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

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

Clinical implications of DLL4 expression in gastric cancer

BACKGROUND: Delta-like ligand 4 (DLL4)-Notch signaling plays a key role in tumor neovascular development and angiogenesis during tumor growth. The clinical significance of DLL4 expression in gastric cancer has not been clarified. METHODS: Gastric cancer cell lines and 180 gastric cancer patients were enrolled. DLL4 expression in gastric cancer cells and stroma was identified and evaluated immunohistochemically. The association between DLL4 and clinicopathological factors was also assessed. RESULTS: DLL4 expression was identified in the cellular membrane and cytoplasm of gastric cancer cells by immunoblotting and immunohistochemical staining. DLL4 positivity in cancer cells and stroma was found in 88 (48%) and 41 (22%) of the 180 gastric cancer patients respectively. Both cancer and stromal DLL4 expression significantly correlated with more advanced tumor depth, nodal involvement, and lymphatic and venous invasion. A strongly positive association between cancerous and stromal DLL4 expression was identified (p < 0.01). Both cancerous and stromal DLL4 expression were prognostic markers in gastric cancer as determined by univariate analysis. CONCLUSIONS: Cancerous and stromal DLL4 expression was found in 48% and 22% in gastric cancer, and significantly affected postoperative clinical outcomes. Cancerous and stromal DLL4 expression may be an effective target of anti-DLL4 treatment in gastric cancer