Affinage

BBC3

Bcl-2-binding component 3, isoforms 1/2 · UniProt Q9BXH1

Length
193 aa
Mass
20.5 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BBC3 (PUMA) is a BH3-only member of the Bcl-2 family that serves as a central integrator of pro-apoptotic signaling, coupling diverse stress inputs to mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, and caspase activation. PUMA is transcriptionally induced by p53, p73, E2F-1, FOXO3a, Sp1, and AP-1/CHOP complexes in response to DNA damage, ER stress, metabolic deprivation, and lipotoxic signals, while its basal expression is restrained by CTCF-Cohesin occupancy at its locus and HDAC3-mediated promoter repression (PMID:11463392, PMID:14634023, PMID:20478995, PMID:22763818, PMID:19638343). An intrinsically disordered protein in isolation, PUMA folds into an alpha-helix upon binding anti-apoptotic Bcl-2 proteins (Bcl-xL, Mcl-1) to neutralize them and also directly activates Bax and Bak (KD ~26 nM for Bak) to trigger MOMP; its stability is regulated by IKK-mediated Ser10 phosphorylation, which directs proteasomal or chaperone-mediated autophagic degradation depending on context (PMID:24654952, PMID:24265320, PMID:19917256, PMID:21997190, PMID:26212789). Beyond classical apoptosis, PUMA couples nuclear p53 transcriptional activity to cytoplasmic p53 mitochondrial function by displacing p53 from Bcl-xL, amplifies necroptosis through mitochondrial DNA release and STING/DAI activation, and promotes angiogenesis via ERK and calcium signaling (PMID:16151013, PMID:29581256, PMID:23122957).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2001 High

    The identity of PUMA as a p53-induced BH3-only apoptotic effector was established, resolving how p53 engages the mitochondrial death pathway through a dedicated transcriptional target that binds Bcl-2, localizes to mitochondria, and triggers cytochrome c release.

    Evidence Transfection, co-IP with Bcl-2, subcellular fractionation, antisense inhibition of PUMA in p53-expressing cells

    PMID:11463392

    Open questions at the time
    • Direct binding to pro-apoptotic effectors Bax/Bak not yet tested
    • Transcription factors other than p53 not examined
    • Physiological confirmation in knockout animals lacking
  2. 2003 High

    Genetic ablation in mice demonstrated that PUMA is essential for p53-dependent apoptosis in lymphocytes and fibroblasts and also mediates p53-independent death from cytokine deprivation and other stimuli, establishing PUMA as a broadly required apoptotic effector beyond genotoxic stress.

    Evidence Puma knockout mice, apoptosis assays across lymphocytes, fibroblasts, and multiple stimuli (cytokine withdrawal, glucocorticoids, staurosporine)

    PMID:14500851

    Open questions at the time
    • Mechanism of p53-independent induction not identified
    • Redundancy with Bim and Noxa not quantified
  3. 2003 High

    PUMA was placed downstream of p73, revealing that the p53 family member p73 transactivates PUMA to cause Bax mitochondrial translocation, broadening the upstream regulatory network beyond p53 itself.

    Evidence p73 isoform overexpression, immunofluorescence showing p73 remains nuclear while Bax translocates, reporter assays

    PMID:14634023

    Open questions at the time
    • Endogenous p73 ChIP on PUMA promoter not shown
    • Relative contribution of p73 vs. p53 in physiological contexts unclear
  4. 2004 High

    The requirement for p53's first activation domain (ADI) for PUMA induction was established, defining the structural basis for selective p53 target gene regulation and showing that PUMA upregulation alone suffices to kill neurons.

    Evidence Adenoviral delivery and p53 knock-in mutations in mouse neurons, apoptosis assays

    PMID:15525786

    Open questions at the time
    • Cofactors mediating ADI-specific PUMA transactivation not identified
  5. 2005 High

    A dual-function model was revealed in which PUMA couples nuclear and cytoplasmic p53 apoptotic activities: nuclear p53 induces PUMA, which then displaces cytoplasmic p53 from Bcl-xL sequestration to enable direct mitochondrial permeabilization by p53.

    Evidence Bcl-xL mutagenesis separating p53- and PUMA-binding, co-IP, cell-free mitochondrial permeabilization

    PMID:16151013

    Open questions at the time
    • Stoichiometric requirements for p53 displacement not quantified
    • Relevance in cell types lacking cytoplasmic p53 pools unknown
  6. 2006 High

    PUMA was shown to induce MOMP in normal cells through a calcium-dependent mechanism involving ER calcium release, distinguishing it from Noxa which requires oncogene sensitization, and PUMA was identified as a p53-independent mediator of ischemia-reperfusion-induced intestinal apoptosis via oxidative stress.

    Evidence Mouse embryonic fibroblasts, calcium measurements, MOMP assays; mesenteric artery occlusion in Puma-KO and p53-KO mice

    PMID:17024184 PMID:17127703

    Open questions at the time
    • Identity of the p53-independent transcription factor for PUMA in I/R not determined
    • Calcium release mechanism not molecularly defined
  7. 2008 High

    Multiple p53-independent transcriptional inputs converging on PUMA were defined: E2F-1 activates the PUMA promoter through six binding sites; Sp1 and p73 cooperatively induce PUMA upon serum starvation; and PUMA is essential for radiation-induced apoptosis in intestinal stem/progenitor cells in vivo.

    Evidence Luciferase reporters with E2F-1 sites, PUMA-/- HCT116 cells; ChIP for Sp1, p73 knockdown; Puma-KO mice with whole-body irradiation and antisense oligonucleotide radioprotection

    PMID:17263886 PMID:18522850 PMID:18579560

    Open questions at the time
    • Hierarchy among multiple transcription factors at PUMA promoter not established
    • Chromatin state requirements for each factor not characterized
  8. 2008 High

    PUMA was shown to primarily function by sequestering anti-apoptotic Bcl-xL and Mcl-1 (not by directly binding Bax or Bak) in the context of IL-3 withdrawal-induced myeloid cell apoptosis, supporting a de-repression model.

