Affinage

PDCD4

Programmed cell death protein 4 · UniProt Q53EL6

Length
469 aa
Mass
51.7 kDa
Annotated
2026-04-29
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDCD4 is a tumor suppressor that restrains cell growth and transformation by inhibiting both translation initiation and transcription factor activity. It binds eIF4A through two MA3 domains, preventing eIF4A helicase domain closure and RNA unwinding, thereby selectively suppressing cap-dependent translation of mRNAs with structured 5′-UTRs including p53 and Sin1/mTORC2 (PMID:19204291, PMID:22033922, PMID:28692058). In the nucleus, PDCD4 suppresses AP-1 transcription by binding c-Jun to block JNK-mediated phosphorylation and p300 recruitment, and inhibits NF-κB by directly sequestering p65 to prevent its nuclear translocation; it also sequesters Twist2 in macrophages to regulate IL-10 production via c-Maf (PMID:15334056, PMID:24413684, PMID:24982420). PDCD4 protein levels are tightly controlled by phosphorylation-dependent proteasomal degradation downstream of Akt/mTORC1/S6K signaling through multiple E3 ligases (β-TrCP, SKP2, CRL3-IBTKα, CUL4-DTL), by p62-mediated autophagy, and by miR-21-directed translational repression that is counteracted by the RNA-binding proteins La and HuR (PMID:18296647, PMID:30760284, PMID:25882842, PMID:31952347, PMID:33288677).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Establishing PDCD4 as a tumor suppressor: antisense depletion converted transformation-resistant cells to a sensitive phenotype, and sense re-expression reversed this, demonstrating that PDCD4 directly suppresses neoplastic transformation.

    Evidence Antisense/sense stable cell lines in mouse JB6 P−/P+ cells with phenotypic reversion

    PMID:10570194

    Open questions at the time
    • Molecular mechanism of transformation suppression unknown
    • No target pathway identified
  2. 2004 High

    Identifying the first mechanistic target: PDCD4 suppresses AP-1 transcription by binding c-Jun, blocking JNK phosphorylation and p300 co-activator recruitment, revealing a nuclear transcriptional mechanism for tumor suppression.

    Evidence Co-immunoprecipitation, in vitro kinase assays, AP-1 luciferase reporter in mammalian cells

    PMID:15334056

    Open questions at the time
    • Whether the c-Jun interaction is direct or requires bridging factors
    • Structural basis of PDCD4–c-Jun interaction unknown
  3. 2005 High

    Revealing how growth signaling inactivates PDCD4: Akt phosphorylates PDCD4 at Ser67/Ser457, causing nuclear translocation and loss of AP-1 suppression, connecting PDCD4 to PI3K/Akt signaling.

    Evidence In vitro kinase assay with site-directed mutagenesis, subcellular fractionation, AP-1 reporter in mammalian cells

    PMID:16357133

    Open questions at the time
    • Whether phosphorylation affects other PDCD4 functions beyond AP-1
    • Degradation consequence of phosphorylation not yet established
  4. 2008 High

    Defining the degradation pathway: phosphorylation by Akt and p70S6K enables β-TrCP E3 ligase recognition, ubiquitination, and proteasomal degradation of PDCD4; Pdcd4-heterozygous mice confirmed haploinsufficient tumor suppression in vivo.

    Evidence In vitro ubiquitination assay, pharmacological pathway inhibitors, Pdcd4-knockout/heterozygous mouse tumor model

    PMID:18296647

    Open questions at the time
    • Whether other E3 ligases contribute
    • Tissue-specific degradation kinetics unknown
  5. 2008 High

    Linking PDCD4 to the DNA-damage response: PDCD4 knockdown increased p21 expression and reduced UV-induced apoptosis, revealing a role in connecting PDCD4 to p53-dependent gene regulation and cell survival decisions.

    Evidence Stable shRNA knockdown in HeLa cells, p53 reporter assay, UV survival assay

    PMID:18427550

    Open questions at the time
    • Whether PDCD4 acts on p53 at the transcriptional or translational level
    • Direct versus indirect mechanism on p53 target genes unresolved
  6. 2009 High

    Structural resolution of the translation-inhibitory mechanism: the crystal structure showed one PDCD4 bridges two eIF4A molecules via its MA3 domains, locking eIF4A in an open conformation that prevents RNA binding and helicase activity.

    Evidence X-ray crystallography of human eIF4A–PDCD4 complex with biochemical and mutagenesis validation

    PMID:19204291

    Open questions at the time
    • Selectivity mechanism for specific mRNA targets unknown
    • Whether both eIF4A molecules must be engaged for inhibition in vivo
  7. 2011 High

    Identifying specific translational targets: PDCD4 associates with p53 mRNA and suppresses its translation via the structured 5′-UTR in an eIF4A-binding-dependent manner; DNA damage reduces PDCD4 to derepress p53 translation.

