Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic 
tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS) 
with the transcription factor FLI-1. However, expression of the EWS/FLI-1 
chimeric oncogene by itself is insufficient for carcinogenesis, suggesting that 
additional events are required. Here, we report the identification of the Akt 
substrate PRAS40 as an EWS target gene. EWS negatively regulates PRAS40 
expression by binding the 3' untranslated region in PRAS40 mRNA. ESFT cell 
proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell 
proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40 
knockdown. Furthermore, PRAS40 knockdown was sufficient to reverse an increased 
cell proliferation elicited by EWS knockdown. In support of a pathologic role 
for PRAS40 elevation in EFST, we documented inverse protein levels of EWS and 
PRAS40 in ESFT cells. Together, our findings suggest that PRAS40 promotes the 
development of ESFT and might therefore represent a novel therapeutic target in 
this aggressive disease.