@article{pmid10753970,

title = {Post-transcriptional regulation of thyroid hormone receptor expression by cis-acting sequences and a naturally occurring antisense RNA},

author = {M L Hastings and H A Ingle and M A Lazar and S H Munroe},

doi = {10.1074/jbc.275.15.11507},

issn = {0021-9258},

year  = {2000},

date = {2000-04-01},

journal = {J Biol Chem},

volume = {275},

number = {15},

pages = {11507--11513},

abstract = {Thyroid hormone (T(3)) coordinates growth, differentiation, and metabolism by binding to nuclear thyroid hormone receptors (TRs). The TRalpha gene encodes T(3)-activated TRalpha1 (NR1A1a) as well as an antagonistic, non-T(3)-binding alternatively spliced product, TRalpha2 (NR1A1b). Thus, the TRalpha1/TRalpha2 ratio is a critical determinant of T(3) action. However, the mechanisms underlying this post-transcriptional regulation are unknown. We have identified a non-consensus, TRalpha2-specific 5' splice site and conserved intronic sequences as key determinants of TRalpha mRNA processing. In addition to these cis-acting elements, a novel regulatory feature is the orphan receptor RevErbAalpha (NR1D1) gene, which is transcribed from the opposite direction at the same locus and overlaps the TRalpha2 coding region. RevErbAalpha gene expression correlates with a high TRalpha1/TRalpha2 ratio in a number of tissues. Here we demonstrate that coexpression of RevErbAalpha and TRalpha regulates the TRalpha1/TRalpha2 ratio in intact cells. Thus, both cis- and trans-regulatory mechanisms contribute to cell-specific post-transcriptional regulation of TR gene expression and T(3) action.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10733574,

title = {The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes},

author = {C Rachez and M Gamble and C P Chang and G B Atkins and M A Lazar and L P Freedman},

doi = {10.1128/MCB.20.8.2718-2726.2000},

issn = {0270-7306},

year  = {2000},

date = {2000-04-01},

journal = {Mol Cell Biol},

volume = {20},

number = {8},

pages = {2718--2726},

abstract = {Transcriptional activation requires both access to DNA assembled as chromatin and functional contact with components of the basal transcription machinery. Using the hormone-bound vitamin D(3) receptor (VDR) ligand binding domain (LBD) as an affinity matrix, we previously identified a novel multisubunit coactivator complex, DRIP (VDR-interacting proteins), required for transcriptional activation by nuclear receptors and several other transcription factors. In this report, we characterize the nuclear receptor binding features of DRIP205, a key subunit of the DRIP complex, that interacts directly with VDR and thyroid hormone receptor in response to ligand and anchors the other DRIP subunits to the nuclear receptor LBD. In common with other nuclear receptor coactivators, DRIP205 interaction occurs through one of two LXXLL motifs and requires the receptor's AF-2 subdomain. Although the second motif of DRIP205 is required only for VDR binding in vitro, both motifs are used in the context of an retinoid X receptor-VDR heterodimer on DNA and in transactivation in vivo. We demonstrate that both endogenous p160 coactivators and DRIP complexes bind to the VDR LBD from nuclear extracts through similar sequence requirements, but they do so as distinct complexes. Moreover, in contrast to the p160 family of coactivators, the DRIP complex is devoid of any histone acetyltransferase activity. The results demonstrate that different coactivator complexes with distinct functions bind to the same transactivation region of nuclear receptors, suggesting that they are both required for transcription activation by nuclear receptors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10681562,

title = {A dominant-negative peroxisome proliferator-activated receptor gamma (PPARgamma) mutant is a constitutive repressor and inhibits PPARgamma-mediated adipogenesis},

author = {M Gurnell and J M Wentworth and M Agostini and M Adams and T N Collingwood and C Provenzano and P O Browne and O Rajanayagam and T P Burris and J W Schwabe and M A Lazar and V K Chatterjee},

