Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence
| Autor: | K E Paulson, Weibin Wang, Amy S. Yee, Hanxiao Li, Xiangguo Liu, Xiaowei Zhang |
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| Rok vydání: | 2010 |
| Předmět: |
Senescence
Cancer Research Time Factors Tumor suppressor gene Transplantation Heterologous Heterologous Mice SCID Oncogene Protein p21(ras) Biology medicine.disease_cause Models Biological Mice Downregulation and upregulation Mice Inbred NOD Transcription (biology) Genetics medicine Animals Humans Molecular Biology Cells Cultured Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 Regulation of gene expression High Mobility Group Proteins Up-Regulation Repressor Proteins Transplantation Cell Transformation Neoplastic Gene Expression Regulation Cancer research Carcinogenesis Transcription Factors |
| Zdroj: | Oncogene. 29:5083-5094 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2010.252 |
| Popis: | 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 p16(INK4A) cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16(INK4A) gene contains an HBP1-binding site at position -426 to -433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16(INK4A) gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16(INK4A) gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16(INK4A) 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. |
| Databáze: | OpenAIRE |
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