Transcriptional Regulation by the Repressor of Estrogen Receptor Activity via Recruitment of Histone Deacetylases

Kurtev, Vladislav; Margueron, Raphaël; Kroboth, Karin; Ogris, Egon; Cavaillès, Vincent; Seiser, Christian

doi:10.1074/jbc.m312300200

Cited by 98 publications

(91 citation statements)

References 68 publications

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“…Phb2 was found to repress the transcriptional activity of the estrogen receptor in breast cancer cell lines by competing for coactivator binding sites on estrogen receptor in the nucleus (21) (57). Due to this inhibitory action, the protein was named repressor of estrogen receptor activity, however, it has recently been shown to interact with histone deacetylases HDAC1 and HDAC5 to mediate repression of COUP-TFs, suggesting a more general nuclear receptor corepressor function (58). Interestingly, nuclear Phb2 was recently shown to protect sister chromatid cohesion during mitosis in the cervical carcinoma cell line, HeLa (59).…”

Section: Discussionmentioning

confidence: 99%

The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells

Ross

Nagy

Kirken

2008

Journal of Biological Chemistry

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Many immune pathologies are the result of aberrant regulation of T lymphocytes. A functional proteomics approach utilizing two-dimensional gel electrophoresis coupled with mass spectrometry was employed to identify differentially expressed proteins in response to T cell activation. Two members of the prohibitin family of proteins, Phb1 and Phb2, were determined to be up-regulated 4 -5-fold upon activation of primary human T cells. Furthermore, their expression was dependent upon CD3 and CD28 signaling pathways that synergistically led to the upregulation (13-15-fold) of Phb1 and Phb2 mRNA levels as early as 48 h after activation. Additionally, orthophosphate labeling coupled with phosphoamino acid analysis identified Phb1 to be serine and Phb2 serine and tyrosine phosphorylated. Tyrosine phosphorylation of Phb2 was mapped to Tyr 248 using mass spectrometry and confirmed by mutagenesis and phosphospecific antibodies. In contrast to previous reports of Phb1 and Phb2 being nuclear localized, subcellular fractionation, immunofluorescent, and electron microscopy revealed both proteins to localize to the mitochondrial inner membrane of human T cells. Accordingly, small interfering RNA-mediated knockdown of Phbs in Kit225 cells resulted in disruption of mitochondrial membrane potential. Additionally, Phb1 and Phb2 protein levels were up-regulated 2.5-fold during cytokine deprivation-mediated apoptosis of Kit225 cells, suggesting this complex plays a protective role in human T cells. Taken together, Phb1 and Phb2 are novel phosphoproteins up-regulated during T cell activation that function to maintain mitochondrial integrity and thus represent previously unrecognized therapeutic targets for regulating T cell activation, differentiation, viability, and function.

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Section: Discussionmentioning

confidence: 99%

The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells

Ross

Nagy

Kirken

2008

Journal of Biological Chemistry

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“…Furthermore, in other cell types, PHB2 has also been suggested to be localized in the nucleus and modulate transcriptional activity by interacting with transcription factors, including nuclear receptors, either directly or indirectly 12,[29][30][31][32] . PHB2 has been shown to interact with and inhibit the transcriptional activity of the ER in breast cancer 12 .…”

Section: Discussionmentioning

confidence: 99%

CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation

et al. 2014

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Abnormal mitochondrial fission participates in the pathogenesis of many diseases. Long non-coding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs operate in the regulation of mitochondrial network is unclear. Here we report that a lncRNA, named cardiac apoptosis-related lncRNA (CARL), can suppress mitochondrial fission and apoptosis by targeting miR-539 and PHB2. The results show that PHB2 is able to inhibit mitochondrial fission and apoptosis. miR-539 is responsible for the dysfunction of PHB2 and regulates mitochondrial fission and apoptosis by targeting PHB2. Further, we show that CARL can act as an endogenous miR-539 sponge that regulates PHB2 expression, mitochondrial fission and apoptosis. Our present study reveals a model of mitochondrial fission regulation that is composed of CARL, miR-539 and PHB2. Modulation of their levels may provide a new approach for tackling apoptosis and myocardial infarction.

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“…Thus, the unexpected maspin/HDAC1 interaction turned out not entirely surprising. Indeed, Kurtev et al (44) recently reported that HDAC1 may bind to chick ovalbumin, a classic noninhibitory serpin homologue of maspin. Interestingly, maspin was not associated with other class I HDACs (e.g., HDAC2 and HDAC3, and data not shown) despite their sequence homologies with HDAC1 (45,46).…”

Section: Discussionmentioning

confidence: 99%

Endogenous Inhibition of Histone Deacetylase 1 by Tumor-Suppressive Maspin

Li¹,

Su²,

Meng³

et al. 2006

Cancer Research

117

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Maspin, a noninhibitory serine protease inhibitor, exerts multifaceted tumor-suppressive effects. Maspin expression is associated with better differentiated phenotypes, better cancer prognosis, and better drug sensitivity. Consistently, maspin also correlates with increased expression of Bax and p21 WAF1/CIP1 . Interestingly, histone deacetylase 1 (HDAC1), a major HDAC responsible for histone deacetylation, was shown to interact with maspin in a yeast two-hybrid screening. In this study, we confirmed the maspin/HDAC1 interaction in human prostate tissues, in prostate cancer cell lines, and with purified maspin. We produced several lines of evidence that support an inhibitory effect of maspin on HDAC1 through direct molecular interaction, which was detected in both the nucleus and the cytoplasm. Both endogenously expressed maspin and purified maspin inhibited HDAC1. In contrast, small interfering RNA (siRNA) silencing of maspin in PC3 cells increased HDAC activity. Accordingly, maspin-transfected DU145 cells exhibited increased expression of HDAC1 target genes Bax, cytokeratin 18 (CK18), and p21 WAF1/CIP1 , whereas maspin siRNA decreased CK18 expression in PC3 cells. The maspin effect on HDAC1 correlated with an increased sensitivity to cytotoxic HDAC inhibitor M344. Interestingly, glutathione S-transferase (GST, another maspin partner) was detected in the maspin/HDAC1 complex. Furthermore, a COOH-terminally truncated maspin mutant, which bound to HDAC1 but not GST, did not increase histone acetylation. Although HDACs, especially the highly expressed HDAC1, are promising therapeutic targets in cancer intervention, our data raise a novel hypothesis that the endogenous inhibitory effect of maspin on HDAC1 is coupled with glutathione-based protein modification, and provide new leads toward future developments of specific HDAC1-targeting strategies. (Cancer Res 2006; 66(18): 9323-9)

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Transcriptional Regulation by the Repressor of Estrogen Receptor Activity via Recruitment of Histone Deacetylases

Cited by 98 publications

References 68 publications

The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells

The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells

CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation

Endogenous Inhibition of Histone Deacetylase 1 by Tumor-Suppressive Maspin

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