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首页> 美国政府科技报告 >Tamoxifen Resistant Breast Cancers: Inappropriate Transcriptional Coregulators
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Tamoxifen Resistant Breast Cancers: Inappropriate Transcriptional Coregulators

机译：他莫昔芬抗性乳腺癌：不适当的转录调节剂

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We speculated that in breast cancers, hormone resistance to antagonists involves the inappropriate recruitment of coregulatory proteins to the transcriptional machinery, which switches antagonists into agonists. We set out to discover transcriptional coregulators that influence this switch. We describe here the discovery of an entirely new protein. It has the unusual structural property of having three TPR domains involved in protein-protein interactions, plus four NR boxes, through which nuclear receptors interact with coregulators. We have dubbed this protein NRAP (Nuclear Receptor Accessory Protein). We have isolated and characterized the NRAP gene. We describe the full amino acid sequence of NARP. We have defined the tissue distribution of the transcript. We have raised antibodies to the protein, defined the protein's distribution and show high expression levels in ovarian and breast cancers. We have analyzed the biochemistry of the protein. It interacts simultaneously with heat shock protein 90 and with progesterone (PR) and other nuclear receptors. We have mapped the interaction site for PRs to one NR box. The trimeric NRAP/PR/ hsp9O complex is stabilized by antagonist ligands and destabilized by agonists. We speculate that NRAP has scaffolding functions, and that it may be involved in regulating receptor levels by having a role in receptor destruction induced by some antagonists.

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