    Evidence Inducible expression, reciprocal co-IP in knockout cell lines, colony formation

    PMID:19079139

    Open questions at the time
    • Whether PUMA can also directly activate Bax/Bak remained contested at this stage
  9. 2009 High

    PUMA was reclassified from a purely indirect (sensitizer/de-repressor) BH3-only protein to a bona fide direct activator of BAX, shown to expose BAX alpha1 helix and drive oligomerization, resolving a central debate about PUMA's mechanism of action.

    Evidence Structural analysis, mutagenesis, cell-free reconstitution, Bim/Puma double-KO MEFs

    PMID:19917256

    Open questions at the time
    • Binding affinity to Bax not quantified at this point
    • In vivo confirmation of direct activation model pending
  10. 2009 High

    The JNK1/AP-1 pathway was identified as a p53-independent transcriptional inducer of PUMA during hepatocyte lipoapoptosis, with subsequent demonstration that CHOP heterodimerizes with phospho-c-Jun to bind the PUMA promoter AP-1 site.

    Evidence EMSA, ChIP, dominant-negative c-Jun, Puma-KO hepatocytes; CHOP:p-c-Jun co-IP and promoter reporter assays

    PMID:19638343 PMID:20430872

    Open questions at the time
    • Whether CHOP:c-Jun complex represents a general ER stress mechanism beyond hepatocytes unknown
  11. 2010 High

    Epigenetic and metabolic control of PUMA expression was revealed: CTCF-Cohesin complexes repress PUMA basally through intragenic chromatin boundaries, and Akt-glucose metabolism axis controls PUMA protein stability, with PUMA being rapidly stabilized under nutrient deprivation.

    Evidence ChIP for CTCF/Cohesin, histone modifications, CTCF knockdown; glucose deprivation, Akt activation, Puma-KO cells, protein stability assays

    PMID:20478995 PMID:21159778

    Open questions at the time
    • E3 ligase mediating nutrient-dependent PUMA degradation not identified
    • Mechanism linking CTCF occupancy to transcriptional repression at PUMA not fully defined
  12. 2011 High

    Post-translational regulation of PUMA was defined: IKK complex phosphorylates PUMA at Ser10, targeting it for proteasomal degradation, establishing a survival signaling mechanism that directly destabilizes PUMA protein to suppress apoptosis.

    Evidence Site-directed mutagenesis of Ser10, proteasome inhibition, IKK identification by siRNA screen, co-IP with Bcl-2 family

    PMID:21997190

    Open questions at the time
    • Specific E3 ubiquitin ligase for phospho-PUMA not identified
    • Physiological contexts where IKK-PUMA axis is dominant not delineated
  13. 2011 High

    Functional cooperation and partial redundancy between Puma and Bim was quantified: combined loss phenocopies Bax/Bak deficiency in mast cells, but Puma alone can activate Bax in the absence of Bim, Bid, and p53 when anti-apoptotic proteins are neutralized by ABT-737.

    Evidence Double-KO mouse models, primary mast cells, BH3 mimetic ABT-737, cytochrome c release

    PMID:22015606

    Open questions at the time
    • Tissue-specific hierarchy between Puma and Bim not comprehensively mapped
  14. 2013 High

    Direct activation of Bak by PUMA was quantitatively confirmed with high-affinity binding (KD ~26 nM), and structure-function mutagenesis showed that mutations altering BH3-Bak binding produced corresponding changes in oligomerization and killing, firmly establishing PUMA as a dual-function BH3-only protein.

    Evidence Surface plasmon resonance, cross-linking, liposome and mitochondrial permeabilization, site-directed mutagenesis

    PMID:24265320

    Open questions at the time
    • Full-length PUMA-Bak structural complex not resolved
    • Relative contributions of direct activation vs. de-repression in vivo not quantified
  15. 2013 High

    PUMA was revealed to be an intrinsically disordered protein that undergoes coupled folding-and-binding upon engaging MCL-1, with systematic proline scanning showing that residual helical structure in the unbound state is dispensable for association kinetics.

    Evidence Stopped-flow kinetics, proline-scanning mutagenesis, binding assays with MCL-1

    PMID:24654952

    Open questions at the time
    • Whether disorder-to-order transition applies equally to all anti-apoptotic partners not tested
    • Structural basis of selectivity among binding partners not resolved
  16. 2014 High

    Upstream signaling cascades controlling PUMA were extended: p38α phosphorylates Tip60 at T158, enabling p53-K120 acetylation and PUMA promoter binding; FOXO3a was identified as a p53-independent PUMA inducer downstream of ERβ; and Keap1 degradation via p62-autophagy feeds into JNK1-dependent PUMA upregulation during lipoapoptosis.

    Evidence Kinase assays, mutagenesis, ChIP for p53-K120ac; ERβ-KO mice, FOXO3a siRNA; Keap1-KO mice, primary hepatocytes

    PMID:24077289 PMID:24769730 PMID:25544752

    Open questions at the time
    • Integration and hierarchy of multiple signaling pathways converging on PUMA not modeled quantitatively
  17. 2014 High

    Physiological roles of PUMA in germ cell homeostasis were established: PUMA limits the initial ovarian reserve by eliminating migrating germ cells, and Slug (SNAI2) represses PUMA to promote carcinoma cell survival during metastatic colonization.

