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Title: Estrogen down-regulation of the corepressor N-CoR: mechanism and implications for estrogen derepression of N-CoR-regulated genes.

Authors: Frasor, Jonna; Danes, Jeanne M; Funk, Cory C; Katzenellenbogen, Benita S

Published In Proc Natl Acad Sci U S A, (2005 Sep 13)

Abstract: The nuclear receptor corepressor N-CoR plays a crucial role in the repressive activity of diverse transcription factors, yet little is known about what regulates its cellular level. We have found that estrogen markedly down-regulates N-CoR protein levels in estrogen receptor (ER)-positive breast cancer cells without affecting N-CoR mRNA levels, whereas levels of the related corepressor SMRT are unaffected. This effect is attributable to estrogen up-regulation of the ubiquitin ligase Siah2, which is a rapid and primary transcriptional response mediated by the ER, and precedes the loss of N-CoR. Treatment with proteasomal inhibitor or with small interfering RNA against Siah2 prevented the down-regulation of N-CoR by estrogen. Furthermore, the expression of 24-hydroxylase, a gene repressed by unliganded vitamin D receptor through its interaction with N-CoR, was up-regulated by estrogen and required Siah2. Our results illustrate a mechanism by which the estrogen-ER complex markedly reduces the level of N-CoR through a process involving the up-regulation of Siah2 and the subsequent targeting of N-CoR for proteasomal degradation. These findings reveal that, although estrogen directly regulates the transcription of many genes, by regulating a gene such as Siah2 it can exert profound "secondary" effects on cellular activity through mechanisms such as targeting regulatory proteins for degradation. This estrogen-evoked down-regulation of N-CoR could have a global derepressive effect on genes whose repression depends on N-CoR and thereby have broad impact on the activity of transcription factors and nuclear receptors whose actions involve N-CoR.

PubMed ID: 16141343 Exiting the NIEHS site

MeSH Terms: Cell Line, Tumor; Cysteine Endopeptidases/metabolism; Down-Regulation*; Estrogens/pharmacology; Estrogens/physiology*; Female; Humans; Nuclear Proteins/analysis; Nuclear Proteins/genetics*; Nuclear Proteins/metabolism; Nuclear Receptor Co-Repressor 1; RNA, Messenger/analysis; Receptors, Estrogen/metabolism; Repressor Proteins/analysis; Repressor Proteins/genetics*; Repressor Proteins/metabolism; Transcription Factors/genetics*; Transcription Factors/physiology; Ubiquitin-Protein Ligases; Up-Regulation

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