    Evidence RNA immunoprecipitation, 5′-UTR reporter constructs, eIF4A-binding mutant controls

    PMID:22033922

    Open questions at the time
    • Full repertoire of translationally regulated mRNAs not defined
    • Whether PDCD4 contacts mRNA directly or solely via eIF4A
  8. 2011 High

    Connecting PDCD4 to innate immunity: decorin signals through TLR2/4 to upregulate PDCD4 (partly by reducing miR-21), and elevated PDCD4 suppresses IL-10, establishing PDCD4 as a switch between anti- and pro-inflammatory macrophage states.

    Evidence TLR signaling assays, miR-21 quantification, IL-10 ELISA, sepsis and xenograft mouse models

    PMID:22087031

    Open questions at the time
    • Mechanism by which PDCD4 suppresses IL-10 not fully resolved
    • Other innate immune targets of PDCD4 not characterized
  9. 2012 High

    Placing PDCD4 degradation as essential for mTORC1-driven global translation: p70S6K1 phosphorylation of PDCD4 (and eIF4B) is required for mTORC1-stimulated protein synthesis, independent of 4E-BP/eIF4E–eIF4G axis.

    Evidence 4E-BP1/2 double knockout MEFs, rapamycin, polysome profiling

    PMID:23105104

    Open questions at the time
    • Relative contribution of PDCD4 versus eIF4B phosphorylation to global translation not dissected
  10. 2014 High

    Expanding nuclear functions: PDCD4 directly binds NF-κB p65, inhibiting its nuclear localization and NF-κB-dependent transcription independently of IKK/IκBα, and separately sequesters Twist2 in macrophages to control c-Maf–IL-10 production upon LPS stimulation.

    Evidence Reciprocal Co-IP, confocal imaging, ChIP for Twist2 at c-Maf promoter, pathway inhibitors in glioblastoma cells and macrophages

    PMID:24413684 PMID:24982420

    Open questions at the time
    • Whether p65 and Twist2 sequestration are mutually exclusive or cell-type-specific
    • Structural basis of PDCD4–p65 interaction unknown
  11. 2015 High

    Identifying additional E3 ligases: CRL3-IBTKα ubiquitinates PDCD4 downstream of serum stimulation, adding a β-TrCP-independent degradation route that de-represses translation of targets including Bcl-xL.

    Evidence In vitro ubiquitination assay, affinity purification, RNAi knockdown, Bcl-xL reporter assay

    PMID:25882842

    Open questions at the time
    • Phosphorylation requirements for IBTKα recognition not mapped
    • Relative contribution of CRL3 versus β-TrCP in different tissues unknown
  12. 2016 Medium

    Extending PDCD4 function to stem cell biology: Pdcd4 deficiency enhances adipose-derived stem cell self-renewal via AKT activation and promotes white-to-beige transdifferentiation with increased UCP1.

    Evidence Pdcd4 knockout mice, AKT inhibitor rescue, colony formation, UCP1 and metabolic profiling

    PMID:27031966

    Open questions at the time
    • Whether translation of specific mRNAs drives the adipocyte phenotype
    • Not confirmed in independent labs
    • Mechanism linking PDCD4 loss to AKT activation in ADSCs unclear
  13. 2017 High

    Connecting PDCD4 to mTORC2 signaling: PDCD4 suppresses Sin1 translation via the SIN1 5′-UTR in an eIF4A-dependent manner; loss of PDCD4 activates mTORC2 and promotes invasion through Snail upregulation.

    Evidence 5′-UTR reporter assay, eIF4A-binding mutant (D253A/D418A), silvestrol, invasion assays, patient tissue

    PMID:28692058

    Open questions at the time
    • Whether PDCD4 regulates other mTORC2 subunit mRNAs
    • In vivo tumor model validation of Sin1-specific axis incomplete
  14. 2019 High

    Expanding the E3 ligase repertoire further: SKP2 and DTL/CUL4 were each shown to ubiquitinate and degrade PDCD4, demonstrating convergent multi-ligase control of PDCD4 protein levels.

    Evidence Mass spectrometry, reciprocal Co-IP, in vitro ubiquitination, xenograft rescue experiments

    PMID:30760284 PMID:31409387

    Open questions at the time
    • Hierarchy and redundancy among the four E3 ligases not resolved
    • Phosphodegron specificity for each ligase not mapped
  15. 2020 High

    Revealing a dual degradation route: p62/SQSTM1 delivers PDCD4 to autophagosomes alongside proteasomal degradation, and combined inhibition synergistically stabilizes PDCD4, establishing autophagy as a second major turnover pathway.

    Evidence Co-IP of PDCD4–p62–LC3, ATG5-deficient cells, MG132 plus bafilomycin A1 in mammalian cells

    PMID:31952347

    Open questions at the time
    • Signals that partition PDCD4 between proteasomal and autophagic degradation unknown
    • Whether autophagy-mediated degradation is regulated by the same phosphorylation events
  16. 2020 High

    Defining post-transcriptional stabilization of PDCD4 mRNA: La and HuR cooperatively bind the PDCD4 3′-UTR and antagonize miR-21-mediated translational repression, establishing a counterbalance to oncogenic miR-21.