    Evidence Bbc3-KO mice with germ cell counts at multiple timepoints; Slug knockdown/rescue with PUMA RNAi, lung metastasis assays

    PMID:24830722 PMID:24859845

    Open questions at the time
    • Transcription factor mediating PUMA in developmental germ cell death not identified
    • Slug-PUMA axis in human metastasis not confirmed
  18. 2015 High

    A second degradation pathway for PUMA was identified: chaperone-mediated autophagy (CMA) via HSPA8/HSC70 targets PUMA to lysosomes, and paradoxically, IKKβ-mediated Ser10 phosphorylation in the context of TNF signaling stabilizes PUMA by blocking CMA, promoting mitochondrial translocation and apoptosis—revealing context-dependent outcomes of the same phosphorylation event.

    Evidence Co-IP with HSC70, lysosome fractionation, CMA inhibition, Ser10 mutagenesis, TNF treatment, subcellular fractionation

    PMID:26212789

    Open questions at the time
    • How cells resolve the opposing effects of Ser10 phosphorylation (proteasomal degradation vs. CMA stabilization) remains unclear
    • LAMP-2A involvement not directly tested
  19. 2016 High

    Genetic elimination of Bid, Bim, and Puma in HCT116 cells showed that their direct activator functions are dispensable for Bax/Bak activation once anti-apoptotic proteins are neutralized, placing limits on the essentiality of direct activation in certain contexts.

    Evidence CRISPR/TALEN quintuple and hexuple KO HCT116 cells, BH3 mimetics, GFP-Bax reconstitution

    PMID:27310874

    Open questions at the time
    • Whether this applies beyond HCT116 cells and pharmacological neutralization is unclear
    • Identity of residual Bax/Bak activator(s) not determined
  20. 2018 High

    PUMA was linked to non-apoptotic cell death: PUMA amplifies necroptosis by promoting mitochondrial DNA release and activating STING/DAI sensors in a positive feedback loop with RIP3/MLKL, and PUMA deletion partially rescues FADD-deficient embryonic lethality. Separately, PUMA was shown to be essential for chemotherapy-induced primordial follicle depletion, with complete fertility preservation in Puma-null mice.

    Evidence Necroptosis induction, mtDNA measurement, STING/DAI activation, FADD-KO embryo rescue; Puma-KO mice treated with cyclophosphamide/cisplatin, follicle counts, fertility assays

    PMID:29581256 PMID:29795269

    Open questions at the time
    • Mechanism by which PUMA promotes mtDNA release not molecularly defined
    • Whether PUMA's necroptotic role operates independently of its Bcl-2 binding activity unknown
  21. 2021 High

    Cross-species validation in zebrafish null alleles confirmed PUMA as the essential mediator of p53-dependent genotoxic apoptosis and revealed p63 (not p53) as the upstream regulator of PUMA in ER stress-induced apoptosis, delineating stress-specific p53 family member usage.

    Evidence CRISPR knockout of puma, noxa, p53, p63, p73, mdm2 in zebrafish; genotoxic, ER, and oxidative stress assays

    PMID:34193827

    Open questions at the time
    • Whether p63-dependent PUMA induction during ER stress is conserved in mammals not confirmed
    • Partial rescue of mdm2-null by puma-null suggests additional p53 effectors remain unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of full-length PUMA complexes with Bax, Bak, and anti-apoptotic Bcl-2 proteins; the E3 ligase(s) mediating phospho-PUMA proteasomal degradation; how the same Ser10 phosphorylation event produces opposing stability outcomes in different signaling contexts; and the quantitative contribution of direct Bax/Bak activation versus de-repression of anti-apoptotic proteins in physiological tissues.
  • No full-length PUMA co-crystal structure with any partner
  • E3 ligase for PUMA ubiquitination unidentified
  • Context-dependent Ser10 phosphorylation outcome not mechanistically resolved
  • Relative in vivo contribution of direct activation vs. de-repression unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008289 lipid binding 3
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 7 R-HSA-74160 Gene expression (Transcription) 7 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-168256 Immune System 1
Partners
BAK1BAXBCL2BCL2L1HSPA8IKBKBMCL1TP53

