Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing.
The p19(Arf) tumor suppressor, a nucleolar protein, binds to Mdm2 to induce p53-dependent cell cycle arrest. Arf also prevents the proliferation of cells lacking Mdm2 and p53, albeit less efficiently. We show that p19(Arf) inhibits production of ribosomal RNA, retarding processing of 47/45S and 32S precursors. These effects correlate with but do not strictly depend upon inhibition of rRNA biosynthesis or cell cycle arrest, are not mimicked by p53, and require neither p53 nor Mdm2. Arf mutants lacking conserved amino acid residues 2-14 do not block rRNA synthesis and processing or inhibit cell proliferation. Evolution may have linked a primordial nucleolar Arf function to Mdm2 and p53, creating a more efficient checkpoint-signaling pathway for coordinating ribosomal biogenesis and cell cycle progression.
Sugimoto
Masataka
M
Howard Hughes Medical Institute, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Kuo
Mei-Ling
ML
Roussel
Martine F
MF
Sherr
Charles J
CJ
D016475:3T3 Cells; D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006801:Humans; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012323:RNA Processing, Post-Transcriptional; D012335:RNA, Ribosomal / Q000378:metabolism*; D012340:RNA, Ribosomal, 5.8S / Q000378:metabolism; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012335:RNA, Ribosomal; D012340:RNA, Ribosomal, 5.8S; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2