    Evidence RNA immunoprecipitation, subcellular fractionation, reporter assay, siRNA knockdown

    PMID:33288677

    Open questions at the time
    • Precise binding sites on PDCD4 3′-UTR for La/HuR versus miR-21 not mapped at nucleotide resolution
    • Whether other miRNAs are also counteracted by La/HuR
  17. 2020 High

    Linking PDCD4 to mitotic drug sensitivity: during mitotic arrest, reduced mTORC1 activity allows PDCD4 accumulation, which suppresses eIF4A-dependent translation and sensitizes cells to Taxol-induced death.

    Evidence Raptor phosphomutant, PDCD4 monitoring during arrest, eIF4A inhibitor rescue of Taxol sensitivity

    PMID:33027666

    Open questions at the time
    • Specific mRNAs whose suppression mediates mitotic death not identified
    • Clinical relevance of PDCD4 levels for Taxol response not validated in patients

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: the genome-wide repertoire of PDCD4-regulated mRNAs (translatome), the structural basis for PDCD4's nuclear protein–protein interactions with c-Jun and p65, the hierarchy and tissue specificity among the four E3 ligases, and how cells partition PDCD4 between proteasomal and autophagic degradation.
  • No ribosome profiling or CLIP-seq to define the full set of PDCD4-regulated mRNAs
  • No structural data for PDCD4–c-Jun or PDCD4–p65 complexes
  • Relative contribution of each E3 ligase in physiological tissues unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0045182 translation regulator activity 4 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 1
Partners
BTRCDTLEIF4A1JUNRELASKP2SQSTM1TWIST2