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 PUMA (BBC3) is a direct transcriptional target of p53; PUMA-alpha and PUMA-beta proteins contain BH3 domains, bind Bcl-2, localize to mitochondria, induce cytochrome c release, and activate apoptosis via the cytochrome c/Apaf-1-dependent pathway. Antisense inhibition of PUMA reduced p53-induced apoptotic response. Transient transfection, antisense inhibition, co-immunoprecipitation, subcellular fractionation, cytochrome c release assay Molecular cell High 11463392
2003 PUMA (Bbc3) knockout mice show decreased DNA damage-induced apoptosis in fibroblasts and complete protection of lymphocytes from p53-dependent cell death; Puma also mediates p53-independent apoptosis in response to cytokine deprivation, glucocorticoids, staurosporine, and phorbol ester. Gene knockout mouse model, apoptosis assays across multiple cell types and stimuli Science (New York, N.Y.) High 14500851
2005 PUMA couples nuclear and cytoplasmic p53 apoptotic functions: nuclear p53 induces PUMA expression, which then displaces cytoplasmic p53 from its sequestration by Bcl-xL, allowing cytoplasmic p53 to directly permeabilize mitochondria. A Bcl-xL mutant that binds p53 but not PUMA rendered cells resistant to p53-induced apoptosis regardless of PUMA expression. Co-immunoprecipitation, mutagenesis of Bcl-xL, cell-free mitochondrial permeabilization assay, genotoxic stress experiments Science (New York, N.Y.) High 16151013
2003 p73 induces apoptosis by transactivating PUMA, which in turn causes Bax mitochondrial translocation and cytochrome c release; p73 remains nuclear during apoptosis, indicating the effect on Bax translocation is indirect via PUMA. DeltaNp73 isoforms act as dominant negatives to repress the PUMA/Bax system. Overexpression of p73 isoforms, immunofluorescence, mitochondrial fractionation, reporter assays, kinetics analysis The Journal of biological chemistry High 14634023
2009 PUMA directly activates BAX through a stepwise mechanism: activator BH3s (tBID/BIM/PUMA) attack and expose the alpha1 helix of BAX, leading to disengagement of the alpha9 helix, mitochondrial insertion, and homo-oligomerization. Activator BH3s remain associated with N-terminally exposed BAX through the BH1 domain to drive oligomerization. Bim/Puma deficiency impedes ER stress-induced BAX/BAK activation. Structural analysis, mutagenesis, cell-free reconstitution, double-knockout mouse embryonic fibroblasts Molecular cell High 19917256
2008 PUMA is induced in intestinal progenitor/stem cells in a p53-dependent manner following radiation and mediates apoptosis via the mitochondrial pathway. PUMA-deficient mice show blocked apoptosis in intestinal progenitor/stem cells, enhanced crypt regeneration, and prolonged survival after lethal radiation doses. Antisense oligonucleotide suppression of PUMA provided significant intestinal radioprotection. PUMA knockout mouse model, histology, apoptosis assays, antisense oligonucleotide treatment, irradiation Cell stem cell High 18522850
2009 PUMA cooperates with direct activator BH3-only proteins (tBID, BIM) to promote mitochondrial outer membrane permeabilization (MOMP) through two mechanisms: de-repression (binding anti-apoptotic Bcl-2 proteins to free activators) and sensitization. Cell-free MOMP assay, co-immunoprecipitation, liposome permeabilization assay Cell cycle (Georgetown, Tex.) Medium 19652530
2009 JNK1-dependent phosphorylation of c-Jun and binding of an AP-1 complex to the PUMA promoter mediates PUMA transcriptional induction during hepatocyte lipoapoptosis caused by saturated free fatty acids (palmitate). PUMA knockdown or Puma knockout attenuated Bax activation, caspase activity, and cell death. EMSA, chromatin immunoprecipitation, dominant-negative c-Jun, shRNA knockdown, Puma-deficient primary hepatocytes, qPCR The Journal of biological chemistry High 19638343
2010 CHOP and AP-1 (c-Jun) cooperatively mediate PUMA induction during hepatocyte lipoapoptosis: CHOP physically interacts with phosphorylated c-Jun upon palmitate treatment, and the CHOP:p-c-Jun heteromeric complex binds to the AP-1 consensus sequence in the PUMA promoter. No functional CHOP binding sites were identified in the PUMA promoter directly. ChIP, co-immunoprecipitation, promoter reporter assay, shRNA knockdown American journal of physiology. Gastrointestinal and liver physiology High 20430872
2006 p53-independent induction of PUMA mediates intestinal apoptosis in response to ischemia-reperfusion (I/R) through the mitochondrial pathway, involving cytochrome c release, caspase-3 activation, Bax mitochondrial translocation, and Bak multimerization. Oxidative/nitrosative stress (blocked by SOD and L-NAME) mediates PUMA induction in I/R. Superior mesenteric artery occlusion mouse model, PUMA and p53 knockout mice, caspase assays, cytochrome c release, immunofluorescence Gut High 17127703
2004 The first transactivation domain (ADI) of p53 is required for PUMA induction and neuronal cell death, whereas Noxa can be induced by either p53 activation domain. PUMA upregulation alone is sufficient to induce neuronal cell death. Adenoviral gene delivery, knock-in mutation of p53 in mice, apoptosis assays in neurons The Journal of neuroscience : the official journal of the Society for Neuroscience High 15525786
2006 Puma and Noxa differentially regulate p53-mediated apoptosis: Puma induces mitochondrial outer membrane permeabilization (MOMP) in normal cells, involving a pathway that includes calcium release from the endoplasmic reticulum and subsequent caspase activation, whereas Noxa-induced MOMP requires E1A oncogene sensitization. Mouse embryonic fibroblasts, MOMP assays, calcium measurements, gene deletion studies The EMBO journal High 17024184
2008 Puma is required for apoptosis induced by IL-3 withdrawal in myeloid cells. Puma co-immunoprecipitates with anti-apoptotic Bcl-xL and Mcl-1 but not with Bax or Bak, indicating Puma functions primarily by binding and inactivating anti-apoptotic Bcl-2 family members to indirectly activate Bax. Inducible expression, co-immunoprecipitation, knockout cell lines, colony formation assay Cell death and differentiation High 19079139
