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UCSC Genome Browser Gene Interaction Graph
Gene interactions and pathways from curated databases and text-mining
Nature 2004, PMID: 15356634

Cytoplasmic PML function in TGF-beta signalling.

Lin, Hui-Kuan; Bergmann, Stephan; Pandolfi, Pier Paolo

Transforming growth factor beta (TGF-beta) is a pluripotent cytokine that controls key tumour suppressive functions, but cancer cells are often unresponsive to it. The promyelocytic leukaemia (PML) tumour suppressor of acute promyelocytic leukaemia (APL) accumulates in the PML nuclear body, but cytoplasmic PML isoforms of unknown function have also been described. Here we show that cytoplasmic Pml is an essential modulator of TGF-beta signalling. Pml-null primary cells are resistant to TGF-beta-dependent growth arrest, induction of cellular senescence and apoptosis. These cells also have impaired phosphorylation and nuclear translocation of the TGF-beta signalling proteins Smad2 and Smad3, as well as impaired induction of TGF-beta target genes. Expression of cytoplasmic Pml is induced by TGF-beta. Furthermore, cytoplasmic PML physically interacts with Smad2/3 and SARA (Smad anchor for receptor activation) and is required for association of Smad2/3 with SARA and for the accumulation of SARA and TGF-beta receptor in the early endosome. The PML-RARalpha oncoprotein of APL can antagonize cytoplasmic PML function and APL cells have defects in TGF-beta signalling similar to those observed in Pml-null cells. Our findings identify cytoplasmic PML as a critical TGF-beta regulator, and further implicate deregulated TGF-beta signalling in cancer pathogenesis.

Diseases/Pathways annotated by Medline MESH: Leukemia, Promyelocytic, Acute
Document information provided by NCBI PubMed

Text Mining Data

Smad2/3 → PML: " Furthermore, cytoplasmic PML physically interacts with Smad2/3 and SARA ( Smad anchor for receptor activation ) and is required for association of Smad2/3 with SARA and for the accumulation of SARA and TGF-beta receptor in the early endosome "

Smad2/3 → PML: " Furthermore, cytoplasmic PML physically interacts with Smad2/3 and SARA ( Smad anchor for receptor activation ) and is required for association of Smad2/3 with SARA and for the accumulation of SARA and TGF-beta receptor in the early endosome "

