Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: The case of HIC-1 and gamma FBP-B

Hypermethylated in cancer (HIC-1), a new candidate tumor suppressor gene lo cated in 17p13.3, encodes a protein with five C2H2 zinc fingers and an N-te rminal broad complex, tramtrack, and bric a brac/poxviruses and zinc-finger (BTB/POZ) domain found in actin binding proteins or transcriptional regula tors involved in chromatin modeling. In the human B cell lymphoma (BCL-6) a nd promyelocityc leukemia (PLZF) oncoproteins, this domain mediates transcr iptional repression through its ability to recruit a silencing mediator of retinoid and thyroid hormone receptor (SMRT)/nuclear receptor corepressor ( N-CoR)-mSin3A-histone deacetylase (HDAC) complex, a mechanism shared with n umerous transcription factors. HIC-1 appears unique because it contains a 1 3-aa insertion acquired late in evolution, because it is not found in its a vian homologue, gamma F1-binding protein isoform B (gamma FBP-B), a transcr iptional repressor of the gamma f-crystallin gene. This insertion, located in a conserved region involved in the dimerization and scaffolding of the B TB/POZ domain, mainly affects slightly the ability of the HIC-1 and gamma F BP-B BTB/POZ domains to homo- and heterodimerize in vivo, as shown by mamma lian two-hybrid experiments. Both the HIC-1 and gamma FBP-B BTB/POZ domains behave as autonomous transcriptional repression domains. However, in strik ing contrast: with BCL-6 and PLZF, both HIC-1 and gamma FBP-B similarly fai l to interact with members of the HDAC complexes (SMRT/N-CoR, mSin3A or HDA C-1) in vivo and in vitro. In addition, a general and specific inhibitor of HDACs, trichostatin A, did not alleviate the HIC-1- and gamma FBP-B-mediat ed transcriptional repression, as previously shown for BCL-6. Taken togethe r, our studies show that the recruitment onto target promoters of an HDAC c omplex is not a general property of transcriptional repressors containing a conserved BTB/POZ domain.