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

Ignacio Pérez De Castro, Marta Benet, María Jiménez, Saba Alzabin, Marcos Malumbres, Angel Pellicer

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The INK4 family of proteins negatively regulates cell cycle progression at the GI-S transition by inhibiting cyclin-dependent kinases. Two of these cell cycle inhibitors, p16INK4A and p15INK4B, 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 p15INK4B 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 p15INK4B, p10 expression is also induced by oncogenic insults and transforming growth factor-β 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.

Original languageEnglish
Pages (from-to)3249-3256
Number of pages8
JournalCancer Research
Volume65
Issue number8
DOIs
StatePublished - 15 Apr 2005
Externally publishedYes

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