A signature motif in transcriptional co-activators mediates binding to nuclear receptors

Heery, David M.; Kalkhoven, Eric; Hoare, Susan; Parker, Malcolm G.

doi:10.1038/42750

Cited by 1,967 publications

(1,620 citation statements)

References 26 publications

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“…At least four potential nuclear localization signals, distributed throughout the protein sequence, were identi®ed using PSORT, a program designed to search for protein localization motifs (Nakai and Kanehisa, 1992). Interestingly we have also identi®ed four Figure 2 A dot-plot alignment of BRL amino acid sequence with that of BR140 corresponding to an overall 56% identity motifs which could potentially bind nuclear receptors (Heery et al, 1997). These have the consensus sequence LXXLL where L represents leucine and X represents any amino acid and they are found at residues 538 ± 542; 567 ± 571; 718 ± 722 and 791 ± 795.…”

Section: Cloning and Sequence Analysis Of Human Brlmentioning

confidence: 92%

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

McCullagh¹,

Chaplin²,

Meerabux³

et al. 1999

Oncogene

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The MLL gene is reciprocally translocated with one of a number of di erent partner genes in a proportion of human acute leukaemias. The precise mechanism of oncogenic transformation is unclear since most of the partner genes encode unrelated proteins. However, two partner genes, AF10 and AF17 are related through the presence of a cysteine rich region and a leucine zipper. The identi®cation of other proteins with these structures will aid our understanding of their role in normal and leukaemic cells. We report the cloning of a novel human gene (BRL) which encodes a protein containing a cysteine rich region related to that of AF10 and AF17 and is overall most closely related to the previously known protein BR140. BRL maps to chromosome 22q13 and shows high levels of expression in testis and several cell lines. The deduced protein sequence also contains a bromodomain, four potential LXXLL motifs and four predicted nuclear localization signals. A monoclonal antibody raised to a BRL peptide sequence con®rmed its widespread expression as a 120 Kd protein and demonstrated localization to the nucleus within spermatocytes.

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Section: Cloning and Sequence Analysis Of Human Brlmentioning

confidence: 92%

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

McCullagh¹,

Chaplin²,

Meerabux³

et al. 1999

Oncogene

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“…The precise role of some of these factors remains to be determined, but three related 160 kDa proteins (p160 family) named SRC-1/NcoA-1, TIF2/GRIP2 and AIB1/ SRC3/ACTR/RAC3/pCIP clearly potentiate the transcriptional activity of the ER and indeed several other nuclear receptors (McKenna et al, 1999). This interaction, which is tightly ligand-dependent, is mediated by LXXLL motifs present in all of these proteins (Heery et al, 1997;Torchia et al, 1997). If these factors are also required for the activity of the ERBB2 enhancer, it is conceivable that the activated ER may compete for their binding and thereby repress ERBB2 expression.…”

Section: Er Cofactors Also Activate the Erbb2 Enhancermentioning

confidence: 99%

Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer

et al. 2000

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Overexpression of the ERBB2 proto-oncogene in breast tumours, which occurs in 25 ± 30% of patients, correlates with poor prognosis. In oestrogen receptor (ER) positive breast epithelial cells oestrogens reduce ERBB2 mRNA and protein levels, an e ect that is reversed in the presence of anti-oestrogens such as tamoxifen and ICI 182780. Our previous studies have shown that the major e ect of oestrogen on ERBB2 expression is at the level of transcription and that this is mediated through a region within the ERBB2 ®rst intron which can act as an oestrogen-suppressible enhancer in ER positive breast cells. In vitro footprinting of the smallest DNA fragment that retained full activity revealed four transcription factor binding sites. We report here that two of these sites are recognized by AP-2 proteins and the other two are bound by a variety of bZIP factors, including CREB and ATF1, with a major complex containing ATFa/ JunD. However, by using ER mutants it is clear that repression occurs essentially o the DNA. Indeed, the essential domain of the ER responsible for repression of the ERBB2 enhancer is a region termed AF2 which is required for the ligand-dependent association of non-DNA binding cofactors. We further demonstrate that one of these ER cofactors, SRC-1, can relieve oestrogen repression of the ERBB2 enhancer and conclude that these data ®t with a model whereby the ER and the ERBB2 enhancer compete for this limiting, non-DNA binding cofactor. Thus, in oestrogenic conditions SRC-1 preferentially binds to the ER which e ectively sequesters it thereby reducing enhancer activity, but in antioestrogenic media the cofactor is released from the ER and is therefore available to activate the ERBB2 enhancer. Oncogene (2000) 19, 490 ± 497.

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“…The SAND domain is thought to act as a DNA binding domain, and its structure has been determined in a number of nuclear proteins including Sp100 family proteins [6,7]. The LXXLL motifs are found in various proteins and are needed for the binding to nuclear receptors, mainly in a ligand-dependent manner [8]. Interestingly, the AIRE PHD1 domain has also ubiquitin E3 ligase activity.…”

Section: Introductionmentioning

confidence: 99%

The role of AIRE polymorphisms in melanoma

Conteduca

Ferrera

Pastorino

et al. 2010

Clinical Immunology

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Polymorphisms of AIRE, a transcription factor that up-regulates intrathymic expression of tissue-specific antigens including melanoma-associated antigens (MAAs), may variably affect the selection of MAAs-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to melanoma. We found that AIRE single nucleotide polymorphisms (SNPs) rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients, independently from sex, age and stages of melanoma. The presence of these SNPs was associated with increased frequency of two T-cell clonotypes specific for MAGE-1 linking their protective effect to selection/expansion of MAA-specific T cells. Interestingly, mRNA transcribed on the rs1800520 SNP showed increased free energy than the wild type suggesting that its reduced stability may be responsible for the different activity of the polymorphic AIRE molecule. This finding may contribute at identifying subjects with increased risk of developing melanoma or patients with melanoma that may take benefit from immunotherapy.

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A signature motif in transcriptional co-activators mediates binding to nuclear receptors

Cited by 1,967 publications

References 26 publications

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer

The role of AIRE polymorphisms in melanoma

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