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Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Abstract

Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Many studies showed that Ras and p38 mitogen-activated protein kinase (MAPK) participate in premature senescence. Our previous work indicated that the HMG box-containing protein 1 (HBP1) transcription factor is involved in Ras- and p38 MAPK-induced premature senescence, but the mechanism of which has not yet been identified. Here, we showed that the p16INK4A cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16INK4A gene contains an HBP1-binding site at position −426 to −433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16INK4A gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16INK4A gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16INK4A to trigger premature senescence. In addition, we report that HBP1 knockdown is also required for Ras-induced transformation. All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (no. 30770442) to Xiaowei Zhang, and from the National Basic Research Programs of China (no. 2007CB507400) to Tanjun Tong; from the NIH/NCI (CA94187 and CA104236) to Amy S Yee and the Susan B Komen Foundation for the Cure (BCTR0504367) to K Eric Paulson. We thank Dr Wengong Wang for helpful discussion on the paper.

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Li, H., Wang, W., Liu, X. et al. Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence. Oncogene 29, 5083–5094 (2010). https://doi.org/10.1038/onc.2010.252

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