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 PDCD4 protein inhibits tumor promoter-induced neoplastic transformation; antisense-mediated reduction of PDCD4 in promotion-resistant (P-) mouse JB6 cells converts them to a transformation-sensitive (P+) phenotype, and re-expression of PDCD4 sense fragment restores the P- phenotype, establishing PDCD4 as a direct suppressor of neoplastic transformation. Antisense stable cell lines, phenotypic reversion by sense re-expression, mRNA differential display Proceedings of the National Academy of Sciences of the United States of America High 10570194
2004 PDCD4 suppresses AP-1-driven transcription by interacting directly with c-Jun, blocking JNK-mediated phosphorylation of c-Jun and preventing recruitment of the co-activator p300 to c-Jun. Luciferase reporter assays, co-immunoprecipitation, in vitro kinase assays Oncogene High 15334056
2005 Akt phosphorylates PDCD4 at Ser67 and Ser457 in vitro and in vivo, and this phosphorylation causes nuclear translocation of PDCD4 and significantly reduces its ability to suppress AP-1-dependent transcription driven by c-Jun. In vitro kinase assay, site-directed mutagenesis, luciferase reporter assay, subcellular fractionation/imaging Cancer research High 16357133
2008 Tumor promoter TPA triggers proteasomal degradation of PDCD4 via a PKC-PI3K-Akt-mTOR-p70S6K and MEK-ERK signaling cascade; Akt and p70S6K phosphorylate PDCD4, enabling binding of the E3-ubiquitin ligase β-TrCP and subsequent ubiquitylation and proteasomal degradation. Pdcd4-heterozygous mice show increased tumor formation, establishing PDCD4 as a haploinsufficient tumor suppressor. In vitro ubiquitination assay, pharmacological inhibitors, Pdcd4-knockout/heterozygous mouse tumor model, Western blot Cancer research High 18296647
2009 Crystal structure of human eIF4A–PDCD4 complex reveals that one PDCD4 molecule binds two eIF4A molecules through two distinct modes: both MA3 domains of PDCD4 bind one eIF4A, while the C-terminal MA3 domain alone contacts a second eIF4A. PDCD4 MA3 domains bind perpendicular to the eIF4A interdomain interface, preventing domain closure of eIF4A and blocking RNA binding, thereby inhibiting eIF4A helicase activity. X-ray crystallography, biochemical binding assays, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 19204291
2011 PDCD4 is associated with p53 mRNA and suppresses its translation via the structured 5'-UTR of p53 mRNA in an eIF4A-interaction-dependent manner. DNA-damaging agents decrease PDCD4 levels, thereby releasing translational suppression of p53. RNA immunoprecipitation, reporter assay with 5'-UTR constructs, eIF4A-binding mutants, Western blot The Journal of biological chemistry High 22033922
2011 Decorin acts as an endogenous ligand of TLR2 and TLR4 and stimulates PDCD4 production in macrophages; decorin also reduces miR-21 abundance (which normally suppresses PDCD4 translation), thereby increasing PDCD4 levels. Elevated PDCD4 in turn decreases IL-10 release, shifting the cytokine profile toward a proinflammatory state. TLR2/4 signaling assays, miR-21 quantification, PDCD4 protein measurement, IL-10 ELISA, sepsis and xenograft mouse models Science signaling High 22087031
2012 p70S6K1 phosphorylates PDCD4, and this phosphorylation (along with eIF4B phosphorylation) is required for mTORC1-mediated promotion of global protein synthesis; maintenance of eIF4E–eIF4G interaction alone is insufficient without p70S6K1 signaling to PDCD4. Genetic knockout of 4E-BP1/2, rapamycin treatment, polysome profiling, Western blot in MEFs and rat liver The Journal of biological chemistry High 23105104
2008 PDCD4 knockdown in HeLa cells increases expression of p21(Waf1/Cip1) and other p53-regulated genes, and PDCD4 interferes with p53-responsive promoter activation by p53. Pdcd4 knockdown cells show decreased apoptosis and increased survival after UV irradiation, implicating PDCD4 in the DNA-damage response. Stable shRNA knockdown, reporter gene assay, UV survival assay, Western blot Oncogene High 18427550
2014 PDCD4 directly interacts with NF-κB p65 protein (co-immunoprecipitation and confocal co-localization) in glioblastoma cells, inhibiting nuclear localization of p65 (but not p50) and suppressing NF-κB-dependent transcription independently of upstream IKK or IκBα degradation. Co-immunoprecipitation, confocal imaging, luciferase reporter assay, stable PDCD4 overexpression, qPCR of NF-κB target genes Carcinogenesis High 24413684
2014 In macrophages, PDCD4 and transcription factor Twist2 form a complex in unstimulated cells. LPS induces PI3K/mTOR-dependent degradation of PDCD4, releasing Twist2, which then binds the c-Maf promoter to drive IL-10 production. Co-immunoprecipitation, ChIP (Twist2 at c-Maf promoter), PI3K/mTOR pharmacological inhibitors, PDCD4 knockdown, ELISA for IL-10 The Journal of biological chemistry High 24982420
2015 IBtkα forms a CRL3(IBTK) ubiquitin ligase complex and promotes ubiquitylation and proteasomal degradation of PDCD4; serum-induced degradation of PDCD4 requires both IBtkα and Cul3. IBtkα-mediated PDCD4 degradation counteracts PDCD4-dependent translational repression, including of Bcl-xL mRNA. Affinity purification, co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown, luciferase reporter assay The Journal of biological chemistry High 25882842
2017 PDCD4 inhibits Sin1 (mTORC2 component) translation via suppression of eIF4A, using the SIN1 5'-UTR as the regulatory element. PDCD4 mutants that cannot bind eIF4A fail to repress Sin1 translation, and loss of Pdcd4 increases mTORC2 kinase activity and Snail expression, promoting colon tumor cell invasion. 5'-UTR luciferase reporter assay, PDCD4 deletion/point mutants (D253A/D418A eIF4A-binding mutant), siRNA knockdown, eIF4A inhibitor silvestrol, invasion assays, patient tissue analysis Oncogene High 28692058
2019 DTL (a CUL4-DDB1 E3 ligase adaptor) interacts with PDCD4, promotes its ubiquitination, and accelerates its proteasomal degradation, thereby enhancing cancer cell proliferation and migration that are rescued by PDCD4 re-expression. Affinity-purification mass spectrometry, co-immunoprecipitation, in vitro ubiquitination assay, immunofluorescence, stable overexpression/knockdown lines, rescue experiment Journal of experimental & clinical cancer research High 31409387
2019 SKP2 (SCF E3 ligase) promotes PDCD4 phosphorylation, ubiquitination, and proteasomal degradation. SKP2 knockdown increases PDCD4, reduces proliferation, and enhances apoptosis; these effects are reversed by simultaneous PDCD4 knockdown, placing SKP2-mediated PDCD4 degradation upstream of its tumor-suppressive function in breast cancer. Mass spectrometry, reciprocal Co-IP, in vitro ubiquitination, stable overexpression/knockdown, xenograft model Journal of experimental & clinical cancer research High 30760284