doi = {10.1074/jbc.275.8.5754},

issn = {0021-9258},

year  = {2000},

date = {2000-02-01},

journal = {J Biol Chem},

volume = {275},

number = {8},

pages = {5754--5759},

abstract = {The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) promotes adipocyte differentiation, exerts atherogenic and anti-inflammatory effects in monocyte/macrophages, and is believed to mediate the insulin-sensitizing action of antidiabetic thiazolidinedione ligands. As no complete PPARgamma antagonists have been described hitherto, we have constructed a dominant-negative mutant receptor to inhibit wild-type PPARgamma action. Highly conserved hydrophobic and charged residues (Leu(468) and Glu(471)) in helix 12 of the ligand-binding domain were mutated to alanine. This compound PPARgamma mutant retains ligand and DNA binding, but exhibits markedly reduced transactivation due to impaired coactivator (cAMP-response element-binding protein-binding protein and steroid receptor coactivator-1) recruitment. Unexpectedly, the mutant receptor silences basal gene transcription, recruits corepressors (the silencing mediator of retinoid and thyroid receptors and the nuclear corepressor) more avidly than wild-type PPARgamma, and exhibits delayed ligand-dependent corepressor release. It is a powerful dominant-negative inhibitor of cotransfected wild-type receptor action. Furthermore, when expressed in primary human preadipocytes using a recombinant adenovirus, this PPARgamma mutant blocks thiazolidinedione-induced differentiation, providing direct evidence that PPARgamma mediates adipogenesis. Our observations suggest that, as in other mutant nuclear receptor contexts (acute promyelocytic leukemia, resistance to thyroid hormone), dominant-negative inhibition by PPARgamma is linked to aberrant corepressor interaction. Adenoviral expression of this mutant receptor is a valuable means to antagonize PPARgamma signaling.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10940345,

title = {Transcriptional control of adipogenesis},

author = {S M Rangwala and M A Lazar},

doi = {10.1146/annurev.nutr.20.1.535},

issn = {0199-9885},

year  = {2000},

date = {2000-01-01},

journal = {Annu Rev Nutr},

volume = {20},

pages = {535--559},

abstract = {The major transcriptional factors involved in the adipogenic process include proteins belonging to the CCAAT/enhancer binding protein family, peroxisome proliferator-activated receptor gamma, and adipocyte determination and differentiation dependent factor 1, also known as sterol regulatory element-binding protein 1. This process has been characterized with the aid of cell lines that represent various stages in the path of adipocyte commitment, ranging from pluripotent mesodermal fibroblasts to preadipocytes. Molecular analyses have led to a cascade model for adipogenesis based on timed expression of CCAAT/enhancer-binding proteins and peroxisome proliferator-activated receptor gamma. Gene targeting and transgenic-mouse technologies, which allow the manipulation of endogenous genes for these transcription factors, have also contributed to the understanding of adipogenesis. This review aims to integrate this information to gain an understanding of the transcriptional regulation of fat cell formation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10845098,

title = {The mechanism of action of thyroid hormones},

author = {J Zhang and M A Lazar},

doi = {10.1146/annurev.physiol.62.1.439},

issn = {0066-4278},

year  = {2000},

date = {2000-01-01},

journal = {Annu Rev Physiol},

volume = {62},

pages = {439--466},

abstract = {Thyroid hormone is essential for normal development, differentiation, and metabolic balance. Thyroid hormone action is mediated by multiple thyroid hormone receptor isoforms derived from two distinct genes. The thyroid hormone receptors belong to a nuclear receptor superfamily that also includes receptors for other small lipophilic hormones. Thyroid hormone receptors function by binding to specific thyroid hormone-responsive sequences in promoters of target genes and by regulating transcription. Thyroid hormone receptors often form heterodimers with retinoid X receptors. Heterodimerization is regulated through distinct mechanisms that together determine the specificity and flexibility of the sequence recognition. Amino-terminal regions appear to modulate thyroid hormone receptor function in an isoform-dependent manner. Unliganded thyroid hormone receptor represses transcription through recruitment of a corepressor complex, which also includes Sin3A and histone deacetylase. Ligand binding alters the conformation of the thyroid hormone receptor in such a way as to release the corepressor complex and recruit a coactivator complex that includes multiple histone acetyltransferases, including a steroid receptor family coactivator, p300/CREB-binding protein-associated factor (PCAF), and CREB binding protein (CBP). The existence of histone-modifying activities in the transcriptional regulatory complexes indicates an important role of chromatin structure. Stoichiometric, structural, and sequence-specific rules for coregulator interaction are beginning to be understood, as are aspects of the tissue specificity of hormone action. Moreover, knockout studies suggest that the products of two thyroid hormone receptor genes mediate distinct functions in vivo. The increased understanding of the structure and function of thyroid hormone receptors and their interacting proteins has markedly clarified the molecular mechanisms of thyroid hormone action.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10652499,

