Transcriptional factor HBP1 targets P16(INK4A), upregulating its expression and consequently is involved in Ras-induced premature senescence

Oncogene. 2010 Sep 9;29(36):5083-94. doi: 10.1038/onc.2010.252. Epub 2010 Jun 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Gene Expression Regulation
  • High Mobility Group Proteins / genetics
  • High Mobility Group Proteins / metabolism
  • High Mobility Group Proteins / physiology*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Models, Biological
  • Oncogene Protein p21(ras) / genetics
  • Oncogene Protein p21(ras) / metabolism
  • Oncogene Protein p21(ras) / physiology*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Repressor Proteins / physiology*
  • Time Factors
  • Transcription Factors / metabolism
  • Transcription Factors / physiology
  • Transplantation, Heterologous
  • Up-Regulation


  • Cyclin-Dependent Kinase Inhibitor p16
  • HBP1 protein, human
  • High Mobility Group Proteins
  • Repressor Proteins
  • Transcription Factors
  • Oncogene Protein p21(ras)