2012 PDCD4 knockdown in Pdcd4-deficient mice promotes colitis-associated colorectal cancer by upregulating IL-6 expression and enhancing IL-6/STAT3 pathway activation; blockade of IL-6/STAT3 with sgp130Fc reverses the pro-proliferative effect of PDCD4 deficiency in vivo. Pdcd4 knockout mice, DSS/AOM colitis-cancer model, cytokine ELISA, Western blot for STAT3 signaling, BrdU incorporation, sgp130Fc rescue Inflammatory bowel diseases High 26891257
2001 The chicken Pdcd4 gene is a direct transcriptional target of the retroviral oncogene v-Myb; v-Myb regulates Pdcd4 expression in myelomonocytic cells, providing the first evidence that a myb transcription factor directly controls Pdcd4 expression. Differential display, inducible v-Myb expression system, promoter analysis Oncogene Medium 11313950
2012 PDCD4 knockdown increases MAP4K1 expression through upregulation of c-Myc, which directly binds the MAP4K1 promoter (demonstrated by ChIP), leading to enhanced JNK phosphorylation of c-Jun and AP-1-dependent transcription; dominant-negative Tcf4 reduces c-Myc and MAP4K1, connecting β-catenin/Tcf signaling to this pathway. ChIP, promoter-luciferase reporter with mutational analysis, siRNA, dominant-negative Tcf4, Western blot Biochimica et biophysica acta High 22801218
2020 During mitotic arrest, mTORC1 activity is reduced due to raptor phosphorylation; this allows PDCD4 accumulation (normally degraded by mTORC1/S6K pathway), which suppresses eIF4A and sensitizes cells to mitotic death. A non-phosphorylatable raptor mutant reactivates mTORC1, degrades PDCD4, and reduces Taxol cytotoxicity; pharmacological eIF4A inhibition restores Taxol sensitivity in resistant cells. Raptor phosphomutant expression, PDCD4 protein monitoring during mitotic arrest, pharmacological mTORC1 inhibition, eIF4A inhibitor treatment, cell viability assay Cell reports High 33027666
2020 PDCD4 degradation is mediated by both the ubiquitin-proteasome system and autophagy; p62/SQSTM1 associates with PDCD4 and LC3, and PDCD4 colocalizes with autophagosomes. Knockdown of p62 or ATG5 increases PDCD4 levels, and combined proteasome plus autophagy inhibition synergistically elevates PDCD4. Co-immunoprecipitation (anti-PDCD4 pulling down p62 and LC3-II), confocal colocalization, ATG5-deficient cells, pharmacological inhibitors (MG132, bafilomycin A1), RNAi Cells High 31952347
2020 RNA-binding proteins La and HuR cooperatively bind the 3'-UTR of PDCD4 mRNA and mitigate miR-21-mediated translational repression; LPS induces cytoplasmic translocation of HuR while increasing La levels, and their cooperative binding to PDCD4 mRNA reduces cell proliferation and enhances apoptosis. RNA immunoprecipitation, subcellular fractionation, reporter assay, siRNA knockdown, apoptosis/proliferation assays The Journal of biological chemistry High 33288677
2019 In GBM, PDCD4 knockdown induces senescence through p53-independent upregulation of CDK inhibitor p21, inhibition of Rb phosphorylation, and downregulation of CDKs and Rb protein; p21 knockdown rescues the senescence and growth arrest caused by PDCD4 knockdown. Stable PDCD4 knockdown in multiple hepatoma cell lines, β-galactosidase staining for senescence, p21 siRNA rescue, Western blot for Rb phosphorylation and CDKs Frontiers in oncology High 30687637
2020 PDCD4 deficiency in mice activates FGR (a Src-family tyrosine kinase), which upregulates NOTCH1 expression via STAT3 activation, thereby promoting tubular apoptosis and inflammation in acute kidney injury models. Pdcd4 knockout mice, IRI and cisplatin AKI models, FGR overexpression, STAT3/NOTCH1 Western blot, pharmacological tyrosine kinase inhibitor (ponatinib) Acta pharmaceutica Sinica. B Medium 33643819
2020 EIF3H interacts with PDCD4 (co-immunoprecipitation and immunofluorescent co-localization); PDCD4 overexpression reduces EIF3H mRNA and protein by suppressing c-Jun-induced EIF3H transcription. EIF3H promotes lung adenocarcinoma invasion via EMT, and PDCD4 abrogates EIF3H-driven EMT. Co-immunoprecipitation with mass spectrometry, immunofluorescent co-localization, PDCD4 overexpression, c-Jun reporter assay, invasion/migration assays, EMT marker Western blot American journal of cancer research Medium 32064160
2017 BCR-ABL1 activates STAT5 transcription factor (via its kinase activity), which drives miR-21 transcription via STAT binding sites on the miR-21 promoter; miR-21 then suppresses PDCD4 (identified by proteomics). The same phosphoSTAT5-miR-21-PDCD4 axis operates in FLT3-ITD-driven AML. miRNA microarray profiling, STAT5 binding site mutational analysis, proteomics, tyrosine kinase inhibitor treatment, Western blot Oncotarget Medium 29100302
2021 PDCD4 promotes microglial inflammatory activation via a positive feedback loop with MAPK (p38, ERK, JNK) and NF-κB signaling: LPS activates MAPK/NF-κB to upregulate PDCD4, and PDCD4 in turn sustains MAPK/NF-κB activation. PDCD4 shRNA knockdown also reduces BAX and Cleaved-PARP expression, indicating a pro-apoptotic role in neurons. shRNA knockdown, LPS neuroinflammation mouse model, phospho-Western blot for MAPK/NF-κB, nuclear translocation assay for p65, apoptosis protein Western blot Inflammation Medium 34613548
2021 LncRNA HOTAIR binds to Lin28 (an RNA-binding protein) and PDCD4 mRNA, stabilizing PDCD4 protein; RNA pull-down and RIP assays confirmed the HOTAIR-Lin28 and Lin28-PDCD4 interactions. This HOTAIR/Lin28/PDCD4 axis promotes LPS-induced cardiomyocyte inflammation and apoptosis. RNA pull-down, RIP assay, co-transfection knockdown/overexpression, ELISA, flow cytometry apoptosis, in vivo AAV9-sh-HOTAIR mouse model Inflammation Medium 33665757
2016 Pdcd4 deficiency in mice promotes enhanced self-renewal of adipose-derived stem cells (ADSCs) via AKT activation and cyclinD1 upregulation; AKT blockade reverses the proliferative phenotype. Pdcd4 deficiency also drives white-to-beige ADSC transdifferentiation associated with UCP1 upregulation and increased lactate production. Pdcd4 knockout mice, flow cytometry for stem cell markers, colony formation assay, AKT inhibitor rescue, white adipogenic differentiation assay, UCP1 Western blot, metabolic profiling Cell death & disease Medium 27031966
2004 Overexpression of PDCD4 in carcinoid neuroendocrine tumor cells inhibits cell proliferation, associated with downregulation of carbonic anhydrase type II. Stable PDCD4 overexpression, cell proliferation assay, carbonic anhydrase II expression analysis Annals of the New York Academy of Sciences Low 15153438