title = {Transcriptional repression by nuclear hormone receptors},

author = {X Hu and M A Lazar},

doi = {10.1016/s1043-2760(99)00215-5},

issn = {1043-2760},

year  = {2000},

date = {2000-01-01},

journal = {Trends Endocrinol Metab},

volume = {11},

number = {1},

pages = {6--10},

abstract = {Repression by nuclear receptors plays important roles in acute promyelocytic leukemia and other diseases. Nuclear receptor corepressor (N-CoR) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) are corepressor proteins whose modular structure facilitates receptor interaction as well as transduction of repression signals involving histone deacetylation, alterations in chromatin structure and direct interactions with the basal transcription machinery. Interactions between nuclear receptors and corepressor complexes have multiple determinants. This allows regulation, and potentially therapeutic manipulation, of receptor, corepressor, cell-type and target-gene specificity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10640275,

title = {Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway},

author = {E Y Huang and J Zhang and E A Miska and M G Guenther and T Kouzarides and M A Lazar},

issn = {0890-9369},

year  = {2000},

date = {2000-01-01},

journal = {Genes Dev},

volume = {14},

number = {1},

pages = {45--54},

abstract = {Transcriptional repression mediated by corepressors N-CoR and SMRT is a critical function of nuclear hormone receptors, and is dysregulated in human myeloid leukemias. At the present time, these corepressors are thought to act exclusively through an mSin3/HDAC1 complex. Surprisingly, however, numerous biochemical studies have not detected N-CoR or SMRT in mSin3- and HDAC1-containing complexes. Each corepressor contains multiple repression domains (RDs), the significance of which is unknown. Here we show that these RDs are nonredundant, and that one RD, which is conserved in N-CoR and SMRT, represses transcription by interacting directly with class II HDAC4 and HDAC5. Endogenous N-CoR and SMRT each associate with HDAC4 in a complex that does not contain mSin3A or HDAC1. This is the first example of a single corepressor utilizing distinct domains to engage multiple HDAC complexes. The alternative HDAC complexes may mediate specific repression pathways in normal as well as leukemic cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10322388,

title = {Mechanisms by which Thiazolidinediones Enhance Insulin Action},

author = {MJ Reginato and MA Lazar},

doi = {10.1016/s1043-2760(98)00110-6},

issn = {1879-3061},

year  = {1999},

date = {1999-12-01},

journal = {Trends Endocrinol Metab},

volume = {10},

number = {1},

pages = {9--13},

abstract = {Thiazolidinediones (TZDs) are an exciting new class of insulin-sensitizing drugs being used currently for the treatment of non-insulin-dependent diabetes mellitus. The molecular target of these compounds is thought to be the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is expressed predominantly in adipose tissue, yet a major site of TZD-responsive glucose disposal is skeletal muscle. Potential explanations for this paradox are discussed in this review.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10573424,

title = {The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors},

author = {X Hu and M A Lazar},

doi = {10.1038/47069},

issn = {0028-0836},

year  = {1999},

date = {1999-11-01},

journal = {Nature},

volume = {402},

number = {6757},

pages = {93--96},

abstract = {N-CoR and SMRT are transcriptional corepressors that associate with nuclear hormone receptors (NRs) in the absence of ligand. This interaction is the molecular target of differentiation therapy for acute promyelocytic leukaemia, wherein retinoic acid dissociates corepressor from leukaemogenic receptor fusion proteins. Binding of ligand to NRs induces a conformation that attracts coactivator proteins containing an Leu-x-x-Leu-Leu motif (the 'NR box'). Here we show that N-CoR and SMRT contain sequences that are similar to the NR box and are repeated in each of two NR interaction domains. We show that this CoRNR ('corner') box is required for NR interaction, and that CoRNR box peptides specifically block corepressor interaction in vitro and repression in vivo. Sequences flanking the CoRNR box determine NR specificity. Thus, the key feature of hormone action, differential recognition of unliganded and liganded NRs by coactivators and corepressors, is due to very subtle differences between CoRNR and NR boxes. The molecular mechanisms of repression and activation by NRs are thus linked in an unexpected manner.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10510588,

