Gene interactions and pathways from curated databases and text-mining
Nat Cell Biol 2001, PMID: 11283614

TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b.

Seoane, J; Pouponnot, C; Staller, P; Schader, M; Eilers, M; Massagué, J

Transforming growth factor-beta (TGFbeta) is a cytokine that arrests epithelial cell division by switching off the proto-oncogene c-myc and rapidly switching on cyclin-dependent kinase (CDK) inhibitors such as p15INK4b. Gene responses to TGFbeta involve Smad transcription factors that are directly activated by the TGFbeta receptor. Why downregulation of c-myc expression by TGFbeta is required for rapid activation of p15INK4b has remained unknown. Here we provide evidence that TGFbeta signalling prevents recruitment of Myc to the p15INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGFbeta-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. Thus, two separate TGFbeta-dependent inputs - Smad-mediated transactivation and relief of repression by Myc - keep tight control over p15INK4b activation.

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Text Mining Data

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Manually curated Databases

  • OpenBEL Selventa BEL large corpus: Complex of MYC-ZBTB17 → SMAD2 (decreases, MYC/ZBTB17 Activity)
    Evidence: Here we provide evidence that TGFbeta signalling prevents recruitment of Myc to the p15INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGFbeta-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. (from Weinberg - Pathways in Human Cancer poster, SMAD = SMAD 2/3) (MIZ-1 = ZBTB17)
  • OpenBEL Selventa BEL large corpus: ZBTB17 → SMAD2 (increases, SMAD2 Activity, ZBTB17 Activity)
    Evidence: Here we provide evidence that TGFbeta signalling prevents recruitment of Myc to the p15INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGFbeta-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. (from Weinberg - Pathways in Human Cancer poster, SMAD = SMAD 2/3) (MIZ-1 = ZBTB17)
  • OpenBEL Selventa BEL large corpus: Complex of MYC-ZBTB17 → SMAD3 (decreases, MYC/ZBTB17 Activity)
    Evidence: Here we provide evidence that TGFbeta signalling prevents recruitment of Myc to the p15INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGFbeta-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. (from Weinberg - Pathways in Human Cancer poster, SMAD = SMAD 2/3) (MIZ-1 = ZBTB17)
  • OpenBEL Selventa BEL large corpus: ZBTB17 → SMAD3 (increases, SMAD3 Activity, ZBTB17 Activity)
    Evidence: Here we provide evidence that TGFbeta signalling prevents recruitment of Myc to the p15INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGFbeta-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. (from Weinberg - Pathways in Human Cancer poster, SMAD = SMAD 2/3) (MIZ-1 = ZBTB17)
  • OpenBEL Selventa BEL large corpus: MYC → Complex of MYC-ZBTB17 (directlyIncreases, MYC/ZBTB17 Activity)
    Evidence: Here we provide evidence that TGFbeta signalling prevents recruitment of Myc to the p15INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGFbeta-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. (from Weinberg - Pathways in Human Cancer poster, SMAD = SMAD 2/3) (MIZ-1 = ZBTB17)
  • NCI Pathway Database Regulation of nuclear SMAD2/3 signaling: SMAD2-3/SMAD4/SP1/MIZ-1 complex (SMAD2_SMAD3-SMAD4-SP1-ZBTB17) → SMAD2-3/SMAD4/SP1 complex (SMAD2_SMAD3-SMAD4-SP1) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Regulation of nuclear SMAD2/3 signaling: SMAD2-3/SMAD4/SP1/MIZ-1 complex (SMAD2_SMAD3-SMAD4-SP1-ZBTB17) → MIZ-1 (ZBTB17) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Regulation of nuclear SMAD2/3 signaling: SMAD2-3/SMAD4/SP1 complex (SMAD2_SMAD3-SMAD4-SP1) → MIZ-1 (ZBTB17) (modification, collaborate)
    Evidence: mutant phenotype, physical interaction
  • NCI Pathway Database Regulation of nuclear SMAD2/3 signaling: MYC/MIZ-1 complex (MYC-ZBTB17) → p15INK4b (CDKN2B) (transcription, inhibits)
    Evidence: mutant phenotype, reporter gene, physical interaction
  • NCI Pathway Database Regulation of nuclear SMAD2/3 signaling: MYC/MIZ-1 complex (MYC-ZBTB17) → SMAD3/SMAD4 complex (SMAD3-SMAD4) (transcription, inhibits)
    Evidence: mutant phenotype, reporter gene, physical interaction
  • NCI Pathway Database Regulation of nuclear SMAD2/3 signaling: MYC/MIZ-1 complex (MYC-ZBTB17) → SMAD2-3/SMAD4/SP1/MIZ-1 complex (SMAD2_SMAD3-SMAD4-SP1-ZBTB17) (transcription, inhibits)
    Evidence: mutant phenotype, reporter gene, physical interaction
  • NCI Pathway Database Regulation of nuclear SMAD2/3 signaling: SMAD3/SMAD4 complex (SMAD3-SMAD4) → SMAD2-3/SMAD4/SP1/MIZ-1 complex (SMAD2_SMAD3-SMAD4-SP1-ZBTB17) (transcription, inhibits)
    Evidence: mutant phenotype, reporter gene, physical interaction
  • NCI Pathway Database Validated targets of C-MYC transcriptional repression: SMAD2-3/SMAD4/MYC/Max/MIZ-1 complex (MYC-MAX-ZBTB17-SMAD2_SMAD3-SMAD4) → SMAD2-3/SMAD4/SP1 complex (SMAD2_SMAD3-SMAD4-SP1) (transcription, inhibits)
    Evidence: mutant phenotype, reporter gene, physical interaction
In total, 28 gene pairs are associated to this article in curated databases