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A non-tumor suppressor role for basal p19ARF in maintaining nucleolar structure and function
Anthony J Apicelli1, Leonard B Maggi, Angela C Hirbe
1Department of Internal Medicine, Division of Molecular Oncology, Washington University School of Medicine, Campus Box 8069, 660 S. Euclid Avenue, St. Louis, MO 63110, USA. jweber@im.wustl.edu
Molecular and Cellular Biology
|December 12, 2007
Summary
Basal p19(ARF) protein monitors ribosome synthesis and cell growth. Its absence dramatically increases ribosome production and cell volume, revealing a new role for ARF in regulating cell growth.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The nucleolus is central to ribosome synthesis, with nucleophosmin (NPM) and p19(ARF) proteins playing antagonistic roles in cell growth.
- The function of basal NPM and ARF protein complexes within nucleoli is largely unknown.
- Previous studies indicate ARF's role in inhibiting proliferation, but its basal functions are less understood.
Purpose of the Study:
- To investigate the function of basal p19(ARF) protein in regulating nucleolar activities and cell growth.
- To determine the role of ARF in ribosome biogenesis and protein synthesis under normal growth conditions.
- To elucidate the physiological significance of basal ARF in cellular processes beyond proliferation control.
Main Methods:
- Analysis of nucleolar size and ribosome biogenesis in Arf(-/-) cells.
- Assessment of rRNA transcription, processing, and nuclear export of ribosomes in the absence of ARF.
- Utilizing lentiviral RNA interference to knockdown ARF in wild-type mouse embryonic fibroblasts (MEFs).
- Evaluating the in vitro and in vivo activity of postmitotic osteoclasts from Arf-null mice.
- Investigating the effect of NPM knockdown on ribosome output and osteoclast activity in Arf(-/-) cells.
Main Results:
- Arf(-/-) cells exhibited significantly increased nucleolar area, ribosome biogenesis, and protein synthesis, leading to enhanced cell volume.
- Absence of ARF resulted in elevated transcription of ribosomal DNA (rDNA), accelerated rRNA processing, and increased ribosome nuclear export.
- Arf-null osteoclasts showed hyperactivity in vitro and in vivo, confirming a physiological role for basal ARF.
- Knockdown of NPM abrogated the increased ribosome output and osteoclast hyperactivity observed in Arf(-/-) cells.
Conclusions:
- Basal p19(ARF) protein functions as a critical regulator of steady-state ribosome biogenesis and cell growth.
- ARF's role in monitoring ribosome production is independent of its known function in preventing hyperproliferation.
- NPM is essential for mediating the effects of ARF on ribosome biogenesis and cellular growth.
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