title: A system-wide investigation of the dynamics of Wnt signaling reveals novel phases of transcriptional regulation.
abstract: Aberrant Wnt signaling has been implicated in a wide variety of cancers and many components of the Wnt signaling network have now been identified. Much less is known, however, about how these proteins are coordinately regulated. Here, a broad, quantitative, and dynamic study of Wnt3a-mediated stimulation of HEK 293 cells revealed two phases of transcriptional regulation: an early phase in which signaling antagonists were downregulated, providing positive feedback, and a later phase in which many of these same antagonists were upregulated, attenuating signaling. The dynamic expression profiles of several response genes, including MYC and CTBP1, correlated significantly with proliferation and migration (P<0.05). Additionally, their levels tracked with the tumorigenicity of colon cancer cell lines and they were significantly overexpressed in colorectal adenocarcinomas (P<0.05). Our data highlight CtBP1 as a transcription factor that contributes to positive feedback during the early phases of Wnt signaling and serves as a novel marker for colorectal cancer progression.
authors.affiliation: Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Taranjit S
authors.initials: TS
authors.lastname: Gujral
authors.forename: Gavin
authors.initials: G
authors.lastname: MacBeath
mesh_terms: D000429:Alcohol Oxidoreductases / Q000032:analysis / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015398:Signal Transduction; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D004268:DNA-Binding Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein
references.citation: Cancer Res. 2009 Feb 1;69(3):731-4
references.pmid: 19155295
references.citation: Cell. 2009 May 15;137(4):623-34
references.pmid: 19450512
references.citation: Development. 2005 Jun;132(11):2587-97
references.pmid: 15857909
references.citation: PLoS One. 2007 Sep 26;2(9):e945
references.pmid: 17895986
references.citation: Nature. 2003 May 22;423(6938):448-52
references.pmid: 12717451
references.citation: Carcinogenesis. 2008 Mar;29(3):666-72
references.pmid: 18204079
references.citation: Science. 1997 Mar 21;275(5307):1787-90
references.pmid: 9065402
references.citation: Nat Rev Cancer. 2008 May;8(5):387-98
references.pmid: 18432252
references.citation: Oncogene. 2008 Oct 2;27(44):5845-55
references.pmid: 18641688
references.citation: Science. 2007 Aug 10;317(5839):803-6
references.pmid: 17690294
references.citation: CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
references.pmid: 18287387
references.citation: Nat Genet. 2004 Apr;36(4):417-22
references.pmid: 15034581
references.citation: Nature. 2005 Apr 14;434(7035):843-50
references.pmid: 15829953
references.citation: Nucleic Acids Res. 2003 May 1;31(9):2369-80
references.pmid: 12711682
references.citation: Biochem Pharmacol. 2007 Sep 15;74(6):851-9
references.pmid: 17662696
references.citation: Mol Cell. 2002 Feb;9(2):213-24
references.pmid: 11864595
references.citation: J Comput Biol. 2004;11(4):544-61
references.pmid: 15579231
references.citation: Trends Genet. 1997 Apr;13(4):157-62
references.pmid: 9097727
references.citation: J Biol Chem. 2006 Aug 11;281(32):22429-33
references.pmid: 16793760
references.citation: Nat Rev Genet. 2004 Sep;5(9):691-701
references.pmid: 15372092
references.citation: Apoptosis. 2006 Jun;11(6):879-88
references.pmid: 16547590
references.citation: Biochim Biophys Acta. 2003 Jun 5;1653(1):1-24
references.pmid: 12781368
references.citation: BMC Dev Biol. 2002 Jul 02;2:8
references.pmid: 12095419
references.citation: J Mol Signal. 2007 Oct 25;2:11
references.pmid: 17961224
references.citation: J Cell Sci. 2005 Jan 15;118(Pt 2):313-22
references.pmid: 15615777
references.citation: Annu Rev Cell Dev Biol. 1998;14:59-88
references.pmid: 9891778
references.citation: Cell. 1997 Mar 21;88(6):757-66
references.pmid: 9118219
references.citation: Cell Signal. 2007 Mar;19(3):511-8
references.pmid: 17011750
references.citation: Cell. 1997 Mar 21;88(6):747-56
references.pmid: 9118218
references.citation: Biomaterials. 2005 Jul;26(19):4171-9
references.pmid: 15664644
references.citation: Nat Struct Mol Biol. 2005 May;12(5):423-8
references.pmid: 15834423
references.citation: Oncogene. 2005 Apr 21;24(18):3054-8
references.pmid: 15735684
references.citation: Trends Cell Biol. 2005 May;15(5):234-7
references.pmid: 15866026
references.citation: Biochem Biophys Res Commun. 2007 Jun 15;357(4):1119-23
references.pmid: 17462603
references.citation: Dev Biol. 2001 Jul 15;235(2):388-96
references.pmid: 11437445
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14700-5
references.pmid: 17804805
references.citation: Nat Cell Biol. 2001 Jul;3(7):683-6
references.pmid: 11433302