title: Oncogenic c-Myc-induced lymphomagenesis is inhibited non-redundantly by the p19Arf-Mdm2-p53 and RP-Mdm2-p53 pathways.
abstract: The multifaceted oncogene c-Myc plays important roles in the development and progression of human cancer. Recent in vitro and in vivo studies have shown that the p19Arf-Mdm2-p53 and the ribosomal protein (RP)-Mdm2-p53 pathways are both essential in preventing oncogenic c-Myc-induced tumorigenesis. Disruption of each pathway individually by p19Arf deletion or by Mdm2(C305F) mutation, which disrupts RP-Mdm2 binding, accelerates Eμ-myc transgene-induced pre-B/B-cell lymphoma in mice at seemingly similar paces with median survival around 10 and 11 weeks, respectively, compared to 20 weeks for Eμ-myc transgenic mice. Because p19Arf can inhibit ribosomal biogenesis through its interaction with nucleophosmin (NPM/B23), RNA helicase DDX5 and RNA polymerase I transcription termination factor (TTF-I), it has been speculated that the p19Arf-Mdm2-p53 and the RP-Mdm2-p53 pathways might be a single p19Arf-RP-Mdm2-p53 pathway, in which p19Arf activates p53 by inhibiting RP biosynthesis; thus, p19Arf deletion or Mdm2(C305F) mutation would result in similar consequences. Here, we generated mice with concurrent p19Arf deletion and Mdm2(C305F) mutation and investigated the compound mice for tumorigenesis in the absence and the presence of oncogenic c-Myc overexpression. In the absence of Eμ-myc transgene, the Mdm2(C305F) mutation did not elicit spontaneous tumors in mice, nor did it accelerate spontaneous tumors in mice with p19Arf deletion. In the presence of Eμ-myc transgene, however, Mdm2(C305F) mutation significantly accelerated p19Arf deletion-induced lymphomagenesis and promoted rapid metastasis. We found that when p19Arf-Mdm2-p53 and RP-Mdm2-p53 pathways are independently disrupted, oncogenic c-Myc-induced p53 stabilization and activation is only partially attenuated. When both pathways are concurrently disrupted, however, c-Myc-induced p53 stabilization and activation are essentially obliterated. Thus, the p19Arf-Mdm2-p53 and the RP-Mdm2-p53 are non-redundant pathways possessing similar capabilities to activate p53 upon c-Myc overexpression.
authors.affiliation: Department of Radiation Oncology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Radiation Oncology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Carlson
authors.affiliation: Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Radiation Oncology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, China.|Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
references.citation: Nat Rev Cancer. 2006 Sep;6(9):663-73
references.pmid: 16915296
references.citation: J Natl Cancer Inst. 1973 May;50(5):1195-213
references.pmid: 4351393
references.citation: EMBO J. 2007 Jul 25;26(14):3332-45
references.pmid: 17599065
references.citation: Nat Rev Cancer. 2008 Dec;8(12):976-90
references.pmid: 19029958
references.citation: Cell. 1992 Apr 3;69(1):119-28
references.pmid: 1555236
references.citation: Oncogene. 2004 Nov 25;23(55):8931-40
references.pmid: 15467748
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6274-9
references.pmid: 11983916
references.citation: Cancer Res. 1999 May 1;59(9):2217-22
references.pmid: 10232611
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):978-83
references.pmid: 23277542
references.citation: Cancer Cell. 2010 Sep 14;18(3):231-43
references.pmid: 20832751
references.citation: Nature. 1992 Jul 2;358(6381):15-6
references.pmid: 1614522
references.citation: Mol Cell. 2003 Nov;12(5):1151-64
references.pmid: 14636574
references.citation: Springerplus. 2014 Feb 11;3:80
references.pmid: 24570851
references.citation: J Immunol. 2002 Jan 15;168(2):869-74
references.pmid: 11777984
references.citation: J Cereb Blood Flow Metab. 2014 Dec;34(12):1887-97
references.pmid: 25248835
references.citation: Oncotarget. 2011 Mar;2(3):234-8
references.pmid: 21406728
references.citation: Hepatology. 2012 Oct;56(4):1521-31
references.pmid: 22508288
references.citation: Nature. 2004 Oct 7;431(7009):712-7
references.pmid: 15361884
references.citation: Genes Dev. 1993 Jul;7(7A):1126-32
references.pmid: 8319905
references.citation: Cancer Cell. 2009 Nov 6;16(5):369-77
references.pmid: 19878869
references.citation: Nature. 1985 Dec 12-18;318(6046):533-8
references.pmid: 3906410
references.citation: Cancer Res. 2011 Nov 1;71(21):6708-17
references.pmid: 21937682
references.citation: Genes Dev. 1998 Aug 1;12(15):2424-33
references.pmid: 9694806
references.citation: Cell Growth Differ. 1997 Oct;8(10):1039-48
references.pmid: 9342182
references.citation: Nat Cell Biol. 2005 Mar;7(3):303-10
references.pmid: 15723053
references.citation: Mol Cell. 2010 May 28;38(4):539-50
references.pmid: 20513429
references.citation: Blood. 1998 Jan 15;91(2):623-9
references.pmid: 9427718
references.citation: Mol Cell Biol. 2007 Feb;27(3):1056-68
references.pmid: 17116689
references.citation: Mol Cell. 2003 Feb;11(2):415-24
references.pmid: 12620229
references.citation: Nat Rev Cancer. 2010 Apr;10(4):301-9
references.pmid: 20332779
references.citation: Nature. 2003 Jan 16;421(6920):290-4
references.pmid: 12529648
references.citation: Genes Dev. 1999 Oct 15;13(20):2658-69
references.pmid: 10541552
references.citation: Curr Top Microbiol Immunol. 1988;141:94-9
references.pmid: 3265095
references.citation: Oncogene. 2014 Oct 9;33(41):4916-23
references.pmid: 24141778
references.citation: Ann N Y Acad Sci. 1963 Nov 4;108:805-31
references.pmid: 14081516
references.citation: Cell. 1997 Nov 28;91(5):649-59
references.pmid: 9393858
references.citation: Biochim Biophys Acta. 1995 Jul 28;1242(1):11-28
references.pmid: 7626652