Regulation of c-MYC transcriptional activity by transforming growth factor-beta 1-stimulated clone 22

Cancer Sci. 2018 Feb;109(2):395-402. doi: 10.1111/cas.13466. Epub 2018 Jan 9.

Abstract

c-MYC stimulates cell proliferation through the suppression of cyclin-dependent kinase (CDK) inhibitors including P15 (CDKN2B) and P21 (CDKN1A). It also activates E-box-mediated transcription of various target genes including telomerase reverse transcriptase (TERT) that is involved in cellular immortality and tumorigenesis. Transforming growth factor-beta 1 (TGF-β1)-stimulated clone 22 (TSC-22/TSC22D1) encodes a highly conserved leucine zipper protein that is induced by various stimuli, including TGF-β. TSC-22 inhibits cell growth in mammalian cells and in Xenopus embryos. However, underlying mechanisms of growth inhibition by TSC-22 remain unclear. Here, we show that TSC-22 physically interacts with c-MYC to inhibit the recruitment of c-MYC on the P15 (CDKN2B) and P21 (CDKN1A) promoters, effectively inhibiting c-MYC-mediated suppression of P15 (CDKN2B) and also P21 (CDKN1A) promoter activities. In contrast, TSC-22 enhances c-MYC-mediated activation of the TERT promoter. Additionally, the expression of TSC-22 in embryonic stem cells inhibits cell growth without affecting its pluripotency-related gene expression. These results indicate that TSC-22 differentially regulates c-MYC-mediated transcriptional activity to regulate cell proliferation.

Keywords: TSC-22; c-MYC; cyclin-dependent kinase inhibitor; growth inhibition; transcriptional regulation.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Enzyme Activation
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Promoter Regions, Genetic
  • Protein Domains
  • Proto-Oncogene Proteins c-myc / chemistry
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Repressor Proteins / chemistry
  • Repressor Proteins / metabolism*
  • Telomerase / genetics*
  • Transcription, Genetic

Substances

  • CDKN1A protein, human
  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p21
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • TSC22D1 protein, human
  • TERT protein, human
  • Telomerase