title = {Nuclear hormone receptors: from molecules to diseases},

author = {M A Lazar},

issn = {1081-5589},

year  = {1999},

date = {1999-09-01},

journal = {J Investig Med},

volume = {47},

number = {8},

pages = {364--368},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10485914,

title = {Amplification and overexpression of peroxisome proliferator-activated receptor binding protein (PBP/PPARBP) gene in breast cancer},

author = {Y Zhu and C Qi and S Jain and M M Le Beau and R Espinosa and G B Atkins and M A Lazar and A V Yeldandi and M S Rao and J K Reddy},

doi = {10.1073/pnas.96.19.10848},

issn = {0027-8424},

year  = {1999},

date = {1999-09-01},

journal = {Proc Natl Acad Sci U S A},

volume = {96},

number = {19},

pages = {10848--10853},

abstract = {Peroxisome proliferator-activated receptor binding protein (PBP), a nuclear receptor coactivator, interacts with estrogen receptor alpha (ERalpha) in the absence of estrogen. This interaction was enhanced in the presence of estrogen but was reduced in the presence of antiestrogen, tamoxifen. Transfection of PBP in CV-1 cells resulted in enhancement of estrogen-dependent transcription, indicating that PBP serves as a coactivator in ER signaling. To examine whether overexpression of PBP plays a role in breast cancer because of its coactivator function in ER signaling, we determined the levels of PBP expression in breast tumors. High levels of PBP expression were detected in approximately 50% of primary breast cancers and breast cancer cell lines by ribonuclease protection analysis, in situ hybridization, and immunoperoxidase staining. Fluorescence in situ hybridization of human chromosomes revealed that the PBP gene is located on chromosome 17q12, a region that is amplified in some breast cancers. We found PBP gene amplification in approximately 24% (6/25) of breast tumors and approximately 30% (2/6) of breast cancer cell lines, implying that PBP gene overexpression can occur independent of gene amplification. This gene comprises 17 exons that, together, span >37 kilobases. The 5'-flanking region of 2.5 kilobase pairs inserted into a luciferase reporter vector revealed that the promoter activity in CV-1 cells increased by deletion of nucleotides from -2,500 to -273. The -273 to +1 region, which exhibited high promoter activity, contains a typical CCAT box and multiple cis-elements such as C/EBPbeta, YY1, c-Ets-1, AP1, AP2, and NFkappaB binding sites. These observations, in particular PBP gene amplification, suggest that PBP, by its ability to function as ERalpha coactivator, might play a role in mammary epithelial differentiation and in breast carcinogenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10478845,

title = {Coactivators for the orphan nuclear receptor RORalpha},

author = {G B Atkins and X Hu and M G Guenther and C Rachez and L P Freedman and M A Lazar},

doi = {10.1210/mend.13.9.0343},

issn = {0888-8809},

year  = {1999},

date = {1999-09-01},

journal = {Mol Endocrinol},

volume = {13},

number = {9},

pages = {1550--1557},

abstract = {A mutation in the nuclear orphan receptor RORalpha results in a severe impairment of cerebellar development by unknown mechanisms. We have shown previously that RORalpha contains a strong constitutive activation domain in its C terminus. We therefore searched for mammalian RORalpha coactivators using the minimal activation domain as bait in a two-hybrid screen. Several known and putative coactivators were isolated, including glucocorticoid receptor-interacting protein-1 (GRIP-1) and peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP/TRAP220/DRIP205). These interactions were confirmed in vitro and require the intact activation domain of RORalpha although different requirements for interaction with GRIP-1 and PBP were detected. Even in the absence of exogenous ligand, RORalpha interacts with a complex or complexes of endogenous proteins, similar to those that bind to ligand-occupied thyroid hormone and vitamin D receptors. Both PBP and GRIP-1 were shown to be present in these complexes. Thus we have identified several potential RORalpha coactivators that, in contrast to the interactions with hormone receptors, interact with RORalpha in yeast, in bacterial extracts, and in mammalian cells in vivo and in vitro in the absence of exogenous ligand. GRIP-1 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells. Thus, GRIP-1 is the first proven coactivator for RORalpha.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10454590,

title = {A novel role for helix 12 of retinoid X receptor in regulating repression},