2011 PUMA and p21 cooperate in mediating p53-dependent radiation response in intestinal epithelium: PUMA deficiency blocks apoptosis and enhances crypt regeneration and survival, but does not rescue the shortened survival caused by p21 deficiency, which leads to aberrant cell-cycle progression, persistent DNA damage, and nonapoptotic crypt death. p53 KO, PUMA KO, p21 KO, double-KO mouse models, whole-body irradiation, histology, DNA damage markers Molecular cancer research : MCR High 21450905
2011 PUMA protein is phosphorylated at serine 10 by the IKK1/IKK2/Nemo kinase complex in response to serum or IL-3 stimulation. Ser10 phosphorylation targets PUMA for proteasomal degradation, reducing its stability, thereby preventing apoptosis. Phosphorylated PUMA retains the ability to co-immunoprecipitate with anti-apoptotic Bcl-2 family members. Co-immunoprecipitation, site-directed mutagenesis, proteasome inhibition, kinase identification by siRNA screen, IL-3 stimulation Cell death and differentiation High 21997190
2015 PUMA is a bona fide substrate of chaperone-mediated autophagy (CMA): PUMA associates with HSPA8/HSC70 leading to lysosomal translocation and degradation. IKKβ-mediated phosphorylation of PUMA at Ser10 upon TNF treatment stabilizes PUMA by blocking CMA degradation and facilitates PUMA translocation from cytosol to mitochondria, potentiating TNF-induced apoptotic cell death. Co-immunoprecipitation, lysosome fractionation, CMA inhibition, site-directed mutagenesis (Ser10), subcellular fractionation, TNF treatment Autophagy High 26212789
2013 PUMA BH3 domain binds purified Bak with high affinity (KD = 26 ± 5 nM by surface plasmon resonance), leads to Bak homo-oligomerization and membrane permeabilization. Mutations that inhibit or enhance Puma BH3-Bak binding produce corresponding alterations in Bak oligomerization, membrane permeabilization, and Bak-mediated killing in cells, establishing PUMA as a direct Bak activator. Surface plasmon resonance, cross-linking immunoblot, liposome permeabilization, mitochondrial permeabilization, site-directed mutagenesis, cell viability The Journal of biological chemistry High 24265320
2011 Puma and Bim cooperate to cause bone marrow and gastrointestinal tract toxicity from chemo/radiation therapy. Loss of both Puma and Bim provides complete protection in primary mast cells from cytokine starvation and DNA damage, similar to Bax/Bak double knockout. ABT-737 demonstrates Puma is sufficient to activate Bax even without Bim, Bid, and p53. Double-KO mouse models, primary mast cells, BH3 mimetic (ABT-737), Bax activation assays, cytochrome c release Cell death and differentiation High 22015606
2013 PUMA (BBC3) is an intrinsically disordered protein (IDP) in isolation that folds into a single contiguous alpha-helix upon binding MCL-1. Systematic introduction of helix-breaking proline mutations throughout unbound PUMA showed that association rate constants to MCL-1 were largely unaffected, indicating that specific residual helical structure is not required for the coupled folding-and-binding mechanism. Time-resolved stopped-flow kinetics, proline-scanning mutagenesis, binding assays Journal of the American Chemical Society High 24654952
2018 PUMA amplifies necroptosis signaling: following RIP3/MLKL-dependent necroptosis, PUMA is transcriptionally activated via autocrine TNF-α and NF-κB. Induced PUMA promotes cytosolic release of mitochondrial DNA and activation of DNA sensors DAI/Zbp1 and STING, leading to enhanced RIP3 and MLKL phosphorylation in a positive feedback loop. PUMA deletion partially rescues necroptosis-mediated developmental defects in FADD-deficient embryos. RIP3/MLKL-dependent necroptosis induction, PUMA knockout, mtDNA measurement, STING/DAI activation assays, MLKL/RIP3 phosphorylation, FADD-deficient embryo rescue Proceedings of the National Academy of Sciences of the United States of America High 29581256
2008 Sp1 and p73 cooperatively activate PUMA transcription in a p53-independent manner following serum starvation in p53-deficient cells. Sp1 binding to the PUMA promoter increased upon serum starvation; p73 was upregulated and mediated PUMA induction through p53-binding sites. The PI3K/AKT pathway inhibits this induction. ChIP, promoter reporter assays, Sp1 inhibition, p73 knockdown, PI3K inhibition Carcinogenesis High 18579560
2010 CTCF and the Cohesin complex occupy intragenic chromatin boundaries within the PUMA locus and act as gene-specific repressors. CTCF knockdown leads to increased basal PUMA expression without p53 activation, indicating CTCF dampens the p53 apoptotic response in a gene-specific manner independent of other p53 targets. Chromatin immunoprecipitation, histone modification analysis, CTCF siRNA knockdown, RNA polymerase II ChIP Genes & development High 20478995
2013 ERβ induces apoptosis in prostate cancer cells by increasing FOXO3a transcription (mRNA and total protein levels elevated), which in turn increases PUMA expression through a p53-independent mechanism. Knockdown of FOXO3a or ERβ abolished PUMA induction, and ERβ-/- mouse ventral prostate had decreased FOXO3a and PUMA expression. siRNA knockdown, ERβ knockout mouse model, Western blot, qPCR, caspase-9 activation assay Oncogene High 24077289
2014 Slug (SNAI2) directly represses PUMA (Bbc3) expression to promote carcinoma cell survival during metastasis. Slug knockdown increased PUMA expression and decreased lung colonization; inhibition of PUMA by RNAi in Slug-knockdown cells rescued lung colonization; PUMA overexpression in control tumor cells suppressed lung metastasis. shRNA knockdown of Slug, PUMA RNAi, PUMA overexpression, lung metastasis colonization assay, apoptosis assays Cancer research High 24830722
2012 PUMA plays a proangiogenic role in vascular and microglia cell proliferation and survival by regulating autophagy through modulation of ERK activation and intracellular calcium levels. Puma deficiency inhibited developmental and pathological angiogenesis; Puma gene delivery increased angiogenesis and cell survival. Puma genetic deletion, shRNA knockdown, Puma gene delivery, ERK and calcium measurements, autophagy assays, in vivo angiogenesis models Cell reports Medium 23122957
