Inhibition of Ribosome Biogenesisin vivoCauses p53-Dependent Death and p53-Independent Dysfunction

Abstract

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 vivo in adult tissue. Here, we generated mice with conditional deletion ofNat10, an essential gene for RiBi and translation, to investigate effects of RiBi blockadein vivo. 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 betweenNat10deletion 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 ofTrp53could rescue acinar cells from apoptotic cell death; however,Nat10∆/∆; Trp53∆/∆acinar cells remained morphologically and functionally abnormal. Moreover, the deletion ofTrp53did not rescue the lethality of inducible, globally deletedNat10in adult mice nor did it rescue embryonic lethality of globalNat10deletion, emphasizing p53-independent consequences of RiBi inhibition. Deletion ofNat10in acinar cells blockedKras-oncogene-driven pancreatic intraepithelial neoplasia and subsequent pancreatic ductal adenocarcinoma, regardless ofTrp53mutation status. Together, our results provide initial insights into how cells respond to defects in RiBi and translationin vivo.