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A Non-Tumor Suppressor Role for Basal p19^ARF in Maintaining Nucleolar Structure and Function

Departments of Internal Medicine, Division of Molecular Oncology,¹ Cell Biology and Physiology,² Cancer Biology Pathway, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110³

Received 20 March 2007/ Returned for modification 11 May 2007/ Accepted 14 November 2007

The nucleolus is the center of ribosome synthesis, with the nucleophosmin (NPM) and p19^ARF proteins antagonizing one another to either promote or inhibit growth. However, basal NPM and ARF proteins form nucleolar complexes whose functions remain unknown. Nucleoli from Arf^–/– cells displayed increased nucleolar area, suggesting that basal ARF might regulate key nucleolar functions. Concordantly, ribosome biogenesis and protein synthesis were dramatically elevated in the absence of Arf, causing these cells to exhibit tremendous gains in protein amounts and increases in cell volume. The transcription of ribosomal DNA (rDNA), the processing of nascent rRNA molecules, and the nuclear export of ribosomes were all increased in the absence of ARF. Similar results were obtained using targeted lentiviral RNA interference of ARF in wild-type MEFs. Postmitotic osteoclasts from Arf-null mice exhibited hyperactivity in vitro and in vivo, demonstrating a physiological function for basal ARF. Moreover, the knockdown of NPM blocked the increases in Arf^–/– ribosome output and osteoclast activity, demonstrating that these gains require NPM. Thus, basal ARF proteins act as a monitor of steady-state ribosome biogenesis and growth independent of their ability to prevent unwarranted hyperproliferation.

Published ahead of print on 10 December 2007.