers in predicting biochemical recurrence of prostate cancer patients in a survival tree model. Clinical cancer research : an official journal of the American Association for Cancer Research 31 18056181
2018 Repression of Noxa by Bmi1 contributes to deguelin-induced apoptosis in non-small cell lung cancer cells. Journal of cellular and molecular medicine 30 30255595
2022 NOXA expression drives synthetic lethality to RUNX1 inhibition in pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America 29 35197278
2012 D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis. Apoptosis : an international journal on programmed cell death 28 22843330
2022 Evodiamine inhibits ESCC by inducing M-phase cell-cycle arrest via CUL4A/p53/p21 axis and activating noxa-dependent intrinsic and DR4-dependent extrinsic apoptosis. Phytomedicine : international journal of phytotherapy and phytopharmacology 27 36265256
2019 Deubiquitylatinase inhibitor b-AP15 induces c-Myc-Noxa-mediated apoptosis in esophageal squamous cell carcinoma. Apoptosis : an international journal on programmed cell death 27 31342239
2018 Targeting the overexpressed USP7 inhibits esophageal squamous cell carcinoma cell growth by inducing NOXA-mediated apoptosis. Molecular carcinogenesis 27 30182448
2018 The Nedd8-activating enzyme inhibitor MLN4924 (TAK-924/Pevonedistat) induces apoptosis via c-Myc-Noxa axis in head and neck squamous cell carcinoma. Cell proliferation 27 30341788
2021 APR-246 induces apoptosis and enhances chemo-sensitivity via activation of ROS and TAp73-Noxa signal in oesophageal squamous cell cancer with TP53 missense mutation. British journal of cancer 26 34599296
2014 Regulation of Noxa-mediated apoptosis in Helicobacter pylori-infected gastric epithelial cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 25404713
2013 Vinblastine rapidly induces NOXA and acutely sensitizes primary chronic lymphocytic leukemia cells to ABT-737. Molecular cancer therapeutics 26 23723123
2012 MiR-200c regulates Noxa expression and sensitivity to proteasomal inhibitors. PloS one 26 22615771
2014 Zebrafish Noxa promotes mitosis in early embryonic development and regulates apoptosis in subsequent embryogenesis. Cell death and differentiation 25 24608793
2014 The elimination of miR-23a in heat-stressed cells promotes NOXA-induced cell death and is prevented by HSP70. Cell death & disease 25 25429623
2021 Krüppel-Like Factor 4 and Its Activator APTO-253 Induce NOXA-Mediated, p53-Independent Apoptosis in Triple-Negative Breast Cancer Cells. Genes 24 33918002
2017 Arenobufagin Induces Apoptotic Cell Death in Human Non-Small-Cell Lung Cancer Cells via the Noxa-Related Pathway. Molecules (Basel, Switzerland) 24 28892004
2022 Artesunate improves venetoclax plus cytarabine AML cell targeting by regulating the Noxa/Bim/Mcl-1/p-Chk1 axis. Cell death & disease 23 35443722
2018 Autophagy regulates apoptosis by targeting NOXA for degradation. Biochimica et biophysica acta. Molecular cell research 23 29758299
2012 Pro-apoptotic protein Noxa regulates memory T cell population size and protects against lethal immunopathology. Journal of immunology (Baltimore, Md. : 1950) 22 23277490
2010 Noxa mediates p18INK4c cell-cycle control of homeostasis in B cells and plasma cell precursors. Blood 22 21163929
2009 Repression of the BH3-only molecule PMAIP1/Noxa impairs glucocorticoid sensitivity of acute lymphoblastic leukemia cells. Apoptosis : an international journal on programmed cell death 22 19421859
2022 Pituitary adenomas evade apoptosis via noxa deregulation in Cushing's disease. Cell reports 21 36001971
2020 Aspirin Induced Glioma Apoptosis through Noxa Upregulation. International journal of molecular sciences 21 32545774
2015 Sall2 is required for proapoptotic Noxa expression and genotoxic stress-induced apoptosis by doxorubicin. Cell death & disease 21 26181197
2012 NOXA as critical mediator for drug combinations in polychemotherapy. Cell death & disease 21 22717582
2021 LiCl induces apoptosis via CHOP/NOXA/Mcl-1 axis in human choroidal melanoma cells. Cancer cell international 20 33557839
2019 Targeting sphingosine kinase 2 suppresses cell growth and synergizes with BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation in cholangiocarcinoma. American journal of cancer research 20 30949409
2021 NOXA-mediated degradation of MCL1 and BCL2L1 causes apoptosis of daunorubicin-treated human acute myeloid leukemia cells. Journal of cellular physiology 19 33982799
2019 Combination of fenretinide and ABT-263 induces apoptosis through NOXA for head and neck squamous cell carcinoma treatment. PloS one 19 31276572
2016 Plant Homeo Domain Finger Protein 8 Regulates Mesodermal and Cardiac Differentiation of Embryonic Stem Cells Through Mediating the Histone Demethylation of pmaip1. Stem cells (Dayton, Ohio) 19 26866517
2010 Noxa is necessary for hydrogen peroxide-induced caspase-dependent cell death. FEBS letters 19 20085765
2008 The PMAIP1 gene on chromosome 18 is a candidate tumor suppressor gene in human pancreatic cancer. Digestive diseases and sciences 19 18231856
2021 The BH3-only protein NOXA serves as an independent predictor of breast cancer patient survival and defines susceptibility to microtubule targeting agents. Cell death & disease 18 34903710
2016 Arsenic trioxide induces Noxa-dependent apoptosis in rhabdomyosarcoma cells and synergizes with antimicrotubule drugs. Cancer letters 18 27521572
2012 Myocardin-related transcription factor A regulates expression of Bok and Noxa and is involved in apoptotic signalling. Cell cycle (Georgetown, Tex.) 18 22185759
2012 NOXA-induced alterations in the Bax/Smac axis enhance sensitivity of ovarian cancer cells to cisplatin. PloS one 18 22590594
2023 NOXA expression is downregulated in human breast cancer undergoing incomplete pathological response and senescence after neoadjuvant chemotherapy. Scientific reports 17 37741850

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