Mouse p10, an alternative spliced form of p15INK4b, inhibits cell cycle progression and malignant transformation

Cancer Res. 2005 Apr 15;65(8):3249-56. doi: 10.1158/0008-5472.CAN-03-3445.


The INK4 family of proteins negatively regulates cell cycle progression at the G(1)-S transition by inhibiting cyclin-dependent kinases. Two of these cell cycle inhibitors, p16(INK4A) and p15(INK4B), have tumor suppressor activities and are inactivated in human cancer. Interestingly, both INK4 genes express alternative splicing variants. In addition to p16(INK4A), the INK4A locus encodes a splice variant, termed p12--specifically expressed in human pancreas--and ARF, a protein encoded by an alternative reading frame that acts as a tumor suppressor through the p53 pathway. Similarly, the human INK4B locus encodes the p15(INK4B) tumor suppressor and one alternatively spliced form, termed as p10. We show here that p10, which arises from the use of an alternative splice donor site within intron 1, is conserved in the mouse genome and is widely expressed in mouse tissues. Similarly to mouse p15(INK4B), p10 expression is also induced by oncogenic insults and transforming growth factor-beta treatment and acts as a cell cycle inhibitor. Importantly, we show that mouse p10 is able to induce cell cycle arrest in a p53-dependent manner. We also show that mouse p10 is able to inhibit foci formation and anchorage-independent growth in wild-type mouse embryonic fibroblasts, and that these antitransforming properties of mouse p10 are also p53-dependent. These results indicate that the INK4B locus, similarly to INK4A-ARF, harbors two different splicing variants that can be involved in the regulation of both the p53 and retinoblastoma pathways, the two major molecular pathways in tumor suppression.

Publication types

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

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Cycle / genetics
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics*
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • Cyclin-Dependent Kinase Inhibitor p15
  • Genes, ras / genetics
  • Mice
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Protein Isoforms
  • Retinoblastoma Protein / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / pharmacology
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / genetics*


  • Cdkn2b protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p15
  • Protein Isoforms
  • Retinoblastoma Protein
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins