Tumor suppressor, AT motif binding factor 1 (ATBF1), translocates to the nucleus with runt domain transcription factor 3 (RUNX3) in response to TGF-{beta} signal transduction
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya (Japan)
- Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya (Japan)
- Department of Pathology, Niigata Rosai Hospital, Japan Labor Health and Welfare Organization, Niigata (Japan)
Research highlights: {yields} Significant correlation between ATBF1 and RUNX3 nuclear localization in gastric cancer. {yields} Co-IP reveals a physical association between ATBF1 and RUNX3. {yields} ATBF1 and RUNX3 up-regulates p21 promoter activity synergistically. {yields} TGF-{beta}1 induces endogenous ATBF1 and RUNX3 nuclear translocation. -- Abstract: Background and aims: AT motif binding factor 1 (ATBF1), a homeotic transcription factor, was identified as a tumor suppressor, and loss of heterozygosity at ATBF1 locus occurs frequently in gastric cancers. We previously showed that ATBF1 expression inversely correlated with the malignant character of gastric cancer and that ATBF1 enhanced the promoter activity of p21{sup Waf1/Cip1}. We also found that ATBF1 moves between cytoplasm and nucleus, but the precise mechanism of translocation is unknown. In this study, we investigated the mechanism of ATBF1 translocation to the nucleus with the runt domain transcription factor 3 (RUNX3) in cooperation with TGF-{beta} signal transduction. Materials and methods: To analyze the expression of ATBF1 and RUNX3 in gastric cancer cells, we performed immunohistochemistry on 98 resected gastric cancer tissue samples and scored the nuclear staining intensity as grade 0 to grade 5. Co-immunoprecipitation (co-IP) of ATBF1 and RUNX3 was performed. Dual luciferase assays were performed by transfecting ATBF1 and RUNX3 with a p21{sup Waf1/Cip1} reporter vector. To investigate the nuclear translocation of endogenous ATBF1 and RUNX3 in response to TGF-{beta} signal, we examined the subcellular localization of ATBF1 and RUNX3 in gastric cancer cells treated with recombinant TGF-{beta}1 using confocal laser scanning microscopy. Results: Strong immunohistochemical nuclear staining of ATBF1 was observed in 37 (37.8%) of the gastric cancer tissue samples, and RUNX3 nuclear staining was observed in 15 (15.3%). There was a statistically significant correlation between ATBF1 and RUNX3 nuclear localization (rs = 0.433, p < 0.001). Co-IP revealed a physical association between ATBF1 and RUNX3. ATBF1 and RUNX3 up-regulated p21{sup Waf1/Cip1} promoter activity synergistically. In SNU16 gastric cancer cells, ATBF1 and RUNX3 were cytoplasmic before TGF-{beta}1 stimulation, but after 24 h of TGF-{beta}1 stimulation, endogenous ATBF1 and RUNX3 translocated to the nucleus. Conclusion: ATBF1 associates with RUNX3 and translocates to the nucleus in response to TGF-{beta} signal transduction and might function in the nucleus as tumor suppressor and transcriptional regulator.
- OSTI ID:
- 22202706
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 398, Issue 2; Other Information: Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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