Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription.
The transcription factor c-Myc has a critical role in cell proliferation and growth. The control of ribosome biogenesis by c-Myc through the regulation of transcription mediated by all three RNA polymerases is essential for c-Myc-driven proliferation. Specifically, in the nucleolus, c-Myc has been shown to be recruited to ribosomal DNA and activate RNA polymerase (pol) I-mediated transcription of ribosomal RNA (rRNA) genes. In addition, c-Myc accumulates in nucleoli upon inhibition of the proteasome, suggesting nucleolar localization also has a role in c-Myc proteolysis. Nucleophosmin (NPM), a predominantly nucleolar protein, is also critical in ribosome biogenesis and, like c-Myc, is found overexpressed in many types of tumors. Previously, we demonstrated that NPM directly interacts with c-Myc and controls c-Myc-induced hyperproliferation and transformation. Here, we show that NPM is necessary for the localization of c-Myc protein to nucleoli, whereas c-Myc nucleolar localization is independent of p53, Mdm2 and ARF. Conversely, high transient NPM expression enhances c-Myc nucleolar localization, leading to increased c-Myc proteolysis. In addition, NPM is necessary for the ability of c-Myc to induce rRNA synthesis in the nucleolus, and constitutive NPM overexpression stimulates c-Myc-mediated rRNA synthesis. Taken together, these results demonstrate an essential role for NPM in c-Myc nucleolar localization and c-Myc-mediated rDNA transcription.
Department of Cell and Developmental Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232-2175, USA.
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D002466:Cell Nucleolus / Q000378:metabolism*; D049109:Cell Proliferation; D004275:DNA, Ribosomal / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D046988:Proteasome Endopeptidase Complex; D051736:Proto-Oncogene Proteins c-mdm2; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012318:RNA Polymerase I / Q000235:genetics / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000096:biosynthesis; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53
D004275:DNA, Ribosomal; C489427:MYC protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012335:RNA, Ribosomal; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D012318:RNA Polymerase I; D046988:Proteasome Endopeptidase Complex