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and MicroRNA-21. Science signaling 291 22087031
2009 The tumour suppressor Pdcd4: recent advances in the elucidation of function and regulation. Biology of the cell 266 19356152
1999 Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. Proceedings of the National Academy of Sciences of the United States of America 235 10570194
2011 Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo. Neuro-oncology 159 21636706
2017 Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2. Molecular cancer 137 28854977
2005 Akt phosphorylates and regulates Pdcd4 tumor suppressor protein. Cancer research 134 16357133
2011 MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4. Carcinogenesis 132 21934092
2008 Translation inhibitor Pdcd4 is targeted for degradation during tumor promotion. Cancer research 131 18296647
2016 Exosome-shuttling microRNA-21 promotes cell migration and invasion-targeting PDCD4 in esophageal cancer. International journal of oncology 126 27035745
2019 Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions. International journal of molecular sciences 123 31075975
2004 Transformation suppressor protein Pdcd4 interferes with JNK-mediated phosphorylation of c-Jun and recruitment of the coactivator p300 by c-Jun. Oncogene 117 15334056
2012 Role of p70S6K1-mediated phosphorylation of eIF4B and PDCD4 proteins in the regulation of protein synthesis. The Journal of biological chemistry 112 23105104
2016 miR-155 Regulated Inflammation Response by the SOCS1-STAT3-PDCD4 Axis in Atherogenesis. Mediators of inflammation 109 27843203
2018 The role of Pdcd4 in tumour suppression and protein translation. Biology of the cell 99 29806708
2009 Crystal structure of the eIF4A-PDCD4 complex. Proceedings of the National Academy of Sciences of the United States of America 94 19204291
2007 Frequent loss of PDCD4 expression in human glioma: possible role in the tumorigenesis of glioma. Oncology reports 93 17143488
2019 DTL promotes cancer progression by PDCD4 ubiquitin-dependent degradation. Journal of experimental & clinical cancer research : CR 92 31409387
2019 SKP2 promotes breast cancer tumorigenesis and radiation tolerance through PDCD4 ubiquitination. Journal of experimental & clinical cancer research : CR 91 30760284
2016 MiRNA-183-5p promotes cell proliferation and inhibits apoptosis in human breast cancer by targeting the PDCD4. Reproductive biology 86 27476679
2003 Programmed cell death protein 4 (pdcd4): a novel target for antineoplastic therapy? Biology of the cell 75 14630388
2007 Alterations in the expression of PDCD4 in ductal carcinoma of the breast. Oncology reports 73 17982621
2016 SOX6 and PDCD4 enhance cardiomyocyte apoptosis through LPS-induced miR-499 inhibition. Apoptosis : an international journal on programmed cell death 68 26659076
2011 Tumor suppressor protein Pdcd4 inhibits translation of p53 mRNA. The Journal of biological chemistry 68 22033922
2008 siRNA-mediated knockdown of Pdcd4 expression causes upregulation of p21(Waf1/Cip1) expression. Oncogene 67 18427550
2017 MicroRNA-150 promotes cell proliferation, migration, and invasion of cervical cancer through targeting PDCD4. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 66 29091902
2011 MicroRNA-21 and PDCD4 expression in colorectal cancer. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 66 21546206
2014 The PDCD4/miR-21 pathway in medullary thyroid carcinoma. Human pathology 65 25316501
2014 Helicobacter pylori promotes epithelial-mesenchymal transition in gastric cancer by downregulating programmed cell death protein 4 (PDCD4). PloS one 59 25144746
2017 Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma. Oncogene 58 28692058
2016 Quercetin inhibits Cr(VI)-induced malignant cell transformation by targeting miR-21-PDCD4 signaling pathway. Oncotarget 58 28881718
2016 miR-181b functions as an oncomiR in colorectal cancer by targeting PDCD4. Protein & cell 57 27647131
2014 Inflammation and MiR-21 pathways functionally interact to downregulate PDCD4 in colorectal cancer. PloS one 57 25310697
2014 miRNA-183 suppresses apoptosis and promotes proliferation in esophageal cancer by targeting PDCD4. Molecules and cells 55 25518924
2010 Have tumor suppressor PDCD4 and its counteragent oncogenic miR-21 gone rogue? Molecular interventions 55 20368367
2019 MiR-21-5p enhances the progression and paclitaxel resistance in drug-resistant breast cancer cell lines by targeting PDCD4. Neoplasma 51 31169019
2017 Role of microRNA-21 in radiosensitivity in non-small cell lung cancer cells by targeting PDCD4 gene. Oncotarget 51 28423589
