title: Suppression of Myc oncogenic activity by nucleostemin haploinsufficiency.
abstract: Nucleostemin (NS), a nucleolar GTPase, is highly expressed in stem/progenitor cells and in most cancer cells. However, little is known about the regulation of its expression. Here, we identify the NS gene as a novel direct transcriptional target of the c-Myc oncoprotein. We show that Myc overexpression enhances NS transcription in cultured cells and in pre-neoplastic B cells from Eμ-myc transgenic mice. Consistent with NS being downstream of Myc, NS expression parallels that of Myc in a large panel of human cancer cell lines. Using chromatin immunoprecipitation we show that c-Myc binds to a well-conserved E-box in the NS promoter. Critically, we show NS haploinsufficiency profoundly delays Myc-induced cancer formation in vivo. NS+/-Eμ-myc transgenic mice have much slower rates of B-cell lymphoma development, with life spans twice that of their wild-type littermates. Moreover, we demonstrate that NS is essential for the proliferation of Myc-overexpressing cells in cultured cells and in vivo: impaired lymphoma development was associated with a drastic decrease of c-Myc-induced proliferation of pre-tumoural B cells. Finally, we provide evidence that in cell culture NS controls cell proliferation independently of p53 and that NS haploinsufficiency significantly delays lymphomagenesis in p53-deficient mice. Together these data indicate that NS functions downstream of Myc as a rate-limiting regulator of cell proliferation and transformation, independently from its putative role within the p53 pathway. Targeting NS is therefore expected to compromise early tumour development irrespectively of the p53 status.
authors.affiliation: Laboratory for Molecular Cancer Biology, Department of Biomedical Molecular Biology, VIB-UGent, Technologiepark, Ghent, Belgium.
authors.forename: A K
authors.initials: AK
authors.lastname: Zwolinska
authors.forename: A
authors.initials: A
authors.lastname: Heagle Whiting
authors.forename: C
authors.initials: C
authors.lastname: Beekman
authors.forename: J M
authors.initials: JM
authors.lastname: Sedivy
authors.forename: J-C
authors.initials: JC
authors.lastname: Marine
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019204:GTP-Binding Proteins / Q000235:genetics*; D057895:Haploinsufficiency; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C469949:GNL3 protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D019204:GTP-Binding Proteins
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