Cooperation between Rb and Arf in suppressing mouse retinoblastoma.

Publication Type:

Journal Article


The Journal of clinical investigation, Volume 122, Issue 5, p.1726-33 (2012)


ADP-Ribosylation Factors, Animals, Base Sequence, Cell Proliferation, Cell Transformation, Neoplastic, COMPARATIVE GENOMIC HYBRIDIZATION, Cyclin-Dependent Kinase Inhibitor p16, Genes, Retinoblastoma, Humans, loss of heterozygosity, MICE, Mice, Knockout, Retinal Neoplasms, Retinoblastoma, Retinoblastoma Protein, Retinoblastoma-Like Protein p107, Sequence Deletion, Signal Transduction, Tumor Suppressor Protein p53


Retinoblastoma is a pediatric cancer that has served as a paradigm for tumor suppressor gene function. Retinoblastoma is initiated by RB gene mutations, but the subsequent cooperating mutational events leading to tumorigenesis are poorly characterized. We investigated what these additional genomic alterations might be using human retinoblastoma samples and mouse models. Array-based comparative genomic hybridization studies revealed deletions in the CDKN2A locus that include ARF and P16INK4A, both of which encode tumor suppressor proteins, in both human and mouse retinoblastoma. Through mouse genetic analyses, we found that Arf was the critical tumor suppressor gene in the deleted region. In mice, inactivation of one allele of Arf cooperated with Rb and p107 loss to rapidly accelerate retinoblastoma, with frequent loss of heterozygosity (LOH) at the Arf locus. Arf has been reported to exhibit p53-independent tumor suppressor roles in other systems; however, our results showed no additive effect of p53 and Arf coinactivation in promoting retinoblastoma. Moreover, p53 inactivation completely eliminated any selection for Arf LOH. Thus, our data reveal important insights into the p53 pathway in retinoblastoma and show that Arf is a key collaborator with Rb in retinoblastoma suppression.