2016 miR-93 functions as an oncomiR for the downregulation of PDCD4 in gastric carcinoma. Scientific reports 51 27021515
2015 Targeting strategies on miRNA-21 and PDCD4 for glioblastoma. Archives of biochemistry and biophysics 51 26142886
2014 LPS induces the degradation of programmed cell death protein 4 (PDCD4) to release Twist2, activating c-Maf transcription to promote interleukin-10 production. The Journal of biological chemistry 50 24982420
2011 Ars2 is overexpressed in human cholangiocarcinomas and its depletion increases PTEN and PDCD4 by decreasing microRNA-21. Molecular carcinogenesis 50 22213145
2018 Long non-coding RNA CASC15 promotes melanoma progression by epigenetically regulating PDCD4. Cell & bioscience 48 30013768
2016 Regulation of the tumour suppressor PDCD4 by miR-499 and miR-21 in oropharyngeal cancers. BMC cancer 48 26867589
2014 Oxidative stress upregulates PDCD4 expression in patients with gastric cancer via miR-21. Current pharmaceutical design 48 23888942
2012 Tumour suppressive function and modulation of programmed cell death 4 (PDCD4) in ovarian cancer. PloS one 48 22272332
2019 Porphyromonas gingivalis Infection Promoted the Proliferation of Oral Squamous Cell Carcinoma Cells through the miR-21/PDCD4/AP-1 Negative Signaling Pathway. ACS infectious diseases 46 31243990
2001 The chicken Pdcd4 gene is regulated by v-Myb. Oncogene 46 11313950
2018 MicroRNA-16 Promotes Ovarian Granulosa Cell Proliferation and Suppresses Apoptosis Through Targeting PDCD4 in Polycystic Ovarian Syndrome. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 45 30025387
2017 microRNA-21a-5p/PDCD4 axis regulates mesenchymal stem cell-induced neuroprotection in acute glaucoma. Journal of molecular cell biology 45 28655163
2020 LncRNA-GAS5 regulates PDCD4 expression and mediates myocardial infarction-induced cardiomyocytes apoptosis via targeting MiR-21. Cell cycle (Georgetown, Tex.) 43 32308118
2017 MiR-155 inhibits proliferation and invasion by directly targeting PDCD4 in non-small cell lung cancer. Thoracic cancer 43 28842954
2020 Programmed cell death factor 4 (PDCD4), a novel therapy target for metabolic diseases besides cancer. Free radical biology & medicine 42 32745771
2014 Tumor suppressor PDCD4 inhibits NF-κB-dependent transcription in human glioblastoma cells by direct interaction with p65. Carcinogenesis 42 24413684
2004 Programmed cell death protein 4 (PDCD4) acts as a tumor suppressor in neuroendocrine tumor cells. Annals of the New York Academy of Sciences 42 15153438
2016 MiR-499-5p protects cardiomyocytes against ischaemic injury via anti-apoptosis by targeting PDCD4. Oncotarget 40 27231854
2018 Linc00472 suppresses proliferation and promotes apoptosis through elevating PDCD4 expression by sponging miR-196a in colorectal cancer. Aging 39 29930217
2016 miR-208a-3p suppresses cell apoptosis by targeting PDCD4 in gastric cancer. Oncotarget 39 27634902
2014 Pdcd4 modulates markers of macrophage alternative activation and airway remodeling in antigen-induced pulmonary inflammation. Journal of leukocyte biology 39 25097194
2016 PDCD4 Deficiency Aggravated Colitis and Colitis-associated Colorectal Cancer Via Promoting IL-6/STAT3 Pathway in Mice. Inflammatory bowel diseases 38 26891257
2020 miR-15a-5p and miR-21-5p contribute to chemoresistance in cytogenetically normal acute myeloid leukaemia by targeting PDCD4, ARL2 and BTG2. Journal of cellular and molecular medicine 37 33270982
2021 Andrographolide Suppresses the Growth and Metastasis of Luminal-Like Breast Cancer by Inhibiting the NF-κB/miR-21-5p/PDCD4 Signaling Pathway. Frontiers in cell and developmental biology 36 34249905
2019 MicroRNA-21-5p targeting PDCD4 suppresses apoptosis via regulating the PI3K/AKT/FOXO1 signaling pathway in tongue squamous cell carcinoma. Experimental and therapeutic medicine 36 31602231
2018 Berberine regulates the microRNA-21-ITGΒ4-PDCD4 axis and inhibits colon cancer viability. Oncology letters 36 29564000
2016 MicroRNA-21 and PDCD4 expression during in vitro oocyte maturation in pigs. Reproductive biology and endocrinology : RB&E 35 27084064
2010 Programmed cell death 4 (PDCD4) expression during multistep Barrett's carcinogenesis. Journal of clinical pathology 35 20702469
2018 The mechanisms and clinical significance of PDCD4 in colorectal cancer. Gene 34 30243936
2018 PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance. Molecular cancer research : MCR 34 30518628
2014 MicroRNA-21 Down-regulates Rb1 Expression by Targeting PDCD4 in Retinoblastoma. Journal of Cancer 34 25520758
2022 Dissecting the Roles of PDCD4 in Breast Cancer. Frontiers in oncology 33 35795053
