This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pérez de Castro, I. Articles by Pellicer, A. Search for Related Content PubMed PubMed Citation Articles by Pérez de Castro, I. Articles by Pellicer, A.

Mouse p10, an Alternative Spliced Form of p15^INK4b, Inhibits Cell Cycle Progression and Malignant Transformation

¹ Department of Pathology and New York University Cancer Institute, New York University School of Medicine, New York, New York; ² Molecular Oncology and ³ Experimental Therapeutics Programs, Centro Nacional de Investigaciones Oncologicas CNIO, Madrid, Spain

Requests for reprints: Ignacio Pérez de Castro, Molecular Oncology Program, Centro Nacional de Investigaciones Oncologicas, Melchor Fernandez Almagro 3, Madrid 28029, Spain. Phone: 34-91-224-6900; Fax: 34-91-732-8033; E-mail: iperez{at}cnio.es.

The INK4 family of proteins negatively regulates cell cycle progression at the G₁-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-ß 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.