Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression

Abstract

Normal mammalian growth and development are highly dependent on the regulation of the expression and activity of the Myc family of transcription factors. Mxi1-mediated inhibition of Myc activities requires interaction with mammalian Sin3A or Sin3B proteins, which have been purported to act as scaffolds for additional co-repressor factors. The identification of two such Sin3-associated factors, the nuclear receptor co-repressor (N-CoR) and histone deacetylase (HD1), provides a basis for Mxi1/Sin3-induced transcriptional repression and tumour suppression.

Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein

“…Thus mSin3A interacts with PLZF though its PAH1 domain. It is noteworthy that the same motif was shown to mediate interactions with SMRT in yeast and with the Cterminal domain of N-CoR in yeast and in vitro (Alland et al, 1997;Heinzel et al, 1997). In a similar set of experiments, we also examined whether mSin3B associates with PLZF in yeast.…”

“…Localization of the mSin3A (b) and mSin3B (c) domains required for PLZF interactions. Various LexA (DBD)-mSin3A and -mSin3B baits (Alland et al, 1997) were used along with the GAL4(AD) ± PLZF 1 ± 435 or the`control' GAL4(AD)-PRP9 activators to localize the PLZF interaction domain of mSin3 in yeast cells. +++, a LacZ phenotype that is equivalent to that observed for the control PRP9/PRP21 interaction used as a positive control in yeast speci®c inhibitor of histone deacetylases (Yoshida et al, 1995).…”

“…After 48 h, immunoprecipitations under low stringency conditions were performed as described (Alland et al, 1997), resolved by SDS ± PAGE, transferred to nitrocellulose and detected by Western blotting using anti-FLAG M2 (Kodak), anti-HA (Santa Cruz) and anti-BCL6 C19 (Santa Cruz) antibodies. The HA-tagged PLZF expression vector in pSG5 (Stratagene) encoding residues 1 ± 673 of PLZF followed by the HA epitope was generated by standard PCR-based methodology.…”

“…Indeed SMRT and N-CoR interact strongly with unliganded receptors and are released upon ligand binding. A series of recent reports (Alland et al, 1997;Hassig et al, 1997;Heinzel et al, 1997;Kadosh and Struhl, 1997;Laherty et al, 1997;Zhang et al, 1997) have shown that SMRT/ N-CoR co-repressors are part of a multiprotein complex including the Mad co-repressors mSin3A and B (Ayer et al, 1995;Schreiber-Agus et al, 1995) and the histone deacetylases HDAC1/HD1 and HDAC2/mRPD3 (Taunton et al, 1996;Yang et al, 1996). These studies, that strengthen the major role of histone acetylation/deacetylation in transcriptional regulation, provide the basis for the existence of a common repression pathway between nuclear receptors and basic region-helix ± loop ± helix-leucine zipper (bHLH-Zip) proteins.…”

Lack of transcriptional repression by max homodimers

“…The ensuing transcriptional repression occurs through an active process involving the binding of one of more additional proteins related to the yeast transcriptional repressor SIN3 (Ayer et al, 1995;Schreiber-Agus et al, 1995Kastan et al, 1996. In turn, mSin3 (the mammalian homolog of SIN3) binds at least two proteins, a transcriptional co-repressor termed N-CoR/ SMRT and two histone deacetylases, HDAC1 and HDAC2, the mammalian homologs of the yeast protein Rpd3 (Hassig et al, 1997;Laherty et al, 1997;Heinzel et al, 1997;Alland et al, 1997). A highly conserved 30 amino acid segment at the extreme amino terminus of each Mad protein, termed the SID domain, is required for mSin3 binding (Ayer et al, 1995;Schreiber-Agus et al, 1995).…”