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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.

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


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.


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

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