Wnt-mediated down-regulation of Sp1 target genes by a transcriptional repressor Sp5.
Wnt/beta-catenin signaling regulates many processes during vertebrate development. To study transcriptional targets of canonical Wnt signaling, we used the conditional Cre/loxP system in mouse to ectopically activate beta-catenin during central nervous system development. We show that the activation of Wnt/beta-catenin signaling in the embryonic mouse telencephalon results in the up-regulation of Sp5 gene, which encodes a member of the Sp1 transcription factor family. A proximal promoter of Sp5 gene is highly evolutionarily conserved and contains five TCF/LEF binding sites that mediate direct regulation of Sp5 expression by canonical Wnt signaling. We provide evidence that Sp5 works as a transcriptional repressor and has three independent repressor domains, called R1, R2, and R3, respectively. Furthermore, we show that the repression activity of R1 domain is mediated through direct interaction with a transcriptional corepressor mSin3a. Finally, our data strongly suggest that Sp5 has the same DNA binding specificity as Sp1 and represses Sp1 target genes such as p21. We conclude that Sp5 transcription factor mediates the downstream responses to Wnt/beta-catenin signaling by directly repressing Sp1 target genes.
Fujimura
Naoko
N
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic.
Vacik
Tomas
T
Machon
Ondrej
O
Vlcek
Cestmir
C
Scalabrin
Simone
S
Speth
Martin
M
Diep
Dzung
D
Krauss
Stefan
S
Kozmik
Zbynek
Z
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D015536:Down-Regulation / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D016329:Sp1 Transcription Factor; C417217:Sp5 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D056264:Sin3 Histone Deacetylase and Corepressor Complex