Inhibition of Ribosome Biogenesis Causes p53-Dependent Death and p53-Independent Dysfunction.

Ribosomes are critical for cell function; their synthesis (known as ribosome biogenesis; "RiBi") is complex and energy-intensive. Surprisingly little is known about RiBi in differentiated cells in adult tissue. Here, we generated mice with conditional deletion of , an essential gene for RiBi and translation, to investigate effects of RiBi blockade We focused on RiBi in a long-lived, ribosome-rich cell population, pancreatic acinar cells, during homeostasis and tumorigenesis. We observed a surprising latency of several weeks between deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death, which was associated with translocation of ribosomal proteins RPL5 and RPL11 into acinar cell nucleoplasm. Indeed, deletion of could rescue acinar cells from apoptotic cell death; however, acinar cells remained morphologically and functionally abnormal. Moreover, the deletion of did not rescue the lethality of inducible, globally deleted in adult mice nor did it rescue embryonic lethality of global deletion, emphasizing p53-independent consequences of RiBi inhibition. Deletion of in acinar cells blocked -oncogene-driven pancreatic intraepithelial neoplasia and subsequent pancreatic ductal adenocarcinoma, regardless of mutation status. Together, our results provide initial insights into how cells respond to defects in RiBi and translation .