title: RASSF1A inactivation unleashes a tumor suppressor/oncogene cascade with context-dependent consequences on cell cycle progression.
abstract: The RASSF1A gene is one of the most frequently inactivated genes in over 30 different types of cancers (H. Donninger, M. D. Vos, and G. J. Clark, J. Cell Sci. 120:3163-3172, 2007, http://dx.doi.org/10.1242/jcs.010389). Despite the prevalence of RASSF1A silencing in human cancer, the mechanism by which RASSF1A functions as a tumor suppressor is not well understood. Characterization of the consequences of RASSF1A loss on epithelial cell proliferation revealed that RASSF1A expression suppresses both microRNA 21 (miR-21) expression and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. The mechanism of the former is through restraint of SCF(βTrCP)-dependent destruction of the repressor element 1 silencing transcription factor (REST) tumor suppressor and consequent inhibition of miR-21 promoter activation. The mechanism of the latter is through physical sequestration of MST2, which results in accumulation of inactivating S259 phosphorylation of RAF1. Whether or not inactivation of these RASSF1A regulatory relationships can unleash enhanced proliferative capacity is dependent upon the coupling of SCF(βTrCP) and miR-21 to suppression of SKP2 protein translation and stability. Airway epithelial cultures retain this coupling and therefore respond to RASSF1A inactivation by p27-dependent cell cycle arrest. In contrast, colonic crypt-derived epithelial cells have uncoupled SCF(βTrCP) from SKP2 and respond to RASSF1A inactivation by enhanced proliferation rates. These observations help account for context-specific molecular etiology of oncogenic transformation and suggest intervention strategies for recently developed SKP2 inhibitors.
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Rosalyn R
authors.initials: RR
authors.lastname: Ram
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Mendiratta
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Brian O
authors.initials: BO
authors.lastname: Bodemann
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Torres
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ugur
authors.initials: U
authors.lastname: Eskiocak
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, USA michael.white@utsouthwestern.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
mesh_terms: D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008969:Molecular Sequence Data; D009857:Oncogenes; D012097:Repressor Proteins / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D035683:MicroRNAs; D012097:Repressor Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D000099229:RE1-Silencing Transcription Factor; C524940:MIRN21 microRNA, human; C411762:RASSF1 protein, human
references.citation: Cancer Cell. 2010 Sep 14;18(3):282-93
references.pmid: 20832755
references.citation: Biochem Soc Trans. 2009 Aug;37(Pt 4):918-25
references.pmid: 19614619
references.citation: Mol Cell Biol. 2002 Jun;22(12):4309-18
references.pmid: 12024041
references.citation: Cancer Res. 2002 Jun 15;62(12):3498-502
references.pmid: 12067994
references.citation: Clin Cancer Res. 2002 Jul;8(7):2362-8
references.pmid: 12114441
references.citation: Mol Cell. 2007 Sep 21;27(6):962-75
references.pmid: 17889669
references.citation: Nat Genet. 2000 Jul;25(3):315-9
references.pmid: 10888881
references.citation: Oncogene. 2010 Oct 28;29(43):5828-38
references.pmid: 20697351
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7504-9
references.pmid: 11390984
references.citation: Nature. 2010 Mar 18;464(7287):374-9
references.pmid: 20237562
references.citation: Cancer Biol Ther. 2010 Dec 15;10(12):1224-32
references.pmid: 21139417
references.citation: Mol Cancer. 2007 Jul 16;6:49
references.pmid: 17634119
references.citation: Cancer Biol Ther. 2005 Oct;4(10):1116-22
references.pmid: 16096369
references.citation: Nature. 2008 May 8;453(7192):223-7
references.pmid: 18362916
references.citation: Cancer Res. 2011 Jul 1;71(13):4359-65
references.pmid: 21527559
references.citation: Int J Cancer. 2003 May 1;104(5):611-6
references.pmid: 12594816
references.citation: Int J Cancer. 2003 Jun 10;105(2):204-9
references.pmid: 12673680
references.citation: Pathology. 2005 Apr;37(2):125-30
references.pmid: 16028839
references.citation: Oncogene. 2003 Jan 23;22(3):461-6
references.pmid: 12545168
references.citation: Cancer Res. 2007 Feb 1;67(3):1054-61
references.pmid: 17283138
references.citation: Cell. 2005 Jun 17;121(6):837-48
references.pmid: 15960972
references.citation: J Cell Physiol. 2006 Dec;209(3):883-93
references.pmid: 16972248
references.citation: Gastroenterology. 2010 Mar;138(3):1012-21.e1-5
references.pmid: 19962984
references.citation: Mol Cell Biol. 2005 Sep;25(18):8356-67
references.pmid: 16135822
references.citation: J Cell Sci. 2007 Sep 15;120(Pt 18):3163-72
references.pmid: 17878233
references.citation: J Natl Cancer Inst. 2001 May 2;93(9):691-9
references.pmid: 11333291
references.citation: Cancer Res. 2005 Jan 1;65(1):92-8
references.pmid: 15665283
references.citation: Biochim Biophys Acta. 2009 Dec;1796(2):114-28
references.pmid: 19344752
references.citation: Chem Biol. 2012 Dec 21;19(12):1515-24
references.pmid: 23261596
references.citation: Nature. 2005 Aug 4;436(7051):725-30
references.pmid: 16079851
references.citation: Cancer Res. 2005 May 1;65(9):3497-508
references.pmid: 15867337
references.citation: Nature. 2008 Mar 20;452(7185):370-4
references.pmid: 18354483
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14443-8
references.pmid: 15452351
references.citation: J Biol Chem. 2010 May 14;285(20):15076-15087
references.pmid: 20212043
references.citation: Cell. 2013 Aug 1;154(3):556-68
references.pmid: 23911321
references.citation: Science. 2004 Dec 24;306(5705):2267-70
references.pmid: 15618521
references.citation: J Clin Invest. 2010 Nov;120(11):3940-52
references.pmid: 20972333
references.citation: Mol Cell Biol. 2008 May;28(10):3190-7
references.pmid: 18347058
references.citation: Mol Cell. 2011 Feb 18;41(4):458-70
references.pmid: 21329883
references.citation: Nat Cell Biol. 2008 Mar;10(3):361-9
references.pmid: 18297059
references.citation: Nat Rev Cancer. 2008 Jun;8(6):438-49
references.pmid: 18500245
references.citation: Mol Cancer Res. 2011 Sep;9(9):1187-98
references.pmid: 21788308