Cell fate determination factor DACH1 inhibits c-Jun-induced contact-independent growth.
The cell fate determination factor DACH1 plays a key role in cellular differentiation in metazoans. DACH1 is engaged in multiple context-dependent complexes that activate or repress transcription. DACH1 can be recruited to DNA via the Six1/Eya bipartite transcription (DNA binding/coactivator) complex. c-Jun is a critical component of the activator protein ... (AP)-1 transcription factor complex and can promote contact-independent growth. Herein, DACH1 inhibited c-Jun-induced DNA synthesis and cellular proliferation. Excision of c-Jun with Cre recombinase, in c-jun(f1/f1) 3T3 cells, abrogated DACH1-mediated inhibition of DNA synthesis. c-Jun expression rescued DACH1-mediated inhibition of cellular proliferation. DACH1 inhibited induction of c-Jun by physiological stimuli and repressed c-jun target genes (cyclin A, beta-PAK, and stathmin). DACH1 bound c-Jun and inhibited AP-1 transcriptional activity. c-jun and c-fos were transcriptionally repressed by DACH1, requiring the conserved N-terminal (dac and ski/sno [DS]) domain. c-fos transcriptional repression by DACH1 requires the SRF site of the c-fos promoter. DACH1 inhibited c-Jun transactivation through the delta domain of c-Jun. DACH1 coprecipitated the histone deacetylase proteins (HDAC1, HDAC2, and NCoR), providing a mechanism by which DACH1 represses c-Jun activity through the conserved delta domain. An oncogenic v-Jun deleted of the delta domain was resistant to DACH1 repression. Collectively, these studies demonstrate a novel mechanism by which DACH1 blocks c-Jun-mediated contact-independent growth through repressing the c-Jun delta domain.
Mesh Terms:
Animals, Binding Sites, Cell Communication, Cell Lineage, Cell Proliferation, Chromatin Immunoprecipitation, Conserved Sequence, Contact Inhibition, DNA, Eye Proteins, Gene Expression, Humans, Mice, NIH 3T3 Cells, Protein Structure, Tertiary, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Serum Response Element, Transcription Factor AP-1, Transcriptional Activation, Two-Hybrid System Techniques
Animals, Binding Sites, Cell Communication, Cell Lineage, Cell Proliferation, Chromatin Immunoprecipitation, Conserved Sequence, Contact Inhibition, DNA, Eye Proteins, Gene Expression, Humans, Mice, NIH 3T3 Cells, Protein Structure, Tertiary, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Serum Response Element, Transcription Factor AP-1, Transcriptional Activation, Two-Hybrid System Techniques
Mol. Biol. Cell
Date: Mar. 01, 2007
PubMed ID: 17182846
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