2012 HDAC3 binds to the PUMA promoter to repress its expression in gastric cancer cells. HDAC3 knockdown but not other HDACs upregulated PUMA expression; HDAC3 knockdown also promoted interaction of p53 with the PUMA promoter. TSA (pan-HDAC inhibitor) promoted PUMA expression through p53 stabilization in addition to HDAC3 inhibition. ChIP, HDAC3 siRNA knockdown, promoter binding assays, Western blot Journal of molecular medicine (Berlin, Germany) Medium 22763818
2014 p38α phosphorylates Tip60 at T158, which in turn acetylates p53 at K120, enabling p53 binding to the PUMA promoter, PUMA expression, and apoptosis following DNA damage. Tip60-T158A mutant fails to mediate p53-K120 acetylation, PUMA induction, and apoptosis. DNA damage induces p38 activation, Tip60-T158 phosphorylation, and p53-K120 acetylation with similar kinetics. Site-directed mutagenesis, ChIP, co-immunoprecipitation, kinase assay, apoptosis assays Oncotarget High 25544752
2010 Akt-mediated suppression of PUMA requires glucose metabolism; PUMA is uniquely sensitive to metabolic status and is rapidly upregulated in glucose-deficient conditions. Metabolic regulation of PUMA is mediated through combined p53-dependent transcriptional induction and control of PUMA protein stability (PUMA is degraded in nutrient-replete conditions and is long-lived in nutrient deficiency). Puma deficiency protected cells from glucose deprivation and growth factor withdrawal. Glut1 overexpression, glucose deprivation, Akt constitutive activation, Puma knockout cells, DNA fragmentation assays, metabolite supplementation The Journal of biological chemistry High 21159778
2014 Keap1 degradation via p62-dependent autophagy in response to palmitate leads to JNK1-dependent upregulation of PUMA protein levels; stable knockdown or knockout of Keap1 increased PUMA protein and sensitized hepatocytes to lipoapoptosis. Knockdown of PUMA prevented cell toxicity induced by Keap1 loss. shRNA stable knockdown, liver-specific Keap1 KO mice, Western blot, primary hepatocyte isolation, apoptosis assays Cell death and differentiation High 24769730
2021 Using zebrafish null alleles, puma is required for genotoxic stress-induced apoptosis (dependent on p53) and ER stress-induced apoptosis (dependent on p63, not p53). Oxidative stress-induced apoptosis requires p63 and both noxa and puma. Puma is the key mediator of p53-dependent apoptosis; puma null completely rescues mdm2 null apoptosis but only partially rescues the phenotype. Zebrafish CRISPR knockout of puma, noxa, p53, p63, p73, mdm2; genotoxic/ER/oxidative stress assays, apoptosis quantification Cell death & disease High 34193827
2015 MCL-1 prevents PUMA-mediated apoptosis in hematopoietic stem/progenitor cells during recovery from myeloablative stress; loss of one Mcl-1 allele severely compromised hematopoietic recovery, and this was completely rescued in Mcl-1+/-;Puma-/- mice, establishing PUMA inhibition as the key function of MCL-1 in hematopoietic recovery. Mcl-1 heterozygous and Puma-/- mouse models, myeloablative challenge, bone marrow transplantation, hematopoietic recovery assays Blood High 25847014
2018 PUMA is a critical mediator of primordial follicle depletion following cyclophosphamide or cisplatin treatment; Puma-/- mice retained 100% of primordial follicles following either genotoxic treatment and completely preserved fertility. TAp63-/- mice were protected by cisplatin but not cyclophosphamide, suggesting mechanistic differences between these chemotherapies in PUMA induction. Puma-/- and TAp63-/- mouse models, cyclophosphamide/cisplatin treatment, follicle counting, fertility assays Cell death & disease High 29795269
2014 PUMA mediates germ cell death during the migratory phase of oogenesis; targeted disruption of Bbc3 (PUMA) increased germ cell numbers from embryonic day 13.5, resulting in a 1.9-fold increase in primordial follicles on postnatal day 10. PUMA-mediated cell death limits the initial ovarian reserve. Bbc3 knockout mouse, germ cell counting at multiple developmental timepoints, proliferation assays Reproduction (Cambridge, England) High 24859845
2011 Puma is required for apoptosis of mitogen-activated B cells and for control of memory B-cell survival. Puma expression is selectively upregulated upon antigen or mitogen activation of B cells in vitro, coincides with Mcl-1 expression in germinal centers, and Puma-deficient mice show impaired apoptosis of activated B cells and expanded memory B-cell populations. Puma-deficient mouse model, in vitro B-cell activation, germinal center analysis, flow cytometry, apoptosis assays Blood High 21868573
2013 PUMA deficiency leads to better iPSC induction survival, reduced DNA damage, and fewer chromosomal aberrations during somatic reprogramming, establishing PUMA as an independent mediator of the negative effect of p53 on iPSC induction via apoptosis (distinct from p21-mediated cell-cycle arrest). PUMA-, p21-, and p53-deficient mouse strains, iPSC reprogramming assays, chromosomal aberration analysis, DNA damage markers Nature communications High 23873265
2016 In HCT116 TKO cells lacking Bid, Bim, and Puma, simultaneous inactivation of Bcl-xL and Mcl-1 still induced robust apoptosis via Bax/Bak, demonstrating that the direct activation activities of Bid, Bim, and Puma are not essential for Bax/Bak activation once anti-apoptotic Bcl-2 proteins are neutralized. p53 was also shown to be dispensable for this Bid/Bim/Puma-independent Bax/Bak activation. Gene editing (CRISPR/TALEN) to generate quintuple and hexuple KO HCT116 cells, BH3 mimetics, GFP-Bax reconstitution, apoptosis assays Cell death & disease High 27310874
2008 E2F-1 transcriptionally activates PUMA through six putative E2F-1 binding sites in the PUMA promoter; E2F-1 overexpression increased PUMA promoter activity 9.3-fold in SK-MEL-2 cells. E2F-1-induced apoptosis was accompanied by Bax translocation to mitochondria and caspase-9 induction; PUMA-/- HCT116 cells showed more resistance to Ad-E2F-1-mediated cell death. Dual luciferase reporter assay, real-time PCR, Western blot, immunocytochemistry, PUMA-/- cells, caspase-9 assay BMC cancer Medium 17263886

