A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains

Ligand-independent transcriptional repression is an important function of nuclear hormone receptors. An interaction screen with the repression domain of the orphan receptor RevErb identified N-CoR, the corepressor for thyroid hormone receptor (TR) and retinoic acid receptor (RAR). N-CoR is likely to be a bona fide transcriptional corepressor for RevErb because (i) RevErb interacts with endogenous N-CoR, (ii) ectopic N-CoR potentiates RevErb-mediated repression, and (iii) transcriptional repression by RevErb correlates with its ability to bind N-CoR. Remarkably, a region homologous to the CoR box which is necessary for TR and RAR to interact with N-CoR is not required for RevErb. Rather, two short regions of RevErb separated by approximately 200 amino acids are required for interaction with N-CoR. The primary amino acid sequence of the N-terminal region of RevErb essential for N-CoR interaction is not homologous to that of TR or RAR, whereas similarities exist among the C-terminal domains of the receptors. N-CoR contains two adjacent but distinct interaction domains, one of which binds tightly to both RevErb and TR whereas the other binds more weakly and differentially interacts with the nuclear receptors. These results indicate that multiple nuclear receptors, utilizing different primary amino acid sequences, repress transcription by interacting with N-CoR.

[1]  Mary E. McGrath,et al.  A structural role for hormone in the thyroid hormone receptor , 1995, Nature.

[2]  Jean-Paul Renaud,et al.  Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid , 1995, Nature.

[3]  B. O’Malley,et al.  Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily , 1995, Science.

[4]  Thorsten Heinzel,et al.  Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor , 1995, Nature.

[5]  Myles Brown,et al.  Polarity-specific activities of retinoic acid receptors determined by a co-repressor , 1995, Nature.

[6]  R. Evans,et al.  A transcriptional co-repressor that interacts with nuclear hormone receptors , 1995, Nature.

[7]  M. Lazar,et al.  direct repeat . represses transcription as a dimer on a novel The monomer-binding orphan receptor RevErb , 1995 .

[8]  J. Manley,et al.  The transcriptional repressor even-skipped interacts directly with TATA-binding protein , 1995, Molecular and cellular biology.

[9]  P. Kushner,et al.  Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. , 1995, The EMBO journal.

[10]  J. Milbrandt,et al.  Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  H. Jäckle,et al.  Control of transcription by Krüppel through interactions with TFIIB and TFIIEβ , 1995, Nature.

[12]  P. Chambon,et al.  The N‐terminal part of TIF1, a putative mediator of the ligand‐dependent activation function (AF‐2) of nuclear receptors, is fused to B‐raf in the oncogenic protein T18. , 1995, The EMBO journal.

[13]  M. Carlson,et al.  Repression by SSN6-TUP1 is directed by MIG1, a repressor/activator protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[14]  K. Struhl,et al.  Distinct TPR motifs of Cyc8 are involved in recruiting the Cyc8-Tup1 corepressor complex to differentially regulated promoters. , 1995, Genes & development.

[15]  D. Moore,et al.  Interaction of thyroid-hormone receptor with a conserved transcriptional mediator , 1995, Nature.

[16]  P. Chambon,et al.  RAR‐specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit anchorage‐independent cell proliferation. , 1995, The EMBO journal.

[17]  R. Evans,et al.  Evidence for two distinct retinoic acid response pathways for HOXB1 gene regulation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[18]  B. O’Malley,et al.  The tau 4 activation domain of the thyroid hormone receptor is required for release of a putative corepressor(s) necessary for transcriptional silencing , 1995, Molecular and cellular biology.

[19]  P. Chambon,et al.  Activation function 2 (AF‐2) of retinoic acid receptor and 9‐cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF‐2 activity. , 1994, The EMBO journal.

[20]  R. Tjian,et al.  Assembly of recombinant TFIID reveals differential coactivator requirements for distinct transcriptional activators , 1994, Cell.

[21]  B. Raaka,et al.  Functional evidence for ligand-dependent dissociation of thyroid hormone and retinoic acid receptors from an inhibitory cellular factor , 1994, Molecular and cellular biology.

[22]  V. Giguère,et al.  Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator. , 1994, Molecular endocrinology.

[23]  S. Kliewer,et al.  Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors. , 1994, Molecular endocrinology.

[24]  S. Brenner,et al.  A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1 , 1994, Nature.

[25]  K. A. Lehmann,et al.  A new orphan member of the nuclear hormone receptor superfamily closely related to Rev-Erb. , 1994, Molecular endocrinology.

