Transcriptional factor HBP1 targets [P16.sup.INK4A], upregulating its expression and consequently is involved in Ras-induced premature senescence

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.sup.INK4A] cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the [p16.sup.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.sup.INK4A] gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of [p16.sup.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.sup.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. Oncogene (2010) 29, 5083-5094; doi: 10.1038/onc.2010.252; published online 28 June 2010 Keywords: Ras; HBP1; [p16.sup.INK4A]; senescence; transformation