2020 microRNA-199a-3p inhibits hepatic apoptosis and hepatocarcinogenesis by targeting PDCD4. Oncogenesis 33 33099584
2012 Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc. Biochimica et biophysica acta 33 22801218
2018 MicroRNA-421-targeted PDCD4 regulates breast cancer cell proliferation. International journal of molecular medicine 30 30365117
2013 The inhibitory action of PDCD4 in lipopolysaccharide/D-galactosamine-induced acute liver injury. Laboratory investigation; a journal of technical methods and pathology 28 23295647
2017 Effects of Trimetazidine on PDCD4/NF-κB/TNF-α Pathway in Coronary Microembolization. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 27 28683436
2013 Downregulation of programmed cell death 4 (PDCD4) in tumorigenesis and progression of human digestive tract cancers. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 27 23838800
2012 PTEN and PDCD4 are bona fide targets of microRNA-21 in human cholangiocarcinoma. Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih 27 22770403
2021 Long non-coding RNA KCNQ1OT1 increases the expression of PDCD4 by targeting miR-181a-5p, contributing to cardiomyocyte apoptosis in diabetic cardiomyopathy. Acta diabetologica 26 33907874
2020 The mTORC1/S6K/PDCD4/eIF4A Axis Determines Outcome of Mitotic Arrest. Cell reports 26 33027666
2015 IL-6 Inhibits the Targeted Modulation of PDCD4 by miR-21 in Prostate Cancer. PloS one 26 26252635
2020 LncRNA PDCD4-AS1 alleviates triple negative breast cancer by increasing expression of IQGAP2 via miR-10b-5p. Translational oncology 25 33248413
2021 LncRNA HOTAIR Promotes LPS-Induced Inflammation and Apoptosis of Cardiomyocytes via Lin28-Mediated PDCD4 Stability. Inflammation 23 33665757
2019 PDCD4 Knockdown Induces Senescence in Hepatoma Cells by Up-Regulating the p21 Expression. Frontiers in oncology 23 30687637
2017 Reduction of miR-21 induces SK-N-SH cell apoptosis and inhibits proliferation via PTEN/PDCD4. Oncology letters 23 28599474
2020 MicroRNA-21/PDCD4 Proapoptotic Signaling From Circulating CD34+ Cells to Vascular Endothelial Cells: A Potential Contributor to Adverse Cardiovascular Outcomes in Patients With Critical Limb Ischemia. Diabetes care 22 32358022
2017 A tyrosine kinase-STAT5-miR21-PDCD4 regulatory axis in chronic and acute myeloid leukemia cells. Oncotarget 22 29100302
2015 CRL3IBTK Regulates the Tumor Suppressor Pdcd4 through Ubiquitylation Coupled to Proteasomal Degradation. The Journal of biological chemistry 22 25882842
2016 Pdcd4 restrains the self-renewal and white-to-beige transdifferentiation of adipose-derived stem cells. Cell death & disease 21 27031966
2021 PDCD4 Simultaneously Promotes Microglia Activation via PDCD4-MAPK-NF-κB Positive Loop and Facilitates Neuron Apoptosis During Neuroinflammation. Inflammation 20 34613548
2021 miR-21-5p inhibits inflammation injuries in LPS-treated H9c2 cells by regulating PDCD4. American journal of translational research 20 34786071
2020 EIF3H interacts with PDCD4 enhancing lung adenocarcinoma cell metastasis. American journal of cancer research 20 32064160
2019 MicroRNA (miRNA)-to-miRNA Regulation of Programmed Cell Death 4 (PDCD4). Molecular and cellular biology 20 31235478
2021 Upregulation of miR-499a-5p Decreases Cerebral Ischemia/Reperfusion Injury by Targeting PDCD4. Cellular and molecular neurobiology 19 33837492
2021 circ-NOL10 regulated by MTDH/CASC3 inhibits breast cancer progression and metastasis via multiple miRNAs and PDCD4. Molecular therapy. Nucleic acids 19 34729247
2020 Gene deficiency or pharmacological inhibition of PDCD4-mediated FGR signaling protects against acute kidney injury. Acta pharmaceutica Sinica. B 19 33643819
2019 Long noncoding RNA TALNEC2 regulates myocardial ischemic injury in H9c2 cells by regulating miR-21/PDCD4-medited activation of Wnt/β-catenin pathway. Journal of cellular biochemistry 19 30861181
2022 Optimizing component formula suppresses lung cancer by blocking DTL-mediated PDCD4 ubiquitination to regulate the MAPK/JNK pathway. Journal of ethnopharmacology 18 35850313
2017 miR‑21 attenuates contrast‑induced renal cell apoptosis by targeting PDCD4. Molecular medicine reports 18 28901491
2021 Hsa_circ_0053063 inhibits breast cancer cell proliferation via hsa_circ_0053063/hsa-miR-330-3p/PDCD4 axis. Aging 17 33744861
2020 Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy. Cells 17 31952347
2020 RNA-binding proteins La and HuR cooperatively modulate translation repression of PDCD4 mRNA. The Journal of biological chemistry 17 33288677
2021 CircMKLN1 Suppresses the Progression of Human Retinoblastoma by Modulation of miR-425-5p/PDCD4 Axis. Current eye research 16 33988065