A system-wide investigation of the dynamics of Wnt signaling reveals novel phases of transcriptional regulation.
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.
Gujral
Taranjit S
TS
Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
MacBeath
Gavin
G
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
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
Cancer Res. 2009 Feb 1;69(3):731-4
19155295
Cell. 2009 May 15;137(4):623-34
19450512
Development. 2005 Jun;132(11):2587-97
15857909
PLoS One. 2007 Sep 26;2(9):e945
17895986
Nature. 2003 May 22;423(6938):448-52
12717451
Carcinogenesis. 2008 Mar;29(3):666-72
18204079
Science. 1997 Mar 21;275(5307):1787-90
9065402
Nat Rev Cancer. 2008 May;8(5):387-98
18432252
Oncogene. 2008 Oct 2;27(44):5845-55
18641688
Science. 2007 Aug 10;317(5839):803-6
17690294
CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
18287387
Nat Genet. 2004 Apr;36(4):417-22
15034581
Nature. 2005 Apr 14;434(7035):843-50
15829953
Nucleic Acids Res. 2003 May 1;31(9):2369-80
12711682
Biochem Pharmacol. 2007 Sep 15;74(6):851-9
17662696
Mol Cell. 2002 Feb;9(2):213-24
11864595
J Comput Biol. 2004;11(4):544-61
15579231
Trends Genet. 1997 Apr;13(4):157-62
9097727
J Biol Chem. 2006 Aug 11;281(32):22429-33
16793760
Nat Rev Genet. 2004 Sep;5(9):691-701
15372092
Apoptosis. 2006 Jun;11(6):879-88
16547590
Biochim Biophys Acta. 2003 Jun 5;1653(1):1-24
12781368
BMC Dev Biol. 2002 Jul 02;2:8
12095419
J Mol Signal. 2007 Oct 25;2:11
17961224
J Cell Sci. 2005 Jan 15;118(Pt 2):313-22
15615777
Annu Rev Cell Dev Biol. 1998;14:59-88
9891778
Cell. 1997 Mar 21;88(6):757-66
9118219
Cell Signal. 2007 Mar;19(3):511-8
17011750
Cell. 1997 Mar 21;88(6):747-56
9118218
Biomaterials. 2005 Jul;26(19):4171-9
15664644
Nat Struct Mol Biol. 2005 May;12(5):423-8
15834423
Oncogene. 2005 Apr 21;24(18):3054-8
15735684
Trends Cell Biol. 2005 May;15(5):234-7
15866026
Biochem Biophys Res Commun. 2007 Jun 15;357(4):1119-23
17462603
Dev Biol. 2001 Jul 15;235(2):388-96
11437445
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14700-5
17804805
Nat Cell Biol. 2001 Jul;3(7):683-6
11433302