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.
Wu
Kongming
K
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Liu
Manran
M
Li
Anping
A
Donninger
Howard
H
Rao
Mahadev
M
Jiao
Xuanmao
X
Lisanti
Michael P
MP
Cvekl
Ales
A
Birrer
Michael
M
Pestell
Richard G
RG
D000818:Animals; D001665:Binding Sites; D002450:Cell Communication; D019070:Cell Lineage; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D017124:Conserved Sequence; D003260:Contact Inhibition; D004247:DNA / Q000096:biosynthesis; D005136:Eye Proteins / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D027602:Serum Response Element / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D020798:Two-Hybrid System Techniques
C456264:Dach1 protein, mouse; D005136:Eye Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D004247:DNA