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Background  Most human cancers show inactivation of both pRB- and p53-pathways. While retinoblastomas are initiated by loss of the  RB1  tumor suppressor gene,  TP53  mutations have not been found. High expression of the p53-antagonist MDM2 in human retinoblastomas may compromise p53 tumor surveillance so that  TP53  mutations are not selected for in retinoblastoma tumorigenesis. We previously showed that p14 ARF  protein, which activates p53 by inhibiting MDM2, is low in retinoblastomas despite high mRNA expression.    Methods  In human fetal retinas, adult retinas, and retinoblastoma cells, we determined endogenous  p14 ARF   mRNA, ARF protein, and miR-24 expression, while integrity of p53 signalling in WERI-Rb1 cells was tested using an adenovirus vector expressing p14 ARF . To study p14 ARF  biogenesis, retinoblastoma cells were treated with the proteasome inhibitor, MG132, and siRNA against miR-24.    Results  In human retinoblastoma cell lines,  p14 ARF   mRNA was disproportionally high relative to the level of p14 ARF  protein expression, suggesting a perturbation of p14 ARF  regulation. When p14 ARF  was over-expressed by an adenovirus vector, expression of p53 and downstream targets increased and cell growth was inhibited indicating an intact p14 ARF -p53 axis. To investigate the discrepancy between  p14 ARF   mRNA and protein in retinoblastoma, we examined p14 ARF  biogenesis. The proteasome inhibitor, MG132, did not cause p14 ARF  accumulation, although p14 ARF  normally is degraded by proteasomes. miR-24, a microRNA that represses p14 ARF  expression, is expressed in retinoblastoma cell lines and correlates with lower protein expression when compared to other cell lines with high  p14 ARF   mRNA. Transient over-expression of siRNA against miR-24 led to elevated p14 ARF  protein in retinoblastoma cells.    Conclusions  In retinoblastoma cells where high levels of  p14 ARF   mRNA are not accompanied by high p14 ARF  protein, we found a correlation between miR-24 expression and low p14 ARF  protein. p14 ARF  protein levels were restored without change in mRNA abundance upon miR-24 inhibition suggesting that miR-24 could functionally repress expression, effectively blocking p53 tumor surveillance. During retinal tumorigenesis, miR-24 may intrinsically compromise the p53 response to  RB1  loss.

Regulation of p14ARF expression by miR-24: a potential mechanism compromising the p53 response during retinoblastoma development