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

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

Author information

1
Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
2
Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

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

PMID:
29224245
PMCID:
PMC5797808
DOI:
10.1111/cas.13466
[Indexed for MEDLINE]
Free PMC Article

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