[26]  M. Arnaud,et al.  Transcriptional repression directed by the yeast α2 protein in vitro , 1994, Nature.

[27]  D. Barettino,et al.  Characterization of the ligand‐dependent transactivation domain of thyroid hormone receptor. , 1994, The EMBO journal.

[28]  G. Martin,et al.  Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription. , 1994, Science.

[29]  H. Thiesen,et al.  Krüppel-associated boxes are potent transcriptional repression domains. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Tom Maniatis,et al.  Transcriptional activation: A complex puzzle with few easy pieces , 1994, Cell.

[31]  R. Tjian,et al.  Drosophila TAFII40 interacts with both a VP16 activation domain and the basal transcription factor TFIIB , 1993, Cell.

[32]  M. Lazar,et al.  Dominant negative activity of an endogenous thyroid hormone receptor variant (alpha 2) is due to competition for binding sites on target genes. , 1993, The Journal of biological chemistry.

[33]  M. Lazar,et al.  Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation. , 1993, The Journal of biological chemistry.

[34]  R. Roeder,et al.  Unliganded thyroid hormone receptor inhibits formation of a functional preinitiation complex: implications for active repression. , 1993, Genes & development.

[35]  M. Lazar,et al.  The orphan receptor Rev-ErbA alpha activates transcription via a novel response element , 1993, Molecular and cellular biology.

[36]  K. Umesono,et al.  Functional inhibition of retinoic acid response by dominant negative retinoic acid receptor mutants. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M. Pfahl,et al.  A retinoic acid response element from the rat CRBPI promoter is activated by an RAR/RXR heterodimer. , 1992, Biochemical and biophysical research communications.

[38]  M. Lazar,et al.  The unique C-termini of the thyroid hormone receptor variant, c-erbA alpha 2, and thyroid hormone receptor alpha 1 mediate different DNA-binding and heterodimerization properties. , 1992, Molecular endocrinology.

[39]  J. Lees,et al.  Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. , 1992, The EMBO journal.

[40]  R. Renkawitz,et al.  A transferable silencing domain is present in the thyroid hormone receptor, in the v‐erbA oncogene product and in the retinoic acid receptor. , 1992, The EMBO journal.

[41]  M. Ewen,et al.  Interaction of p107 with cyclin A independent of complex formation with viral oncoproteins. , 1992, Science.

[42]  M. Ewen,et al.  Interaction between human cyclin A and adenovirus E1A-associated p107 protein. , 1992, Science.

[43]  P. Chambon,et al.  A retinoic acid response element is present in the mouse cellular retinol binding protein I (mCRBPI) promoter. , 1991, The EMBO journal.

[44]  H. Samuels,et al.  Interactions among a subfamily of nuclear hormone receptors: the regulatory zipper model. , 1990, Molecular endocrinology.

[45]  J. Harney,et al.  Thyroid hormone aporeceptor represses T3-inducible promoters and blocks activity of the retinoic acid receptor. , 1989, The New biologist.

[46]  E. A. O'neill,et al.  The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain , 1989, Cell.

[47]  M. Pfahl,et al.  Dual regulatory role for thyroid-hormone receptors allows control of retinoic-acid receptor activity , 1989, Nature.

[48]  Klaus Damm,et al.  Protein encoded by v-erbA functions as a thyroid-hormone receptor antagonist , 1989, Nature.

[49]  Nobuyuki Miyajima,et al.  Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus , 1989, Cell.

[50]  M. Lazar,et al.  A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit , 1989, Molecular and cellular biology.

[51]  R. Tjian,et al.  Analysis of Sp1 in vivo reveals mutiple transcriptional domains, including a novel glutamine-rich activation motif , 1988, Cell.

[52]  Jun Ma,et al.  A new class of yeast transcriptional activators , 1987, Cell.

[53]  K. Struhl,et al.  Functional dissection of a eukaryotic transcriptional activator protein, GCN4 of Yeast , 1986, Cell.

[54]  D. Moore,et al.  Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. , 1995, Molecular endocrinology.

[55]  D. Reinberg,et al.  Common themes in assembly and function of eukaryotic transcription complexes. , 1995, Annual review of biochemistry.

[56]  A. Johnson,et al.  Transcriptional repression directed by the yeast alpha 2 protein in vitro. , 1994, Nature.

[57]  M. Lazar,et al.  The Orphan Receptor Rev-ErbAot Activates Transcription via a Novel Response Element , 2022 .