author = {J Zhang and X Hu and M A Lazar},

doi = {10.1128/MCB.19.9.6448},

issn = {0270-7306},

year  = {1999},

date = {1999-09-01},

journal = {Mol Cell Biol},

volume = {19},

number = {9},

pages = {6448--6457},

abstract = {Nutrients, drugs, and hormones influence transcription during differentiation and metabolism by binding to high-affinity nuclear receptors. In the absence of ligand, some but not all nuclear receptors repress transcription as a heterodimer with retinoid X receptor (RXR). Here we define a novel role for helix 12 (H12) in sterically masking the corepressor (CoR) binding site in apo-RXR. Removing H12 converts RXR to a potent transcriptional repressor. The length but not the specific sequence of H12 is critical for masking RXR's intrinsic repression function. This contrasts with the amphipathic character required for mediating ligand-dependent activation and coactivator recruitment. Physiologically, we show that heterodimerization of RXR with apo-thyroid hormone receptor (TR) unmasks the CoR binding site in RXR and allows the TR-RXR heterodimer to repress. A molecular mechanism that involves sequence-specific interaction between RXR H12 and the coactivator-binding surface of the nuclear receptor is proposed for this heterodimerization-mediated unmasking. Peroxisome proliferator-activated receptor gamma does not interact as well with RXR H12, thus explaining its inability to repress transcription as an RXR heterodimer. The requirement to unmask RXR's latent repression function explains why only certain RXR partners repress transcription.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10453361,

title = {Citation for the 1999 Edwin B. Astwood Lecture Award of the Endocrine Society to Dr. David D. Moore},

author = {M A Lazar},

issn = {0163-769X},

year  = {1999},

date = {1999-08-01},

journal = {Endocr Rev},

volume = {20},

number = {4},

pages = {589--590},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10449430,

title = {A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response},

author = {C G Su and X Wen and S T Bailey and W Jiang and S M Rangwala and S A Keilbaugh and A Flanigan and S Murthy and M A Lazar and G D Wu},

doi = {10.1172/JCI7145},

issn = {0021-9738},

year  = {1999},

date = {1999-08-01},

journal = {J Clin Invest},

volume = {104},

number = {4},

pages = {383--389},

abstract = {Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily originally shown to play a critical role in adipocyte differentiation and glucose homeostasis, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Colonic epithelial cells, which express high levels of PPAR-gamma protein, have the ability to produce inflammatory cytokines that may play a role in inflammatory bowel disease (IBD). We report here that PPAR-gamma ligands dramatically attenuate cytokine gene expression in colon cancer cell lines by inhibiting the activation of nuclear factor-kappaB via an IkappaB-alpha-dependent mechanism. Moreover, thiazolidinedione ligands for PPAR-gamma markedly reduce colonic inflammation in a mouse model of IBD. These results suggest that colonic PPAR-gamma may be a therapeutic target in humans suffering from IBD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10377165,

title = {Modulating nuclear receptor function: may the phos be with you},

author = {D Shao and M A Lazar},

doi = {10.1172/JCI7421},

issn = {0021-9738},

year  = {1999},

date = {1999-06-01},

journal = {J Clin Invest},

volume = {103},

number = {12},

pages = {1617--1618},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid20487930,

title = {Dephosphorylation of purified brain tyrosine hydroxylase by rat striatal extracts},

author = {M A Lazar and J D Raese and J D Barchas},

doi = {10.1016/0197-0186(83)90016-5},

issn = {0197-0186},

year  = {1983},

date = {1983-01-01},

journal = {Neurochem Int},

volume = {5},

number = {1},

pages = {107--111},

abstract = {Tyrosine hydroxylase (TH) was purified from bovine brain and enzymatically phosphorylated in vitro. Radioactively phosphorylated TH was dephosphorylated by rat tissue extracts. Of tissues examined, rat corpus striatal extracts were highest in specific activity in the TH dephosphorylating assay. Phosphorylated histone did not inhibit dephosphorylation of TH by rat striatal extracts. The thermal decay of dephosphorylating activity of rat striatal extracts varied with substrate, with TH dephosphorylating activity most unstable of the activities assayed. The results suggest that TH can be enzymatically dephosphorylated and that, in corpus striatum, this process differs quantitatively from the dephosphorylation of phosphohistone and phosphoprotamine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Lazar Pubs},

author = {Lazar MA},

keywords = {},

pubstate = {published},

tppubtype = {article}

}