title: Identification and functional characterization of FMN2, a regulator of the cyclin-dependent kinase inhibitor p21.
abstract: The ARF tumor suppressor is a central component of the cellular defense against oncogene activation in mammals. p14ARF activates p53 by binding and inhibiting HDM2, resulting, inter alia, in increased transcription and expression of the cyclin-dependent kinase inhibitor p21 and consequent cell-cycle arrest. We analyzed the effect of p14ARF induction on nucleolar protein dynamics using SILAC mass spectrometry and have identified the human Formin-2 (FMN2) protein as a component of the p14ARF tumor suppressor pathway. We show that FMN2 is increased upon p14ARF induction at both the mRNA and the protein level via a NF-κB-dependent mechanism that is independent of p53. FMN2 enhances expression of the cell-cycle inhibitor p21 by preventing its degradation. FMN2 is also induced by activation of other oncogenes, hypoxia, and DNA damage. These results identify FMN2 as a crucial component in the regulation of p21 and consequent oncogene/stress-induced cell-cycle arrest in human cells.
authors: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, UK.
authors: Kayo
authors: K
authors: Yamada
authors: Motoharu
authors: M
authors: Ono
authors: Neil D
authors: ND
authors: Perkins
authors: Sonia
authors: S
authors: Rocha
authors: Angus I
authors: AI
authors: Lamond
mesh_terms: D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002466:Cell Nucleolus; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D016328:NF-kappa B / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D012333:RNA, Messenger / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF
references: Nature. 2006 Sep 14;443(7108):214-7
references: 16957739
references: Curr Biol. 2002 Jan 8;12(1):1-11
references: 11790298
references: Mol Cell. 2007 Jun 22;26(6):831-42
references: 17588518
references: Nat Cell Biol. 2001 May;3(5):445-52
references: 11331871
references: Mol Cell. 2007 Aug 17;27(4):622-35
references: 17707233
references: Cancer Res. 2009 Mar 15;69(6):2324-31
references: 19276347
references: Biochem Soc Trans. 2004 Dec;32(Pt 6):1087-9
references: 15506973
references: Mol Cell. 2007 Jun 22;26(6):843-52
references: 17588519
references: Mol Cell. 2010 Aug 27;39(4):493-506
references: 20797623
references: Cold Spring Harb Perspect Biol. 2011 Mar 01;3(3):
references: 21106648
references: Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
references: 17183360
references: Mol Cell Biol. 2010 Oct;30(20):4901-21
references: 20696840
references: Br J Cancer. 2004 Jan 26;90(2):503-9
references: 14735200
references: Genes Dev. 2001 Apr 15;15(8):981-94
references: 11316792
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):574-85
references: 17519961
references: EMBO J. 1998 Sep 1;17(17):5001-14
references: 9724636
references: Science. 2007 May 25;316(5828):1160-6
references: 17525332
references: Mol Cell. 2010 Oct 22;40(2):216-27
references: 20965417
references: Cell Cycle. 2010 Jan 1;9(1):86-9
references: 20016279
references: Nature. 1994 Oct 6;371(6497):534-7
references: 7935768
references: Biochim Biophys Acta. 2002 Mar 14;1602(1):47-59
references: 11960694
references: Mol Cell. 2004 Mar 26;13(6):853-65
references: 15053878
references: J Med Genet. 2007 Feb;44(2):99-106
references: 16905682
references: Nat Rev Cancer. 2012 Jan 19;12(2):121-32
references: 22257950
references: Genes Dev. 2000 Sep 15;14(18):2358-65
references: 10995391
references: Nature. 2006 Sep 14;443(7108):159
references: 16971940
references: Int J Cancer. 2010 Nov 15;127(10):2239-47
references: 20549699
references: Blood. 2011 Feb 10;117(6):1899-910
references: 21135260
references: Cell Cycle. 2008 Jan 1;7(1):112-9
references: 18196972
references: Mol Cell Proteomics. 2010 May;9(5):861-79
references: 20023298
references: Int J Mol Med. 2004 Sep;14(3):469-74
references: 15289902
references: J Cell Biol. 2011 Sep 5;194(5):689-703
references: 21893597
references: Sci Signal. 2009 Aug 18;2(84):ra44
references: 19690330
references: Dev Cell. 2006 Jun;10(6):693-706
references: 16740473
references: Oncogene. 2002 Jun 20;21(27):4220-30
references: 12082609
references: EMBO J. 2005 Mar 23;24(6):1157-69
references: 15775976
references: Exp Cell Res. 2004 May 15;296(1):43-50
references: 15120992
references: Mol Cell. 2003 Jul;12(1):15-25
references: 12887889
references: J Cell Biol. 2009 Mar 23;184(6):771-6
references: 19289796
references: N Engl J Med. 2005 Nov 17;353(20):2135-47
references: 16291983
references: Curr Biol. 2007 May 1;17(9):749-60
references: 17446074
references: Nat Rev Mol Cell Biol. 2001 Oct;2(10):731-7
references: 11584300
references: Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a001883
references: 20066118
references: J Biol Chem. 2002 Sep 27;277(39):36665-70
references: 12145279
references: Nat Rev Cancer. 2008 Jun;8(6):438-49
references: 18500245
references: Mol Cell Proteomics. 2012 Mar;11(3):M111.011429
references: 21937730
references: Nat Cell Biol. 2002 Dec;4(12):921-8
references: 12447394
references: Nat Rev Cancer. 2009 Jun;9(6):400-14
references: 19440234
references: Nature. 2005 Jan 6;433(7021):77-83
references: 15635413