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 PUMA, a novel proapoptotic gene, is induced by p53. Molecular cell 1912 11463392
2003 p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science (New York, N.Y.) 1088 14500851
2003 PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nature medicine 640 12563315
2009 Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Molecular cell 499 19917256
2008 PUMA, a potent killer with or without p53. Oncogene 465 19641508
2005 PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science (New York, N.Y.) 465 16151013
2003 p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. The Journal of biological chemistry 307 14634023
2010 MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma. Molecular cancer 260 20813046
2010 Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. Journal of hepatology 204 20206402
2008 PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. Cell stem cell 180 18522850
2017 Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma. Oncotarget 175 28445976
2009 JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis. The Journal of biological chemistry 166 19638343
2018 PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proceedings of the National Academy of Sciences of the United States of America 159 29581256
2010 CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis. American journal of physiology. Gastrointestinal and liver physiology 155 20430872
2004 Suppression of tumorigenesis by the p53 target PUMA. Proceedings of the National Academy of Sciences of the United States of America 146 15192153
2006 The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target. Trends in pharmacological sciences 143 16766048
2007 6-Hydroxydopamine activates the mitochondrial apoptosis pathway through p38 MAPK-mediated, p53-independent activation of Bax and PUMA. Journal of neurochemistry 122 17996028
2008 Role of p53, PUMA, and Bax in wogonin-induced apoptosis in human cancer cells. Biochemical pharmacology 116 18377871
2012 PUMA, a critical mediator of cell death--one decade on from its discovery. Cellular & molecular biology letters 112 23001513
2018 Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility. Cell death & disease 105 29795269
2013 Estrogen receptor β upregulates FOXO3a and causes induction of apoptosis through PUMA in prostate cancer. Oncogene 100 24077289
2011 Uncoupling p53 functions in radiation-induced intestinal damage via PUMA and p21. Molecular cancer research : MCR 99 21450905
2014 Coupled folding and binding of the disordered protein PUMA does not require particular residual structure. Journal of the American Chemical Society 98 24654952
2008 Glucose metabolism attenuates p53 and Puma-dependent cell death upon growth factor deprivation. The Journal of biological chemistry 98 18990690
2014 Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis. Clinical cancer research : an official journal of the American Association for Cancer Research 92 24763611
2006 p53 independent induction of PUMA mediates intestinal apoptosis in response to ischaemia-reperfusion. Gut 92 17127703
2009 PUMA cooperates with direct activator proteins to promote mitochondrial outer membrane permeabilization and apoptosis. Cell cycle (Georgetown, Tex.) 84 19652530
2006 Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways. The EMBO journal 83 17024184
2004 p53 activation domain 1 is essential for PUMA upregulation and p53-mediated neuronal cell death. The Journal of neuroscience : the official journal of the Society for Neuroscience 83 15525786
2010 Akt requires glucose metabolism to suppress puma expression and prevent apoptosis of leukemic T cells. The Journal of biological chemistry 82 21159778
2006 PUMA sensitizes lung cancer cells to chemotherapeutic agents and irradiation. Clinical cancer research : an official journal of the American Association for Cancer Research 82 16675590
2020 MicroRNA-221/222 Mediates ADSC-Exosome-Induced Cardioprotection Against Ischemia/Reperfusion by Targeting PUMA and ETS-1. Frontiers in cell and developmental biology 80 33344446
2015 Targeting the miR-221-222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma. Cancer research 79 26249174
2003 Zebrafish puma mutant decouples pigment pattern and somatic metamorphosis. Developmental biology 77 12679100
2021 The role of P53 up-regulated modulator of apoptosis (PUMA) in ovarian development, cardiovascular and neurodegenerative diseases. Apoptosis : an international journal on programmed cell death 76 33783663
2021 Puma, noxa, p53, and p63 differentially mediate stress pathway induced apoptosis. Cell death & disease 76 34193827
2010 Gene-specific repression of the p53 target gene PUMA via intragenic CTCF-Cohesin binding. Genes & development 76 20478995
2011 p53 and PUMA independently regulate apoptosis of intestinal epithelial cells in patients and mice with colitis. Gastroenterology 75 21699775
2005 Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation. Leukemia 75 15674362
2008 Sp1 and p73 activate PUMA following serum starvation. Carcinogenesis 73 18579560
2008 Puma indirectly activates Bax to cause apoptosis in the absence of Bid or Bim. Cell death and differentiation 68 19079139
2022 BH3-Only Proteins Noxa and Puma Are Key Regulators of Induced Apoptosis. Life (Basel, Switzerland) 67 35207544
2011 A role for miR-296 in the regulation of lipoapoptosis by targeting PUMA. Journal of lipid research 66 21633093
2015 Chaperone-mediated autophagy prevents apoptosis by degrading BBC3/PUMA. Autophagy 61 26212789
2016 Bax/Bak activation in the absence of Bid, Bim, Puma, and p53. Cell death & disease 60 27310874
2017 The role of ROS and subsequent DNA-damage response in PUMA-induced apoptosis of ovarian cancer cells. Oncotarget 57 28423586
2013 Evaluation of the BH3-only protein Puma as a direct Bak activator. The Journal of biological chemistry 55 24265320
2021 Fas/FasL mediates NF-κBp65/PUMA-modulated hepatocytes apoptosis via autophagy to drive liver fibrosis. Cell death & disease 51 33980818
2016 4EBP1/c-MYC/PUMA and NF-κB/EGR1/BIM pathways underlie cytotoxicity of mTOR dual inhibitors in malignant lymphoid cells. Blood 51 26917778
2013 The p53-PUMA axis suppresses iPSC generation. Nature communications 50 23873265
2013 Hsp90 inhibitors promote p53-dependent apoptosis through PUMA and Bax. Molecular cancer therapeutics 46 23966620
