Histone Deacetylases Associated with the mSin3 Corepressor Mediate Mad Transcriptional Repression

Laherty, Carol D.; Yang, Wen‐Ming; Sun, Jian-Min; Davie, James R.; Seto, Edward; Eisenman, Robert N.

doi:10.1016/s0092-8674(00)80215-9

Cited by 895 publications

(767 citation statements)

References 43 publications

(17 reference statements)

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“…The function of each of the MAD transcriptional repressors in the ®ne tuning of the transition between proliferation and di erentiation might actually be identical. Each would downregulate the same set of target genes by recruiting mSIN3-histone deacetylase complexes into gene regulatory regions (Alland et al, 1997;Hassig et al, 1997;Laherty et al, 1997). Alternatively the four Mad family members may di er functionally in terms of DNA binding a nity or speci®city, or strength and mode of transcriptional repression in ways that have not yet been detected in the biochemical or biological assays carried out thus far.…”

Section: Mad Protein Functionmentioning

confidence: 99%

“…MAD ± MAX heterodimers appear to recruit a complex containing mSIN3 and the histone-deacetylases HDAC1 or HDAC2. This has led to the proposal that modi®cation of chromatin into a repressive structure by deacetylation of histones is responsible for MAD-and MNT-mediated transcriptional repression (Alland et al, 1997;Hassig et al, 1997;Laherty et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Sequential expression of the MAD family of transcriptional repressors during differentiation and development

et al. 1998

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Members of the Myc proto-oncogene family encode transcription factors that function in multiple aspects of cell behavior, including proliferation, di erentiation, transformation and apoptosis. Recent studies have shown that MYC activities are modulated by a network of nuclear bHLH-Zip proteins. The MAX protein is at the center of this network in that it associates with MYC as well as with the family of MAD proteins: MAD1, MXI1, MAD3 and MAD4. Whereas MYC ± MAX complexes activate transcription, MAD ± MAX complexes repress transcription through identical E-box binding sites. MAD proteins therefore act as antagonists of MYC. Here we report the expression patterns of the Mad gene family in the adult and developing mouse. High level of Mad gene expression in the adult is limited to tissues that display constant renewal of di erentiated cell populations. In embryos, Mad transcripts are widely distributed with expression peaking during organogenesis at the onset of di erentiation. A detailed analysis of their pattern of expression during chrondrocyte and neuronal di erentiation in vivo, and during neuronal di erentiation of P19 cells in vitro, shows that Mad family genes are sequentially induced. Mad3 transcripts and proteins are detected in proliferating cells prior to di erentiation. Mxi1 and Mad4 transcripts are most abundant in cells that have further advanced along the di erentiation pathway, whereas Mad1 is primarily expressed late in di erentiation. Taken together, our data suggest that the di erent members of the MAD protein family exert their functions at distinct steps during the transition between proliferation and di erentiation.

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Section: Mad Protein Functionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sequential expression of the MAD family of transcriptional repressors during differentiation and development

et al. 1998

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1998

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The PLZF gene was identi®ed ®rst by its fusion with the retinoic acid receptor a gene in the t(11;17) translocation associated with a retinoic acid resistant form of acute promyelocytic leukemia (APL). It encodes a kruÈppel-like zinc ®nger protein with a POZ domain shared with a subset of regulatory proteins including the BCL6 leukemogenic protein. PLZF, like BCL6, strongly represses transcription initiated from di erent promoters. Here we show that PLZF associates in vitro and in vivo with the Mad co-repressor mSin3A and the histone deacetylase HDAC1. Two domains in PLZF and the PAH1 structure of mSin3A mediate these interactions. Trichostatin A, a speci®c inhibitor of histone deacetylases, signi®cantly reduces PLZF repression. These data strongly suggest that, like nuclear receptors and Mad, PLZF represses transcription by recruiting a histone deacetylase through the SMRT-mSin3-HDAC co-repressor complex. We also show that BCL6 associates with HDAC1 indicating that this type of regulation might be common to POZ/Zinc ®nger proteins involved in human leukemias. This work supports a role for deregulated histone deacetylation in the development of both lymphoid and myeloid neoplasia in human and suggests that targeted histone deacetylase inhibitors may be useful for treatment of certain types of malignancies.

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“…The Mad family proteins (Ayer et al, 1993;Zervos et al, 1993;Hurlin et al, 1995), among which Mxi1, can antagonize Myc by interacting with Max. This complex recruits Sin3A or Sin3B transcriptional repressors, the co-repressor N-CoR, and the histone deacetylase HDAC1 (Schreiber-Agus et al, 1995;Rao et al, 1996;Alland et al, 1997;Hassig et al, 1997;Laherty et al, 1997). Direct repression of the c-Myc promoter by Mxi1 can also take place (Lee and Ziff, 1999).…”

mentioning

confidence: 99%

Mxi1 inhibits the proliferation of U87 glioma cells through down-regulation of cyclin B1 gene expression

Manni¹,

Tunici

Cirenei

et al. 2002

Br J Cancer

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Mxi1 is a Mad family member that plays a role in cell proliferation and differentiation. To test the role of Mxi1 on tumorigenesis of glioma cells we transfected a CMV-driven MXI1 cDNA in U87 human glioblastoma cells. Two clones were isolated expressing MXI1 levels 18-and 3.5-fold higher than wild-type U87 cells (clone U87.Mxi1.14 and U87.Mxi1.22, respectively). In vivo, U87.Mxi1.14 cells were not tumorigenic in nude mice and delayed development of tumours was observed with U87.Mxi1.22 cells. In vitro, the proliferation rate was partially and strongly inhibited in U87.Mxi1.22 and U87.Mxi1.14 cells respectively. The cell cycle analysis revealed a relevant accumulation of U87.Mxi1.14 cells in the G 2 /M phase. Interestingly, the expression of cyclin B1 was inhibited to about 60% in U87.Mxi1.14 cells. This inhibition occurs at the transcriptional level and depends, at least in part, on the E-box present on the cyclin B1 promoter. Consistent with this, the endogenous Mxi1 binds this E-box in vitro. Thus, our findings indicate that Mxi1 can act as a tumour suppressor in human glioblastomas through a molecular mechanism involving the transcriptional down-regulation of cyclin B1 gene expression.

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Histone Deacetylases Associated with the mSin3 Corepressor Mediate Mad Transcriptional Repression

Cited by 895 publications

References 43 publications

Sequential expression of the MAD family of transcriptional repressors during differentiation and development

Sequential expression of the MAD family of transcriptional repressors during differentiation and development

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

Mxi1 inhibits the proliferation of U87 glioma cells through down-regulation of cyclin B1 gene expression

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