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| Retinoblastoma: Adding p53 to the mix
Retinoblastomas amplify inhibitors of the p53 signaling pathway leading to cell survival and tumor progression. p53 and Retinoblastoma (Rb) were the first two tumor-suppressor genes discovered and both have subsequently been implicated in almost all cancers. Rb controls cell proliferation and p53 mediates cell cycle arrest or apoptosis in response to cellular stress. While p53 is inactivated almost universally in cancers, retinoblastomas — which are initiated by an Rb mutation — express wild-type p53. It was hypothesized that retinoblastoma arises from cells that are intrinsically resistant to death and are therefore able to bypass the p53 pathway. However, findings presented in Nature reveal that Rb-deficient retinoblastomas can undergo p53-mediated apoptosis and that the p53 pathway is inactivated through amplification of the p53 antagonists MDMX or MDM2.
p14ARF is a key player in the p53 cellular response pathway; upon cellular stress E2F activates p14ARF transcription leading to the inactivation of the ubiquitin ligase MDM2 and hence de-repression of p53-mediated apoptosis. The authors demonstrate that p14ARF expression is increased in retinoblastomas as well as in primary human fetal retinas after siRNA or conditional knockout of Rb. The MDM2-related gene MDMX was amplified in 65% of retinoblastoma samples analyzed, while the p53 pathway downstream of MDMX was intact in retinoblastoma cells. While deletion of Rb and p107 leads to an increased susceptibility to retinoblastoma, additional deletion of p53 causes complete cancer penetrance with highly aggressive tumors. Transient MDMX overexpression in Rb;p107-deficient retinas increased proliferation and survival of the developing retinal cells that expressed the retinoblastoma marker Pax6. Rb siRNA knockdown in human embryonic retinas resulted in extensive apoptosis, which was alleviated by co-expression of MDMX. The use of mutant MDMX that is unable to bind p53 confirmed that the suppression of cell death was specific to the p53 pathway. Nutlin-3, a small molecule inhibitor of the MDM protein-p53 interaction induces the p53 pathway and kills retinoblastoma cells with MDMX amplification in culture. The long standing view that retinoblastoma cells are death-resistant and retain a functional p53 pathway has been challenged by these findings. Furthermore, nutlin-3 may provide an enticing alternative to chemotherapy for children with retinoblastoma, as well as other cancers with MDMX amplifications. Clare Garvey References | |
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