2016 Mir143-BBC3 cascade reduces microglial survival via interplay between apoptosis and autophagy: Implications for methamphetamine-mediated neurotoxicity. Autophagy 44 27464000
2012 JNK- and Akt-mediated Puma expression in the apoptosis of cisplatin-resistant ovarian cancer cells. The Biochemical journal 44 22394200
2019 Long non-coding RNA CRNDE enhances cervical cancer progression by suppressing PUMA expression. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 42 31202167
2014 Slug promotes survival during metastasis through suppression of Puma-mediated apoptosis. Cancer research 42 24830722
2014 PUMA regulates germ cell loss and primordial follicle endowment in mice. Reproduction (Cambridge, England) 41 24859845
2015 PUMA mediates the combinational therapy of 5-FU and NVP-BEZ235 in colon cancer. Oncotarget 38 25965911
2024 Microneedle-assisted dual delivery of PUMA gene and celastrol for synergistic therapy of rheumatoid arthritis through restoring synovial homeostasis. Bioactive materials 37 38450203
2014 Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis. Cell death and differentiation 37 24769730
2014 β-Arrestin2 encourages inflammation-induced epithelial apoptosis through ER stress/PUMA in colitis. Mucosal immunology 36 25354317
2012 Histone deacetylase 3 inhibits expression of PUMA in gastric cancer cells. Journal of molecular medicine (Berlin, Germany) 36 22763818
2014 Aurora kinase inhibition induces PUMA via NF-κB to kill colon cancer cells. Molecular cancer therapeutics 34 24563542
2011 Genetically defining the mechanism of Puma- and Bim-induced apoptosis. Cell death and differentiation 34 22015606
2021 Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor. Cellular and molecular life sciences : CMLS 33 34636989
2015 Antagonism between MCL-1 and PUMA governs stem/progenitor cell survival during hematopoietic recovery from stress. Blood 33 25847014
2015 Role of PUMA in methamphetamine-induced neuronal apoptosis. Toxicology letters 33 26524635
2011 Regulation of memory B-cell survival by the BH3-only protein Puma. Blood 32 21868573
2017 PUMA gene delivery to synoviocytes reduces inflammation and degeneration of arthritic joints. Nature communications 31 28747638
2003 PUMA in head and neck cancer. Cancer letters 31 12963126
2019 Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway. Cancer gene therapy 30 31257364
2017 Betulinic acid derivative B10 inhibits glioma cell proliferation through suppression of SIRT1, acetylation of FOXO3a and upregulation of Bim/PUMA. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 30 28554130
2008 Involvement of p53-transactivated Puma in cisplatin-induced renal tubular cell death. Life sciences 30 18761355
2014 miR-222 regulates the cell biological behavior of oral squamous cell carcinoma by targeting PUMA. Oncology reports 29 24452416
2018 miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2. Cell death & disease 28 29352138
2018 Involvement of NLRP3 inflammasome in methamphetamine-induced microglial activation through miR-143/PUMA axis. Toxicology letters 28 30394308
2013 PUMA Cooperates with p21 to Regulate Mammary Epithelial Morphogenesis and Epithelial-To-Mesenchymal Transition. PloS one 28 23805223
2011 Cytokine receptor signaling activates an IKK-dependent phosphorylation of PUMA to prevent cell death. Cell death and differentiation 28 21997190
2017 PUMA and NF-kB Are Cell Signaling Predictors of Reovirus Oncolysis of Breast Cancer. PloS one 27 28099441
2014 Caspase-9 mediates Puma activation in UCN-01-induced apoptosis. Cell death & disease 27 25356864
2014 MiR-222 targeted PUMA to improve sensitization of UM1 cells to cisplatin. International journal of molecular sciences 27 25474084
2011 RNA interference targeting slug increases cholangiocarcinoma cell sensitivity to cisplatin via upregulating PUMA. International journal of molecular sciences 27 21339993
2009 Puma strikes Bax. The Journal of cell biology 27 19380876
2024 Mir221- and Mir222-enriched adsc-exosomes mitigate PM exposure-exacerbated cardiac ischemia-reperfusion injury through the modulation of the BNIP3-MAP1LC3B-BBC3/PUMA pathway. Autophagy 26 39245438
2012 Proliferative and survival effects of PUMA promote angiogenesis. Cell reports 26 23122957
2022 Synthetical lethality of Werner helicase and mismatch repair deficiency is mediated by p53 and PUMA in colon cancer. Proceedings of the National Academy of Sciences of the United States of America 25 36508676
2007 TAT-RasGAP317-326 requires p53 and PUMA to sensitize tumor cells to genotoxins. Molecular cancer research : MCR 25 17510315
2021 Porcine Epidemic Diarrhea Virus Induces Vero Cell Apoptosis via the p53-PUMA Signaling Pathway. Viruses 24 34202551
2015 MicroRNA-203 induces apoptosis by upregulating Puma expression in colon and lung cancer cells. International journal of oncology 24 26397233
2014 Interdependence of Bad and Puma during ionizing-radiation-induced apoptosis. PloS one 24 24516599
2014 Importance of proapoptotic protein PUMA in cell radioresistance. Folia biologica 24 24785107
2021 Melatonin abated Bisphenol A-induced neurotoxicity via p53/PUMA/Drp-1 signaling. Environmental science and pollution research international 23 33398767
2014 Evolution of puma lentivirus in bobcats (Lynx rufus) and mountain lions (Puma concolor) in North America. Journal of virology 23 24741092
2014 Aβ induces PUMA activation: a new mechanism for Aβ-mediated neuronal apoptosis. Neurobiology of aging 23 25457551
2014 Phosphorylation of Tip60 by p38α regulates p53-mediated PUMA induction and apoptosis in response to DNA damage. Oncotarget 23 25544752
2007 E2F-1 induces melanoma cell apoptosis via PUMA up-regulation and Bax translocation. BMC cancer 23 17263886
2017 Idelalisib induces PUMA-dependent apoptosis in colon cancer cells. Oncotarget 22 28008149
2007 Pro-apoptotic PUMA and anti-apoptotic phospho-BAD are highly expressed in colorectal carcinomas. Digestive diseases and sciences 22 17393317
2020 Knockdown of circHomer1 ameliorates METH-induced neuronal injury through inhibiting Bbc3 expression. Neuroscience letters 21 32450188
2020 PUMA: PANDA Using MicroRNA Associations. Bioinformatics (Oxford, England) 21 32860050
2005 DeltaNp73 antisense activates PUMA and induces apoptosis in neuroblastoma cells. Journal of neuro-oncology 21 15803372