Manually curated Databases

  • IRef Bind Interaction: PML — ZFYVE9
  • IRef Bind Interaction: Complex of PML-SMAD3-ZFYVE9
  • IRef Bind Interaction: Complex of PML-ZFYVE9-SMAD3-TGFBR1
  • IRef Bind Interaction: SMAD2 — PML
  • IRef Bind Interaction: SMAD3 — PML
  • IRef Bind Interaction: TGFBR1 — PML
  • IRef Bind_translation Interaction: PML — ZFYVE9 (coimmunoprecipitation)
  • IRef Bind_translation Interaction: PML — ZFYVE9 (imaging technique)
  • IRef Bind_translation Interaction: PML — ZFYVE9 (cosedimentation through density gradient)
  • IRef Bind_translation Interaction: SMAD2 — PML (coimmunoprecipitation)
  • IRef Bind_translation Interaction: TGFBR2 — PML (coimmunoprecipitation)
  • IRef Bind_translation Interaction: TGFBR2 — PML (cosedimentation through density gradient)
  • IRef Bind_translation Interaction: SMAD3 — PML (coimmunoprecipitation)
  • IRef Bind_translation Interaction: SMAD3 — PML (imaging technique)
  • IRef Bind_translation Interaction: TGFBR1 — PML (cosedimentation through density gradient)
  • IRef Bind_translation Interaction: TGFBR1 — PML (coimmunoprecipitation)
  • IRef Biogrid Interaction: ZFYVE9 — PML (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SMAD3 — ZFYVE9 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SMAD2 — PML (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SMAD3 — PML (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SMAD2 — ZFYVE9 (physical association, affinity chromatography technology)
  • MIPS CORUM PML-SMAD2/3-SARA complex: PML-SMAD2/3-SARA complex complex (PML-SMAD2-SMAD3-ZFYVE9)
  • IRef Corum Interaction: Complex of ZFYVE9-PML-SMAD3-SMAD2 (association, anti tag coimmunoprecipitation)
  • IRef Hprd Interaction: PML — ZFYVE9 (in vivo)
  • IRef Hprd Interaction: Complex of PML-SMAD3-SMAD2-SMAD2-SMAD3-PML-PML-SMAD3-SMAD2 (in vivo)
  • IRef Hprd Interaction: TGFBR2 — PML (in vivo)
  • IRef Hprd Interaction: PML — SMAD3 (in vivo)
  • IRef Hprd Interaction: PML — TGFBR1 (in vivo)
  • NCI Pathway Database TGF-beta receptor signaling: SMAD7/SMURF1-2 complex (SMAD7-SMURF1_SMURF2) → TGFB/TGFBR2/TGFBR1/PML/SARA/SMAD2-3/AP2B2 complex (TGFBR1-PML-ZFYVE9-SMAD2_SMAD3-TGFBR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: SMAD7/SMURF1-2 complex (SMAD7-SMURF1_SMURF2) → TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: SMAD7/SMURF1-2 complex (SMAD7-SMURF1_SMURF2) → Caveolin-1 (CAV1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: SMAD7/SMURF1-2 complex (SMAD7-SMURF1_SMURF2) → TGFB/TGFBR2/TGFBR1/SMAD7/SMURF1-2/CAV1 complex (TGFBR1-SMAD7-SMURF1_SMURF2-CAV1-TGFBR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: SMAD7/SMURF1-2 complex (SMAD7-SMURF1_SMURF2) → PML/SARA/SMAD2-3 complex (ZFYVE9-SMAD2_SMAD3-PML) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: SMAD7/SMURF1-2 complex (SMAD7-SMURF1_SMURF2) → FKBP12 (FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1/PML/SARA/SMAD2-3/AP2B2 complex (TGFBR1-PML-ZFYVE9-SMAD2_SMAD3-TGFBR2) → TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1/PML/SARA/SMAD2-3/AP2B2 complex (TGFBR1-PML-ZFYVE9-SMAD2_SMAD3-TGFBR2) → Caveolin-1 (CAV1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1/PML/SARA/SMAD2-3/AP2B2 complex (TGFBR1-PML-ZFYVE9-SMAD2_SMAD3-TGFBR2) → TGFB/TGFBR2/TGFBR1/SMAD7/SMURF1-2/CAV1 complex (TGFBR1-SMAD7-SMURF1_SMURF2-CAV1-TGFBR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1/PML/SARA/SMAD2-3/AP2B2 complex (TGFBR1-PML-ZFYVE9-SMAD2_SMAD3-TGFBR2) → PML/SARA/SMAD2-3 complex (ZFYVE9-SMAD2_SMAD3-PML) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) → Caveolin-1 (CAV1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) → TGFB/TGFBR2/TGFBR1/SMAD7/SMURF1-2/CAV1 complex (TGFBR1-SMAD7-SMURF1_SMURF2-CAV1-TGFBR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) → PML/SARA/SMAD2-3 complex (ZFYVE9-SMAD2_SMAD3-PML) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1 complex (TGFBR1-TGFBR2) → FKBP12 (FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: Caveolin-1 (CAV1) → TGFB/TGFBR2/TGFBR1/SMAD7/SMURF1-2/CAV1 complex (TGFBR1-SMAD7-SMURF1_SMURF2-CAV1-TGFBR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: Caveolin-1 (CAV1) → PML/SARA/SMAD2-3 complex (ZFYVE9-SMAD2_SMAD3-PML) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: Caveolin-1 (CAV1) → FKBP12 (FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: TGFB/TGFBR2/TGFBR1/SMAD7/SMURF1-2/CAV1 complex (TGFBR1-SMAD7-SMURF1_SMURF2-CAV1-TGFBR2) → PML/SARA/SMAD2-3 complex (ZFYVE9-SMAD2_SMAD3-PML) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
  • NCI Pathway Database TGF-beta receptor signaling: PML/SARA/SMAD2-3 complex (ZFYVE9-SMAD2_SMAD3-PML) → FKBP12 (FKBP1A) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction, other species
In total, 65 gene pairs are associated to this article in curated databases