e myc/+ , l24 , l38 and p53 mice were all maintained on a c57/bl6 background . moribund mice or mice with obvious tumors were sacrificed , and tumors and different organs were analyzed by histology or processed for further analysis . primary b - lymphocytes were isolated from spleen or bone marrow from 4 - 5 week old mice utilizing an automacs separator ( miltenyi biotec ) . primary b - lymphocytes and mefs were synchronized in mitosis by thymidine and aphidicolin block , respectively . ires - dependent expression of the endogenous cdk11/p58 was assessed by western blot utilizing anti - cdk11/p58 ( abcam ) . equal numbers of freshly isolated or cultured primary b - lymphocytes synchronized in s phase or mitosis were incubated in methionine - free dmem and then 50 ci / well ( 25 uci / ml ) of [ s ] methionine was added to the cultures for 35 minutes . radiolabeled proteins were visualized by exposure to x - ray film and quantified by densitometry analysis . freshly isolated and cultured b - lymphocytes from 4 - 5 week old mice were fixed and stained with the following combination of mabs conjugated with fitc or pe : cd19-pe / cd3-fitc , cd4-pe / cd8-fitc , cd43-pe / cd45r - b220-fitc . genomic dna extracted from lymphomas of emyc/+ mice , and emyc/+;l24 mice was subjected to cgh analysis by standard methods . for cytokinesis analysis , primary mefs were stably transfected with mycer harboring puromycin resistance or p58 cdna plus mycer via a phoenix viral vector and cultured . upon release from aphidicolin , myc was activated by the addition of hydroxytamoxifen . at the 20 hour time point , cells were fixed and stained . e myc/+ , l24 , l38 and p53 mice were all maintained on a c57/bl6 background . moribund mice or mice with obvious tumors were sacrificed , and tumors and different organs were analyzed by histology or processed for further analysis . primary b - lymphocytes were isolated from spleen or bone marrow from 4 - 5 week old mice utilizing an automacs separator ( miltenyi biotec ) . primary b - lymphocytes and mefs were synchronized in mitosis by thymidine and aphidicolin block , respectively . ires - dependent expression of the endogenous cdk11/p58 was assessed by western blot utilizing anti - cdk11/p58 ( abcam ) . equal numbers of freshly isolated or cultured primary b - lymphocytes synchronized in s phase or mitosis were incubated in methionine - free dmem and then 50 ci / well ( 25 uci / ml ) of [ s ] methionine was added to the cultures for 35 minutes . radiolabeled proteins were visualized by exposure to x - ray film and quantified by densitometry analysis . freshly isolated and cultured b - lymphocytes from 4 - 5 week old mice were fixed and stained with the following combination of mabs conjugated with fitc or pe : cd19-pe / cd3-fitc , cd4-pe / cd8-fitc , cd43-pe / cd45r - b220-fitc . genomic dna extracted from lymphomas of emyc/+ mice , and emyc/+;l24 mice was subjected to cgh analysis by standard methods . for cytokinesis analysis , primary mefs were stably transfected with mycer harboring puromycin resistance or p58 cdna plus mycer via a phoenix viral vector and cultured . upon release from aphidicolin , myc was activated by the addition of hydroxytamoxifen . at the 20 hour time point , cells were fixed and stained .
the myc oncogene regulates the expression of multiple components of the protein synthetic machinery , including ribosomal proteins , initiation factors of translation , pol iii , and rdna1,2 . 
 an outstanding question is whether and how increasing the cellular protein synthesis capacity can affect the multi - step process leading to cancer . 
 we utilized ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in emyc/+ transgenic mice to normal levels and show that in this context myc 's oncogenic potential is suppressed . 
 our findings demonstrate that the ability of myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by myc . 
 in addition , when protein synthesis is restored to normal levels , myc overexpressing precancerous cells are more efficiently eliminated by programmed cell death . 
 our findings reveal a novel paradigm that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation employed to regulate the expression of selective mrnas . 
 we show that an aberrant increase in cap - dependent translation downstream myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site ( ires)-dependent translation required for accurate mitotic progression . 
 failure of this translational switch results in reduced mitotic - specific expression of the endogenous ires - dependent form of cdk11 ( p58-pitslre)3 - 5 , which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in emyc/+ mice . when accurate translational control is re - established in emyc/+ mice , genome instability is suppressed . 
 our findings reveal how perturbations in translational control provide a highly specific outcome on gene expression , genome stability , and cancer initiation that have important implications for understanding the molecular mechanism of cancer formation at the post - genomic level .