Estrogenically regulated LRP16 interacts with estrogen receptor α and enhances the receptor’s transcriptional activity

Han, Wei; Zhao, Yanbin; Yg, Meng; Zang, Lili; Wu, Zihao; Q, Li; Yl, Si; Huang, Kuang-Tzu; Jm, Ba; Morinaga, Hidetaka; Nomura, Masatoshi; Ym, Mu

doi:10.1677/erc-06-0082

Cited by 45 publications

(71 citation statements)

References 55 publications

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“…Finally, knockdown of macro domain protein 1 (LRP16), a coactivator for both ERα and NF-κB (Han et al, 2007; Wu et al, 2011), also dampened the TNFα response, but did not affect suppression of IL-6 by either E2 or resveratrol (Figure 5—figure supplement 1). …”

Section: Resultsmentioning

confidence: 99%

Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network

Nwachukwu

Srinivasan

Bruno

et al. 2014

eLife

118

102

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Resveratrol has beneficial effects on aging, inflammation and metabolism, which are thought to result from activation of the lysine deacetylase, sirtuin 1 (SIRT1), the cAMP pathway, or AMP-activated protein kinase. In this study, we report that resveratrol acts as a pathway-selective estrogen receptor-α (ERα) ligand to modulate the inflammatory response but not cell proliferation. A crystal structure of the ERα ligand-binding domain (LBD) as a complex with resveratrol revealed a unique perturbation of the coactivator-binding surface, consistent with an altered coregulator recruitment profile. Gene expression analyses revealed significant overlap of TNFα genes modulated by resveratrol and estradiol. Furthermore, the ability of resveratrol to suppress interleukin-6 transcription was shown to require ERα and several ERα coregulators, suggesting that ERα functions as a primary conduit for resveratrol activity.DOI: http://dx.doi.org/10.7554/eLife.02057.001

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Section: Resultsmentioning

confidence: 99%

Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network

Nwachukwu

Srinivasan

Bruno

et al. 2014

eLife

118

102

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“…In contrast, PARP14, also named CoaSt6 because of its co-activator function for the transcription factor Stat6, promotes interleukin-4 dependent gene activation in a manner dependent on its macrodomains as well on its mono-ADP-ribosyl-transferase activity (Goenka and Boothby, 2006; Goenka et al, 2007). MacroD1, originally named leukemia related protein 16 (LRP16), was identified as a co-activator of androgen and estrogen receptor transcriptional activity as well as of NF-κB (Han et al, 2007; Wu et al, 2011; Yang et al, 2009). This transcriptional co-activation of macroD1 is dependent on its macro domain.…”

Section: Protein Modules Involved In Non-covalent Interactions Witmentioning

confidence: 99%

Reprogramming cellular events by poly(ADP-ribose)-binding proteins

Krietsch

Rouleau

Pic

et al. 2013

Molecular Aspects of Medicine

145

143

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Poly(ADP-ribosyl)ation is a posttranslational modification catalyzed by the poly(ADP-ribose) polymerases (PARPs). These enzymes covalently modify glutamic, aspartic and lysine amino acid side chains of acceptor proteins by the sequential addition of ADP-ribose (ADPr) units. The poly(ADP-ribose) (pADPr) polymers formed alter the physico-chemical characteristics of the substrate with functional consequences on its biological activities. Recently, non-covalent binding to pADPr has emerged as a key mechanism to modulate and coordinate several intracellular pathways including the DNA damage response, protein stability and cell death. In this review, we describe the basis of non-covalent binding to pADPr that has led to the emerging concept of pADPr-responsive signaling pathways. This review emphasizes the structural elements and the modular strategies developed by pADPr-binding proteins to exert a fine-tuned control of a variety of pathways. Poly(ADP-ribosyl)ation reactions are highly regulated processes, both spatially and temporally, for which at least four specialized pADPr-binding modules accommodate different pADPr structures and reprogram protein functions. In this review, we highlight the role of well-characterized and newly discovered pADPr-binding modules in a diverse set of physiological functions.

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“…More recent work demonstrates that MACRO domain containing proteins are involved with mono-ADP ribosylation, and can regulate cell signaling pathways and modify proteins involved with gene transcription (20). Interestingly, MACROD1 (LRP16) has been implicated in modulating ER and androgen receptor (AR) signaling in prior studies (21,22). Additionally, recent reports suggest that the locus encompassing the MACROD2 gene at chromosome 20p12.1 may be a cancer-specific fragile site leading to frequent somatic deletions (23).…”

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confidence: 99%

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

Mohseni

Cidado

Croessmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tamoxifen is effective for treating estrogen receptor-alpha (ER) positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. Here we describe a previously unidentified gene, MACROD2 that confers tamoxifen resistance and estrogen independent growth. We found MACROD2 is amplified and overexpressed in metastatic tamoxifen-resistant tumors. Transgene overexpression of MACROD2 in breast cancer cell lines results in tamoxifen resistance, whereas RNAi-mediated gene knock down reverses this phenotype. MACROD2 overexpression also leads to estrogen independent growth in xenograft assays. Mechanistically, MACROD2 increases p300 binding to estrogen response elements in a subset of ER regulated genes. Primary breast cancers and matched metastases demonstrate MACROD2 expression can change with disease evolution, and increased expression and amplification of MACROD2 in primary tumors is associated with worse overall survival. These studies establish MACROD2 as a key mediator of estrogen independent growth and tamoxifen resistance, as well as a potential novel target for diagnostics and therapy.breast cancer | tamoxifen | resistance | MACROD2 | ER positive T he selective estrogen receptor modulator (SERM) tamoxifen is a highly effective drug for the prevention and treatment of estrogen receptor-alpha (ER) positive breast cancers (1). However, resistance to this drug remains a clinically important problem. The molecular mediators of tamoxifen resistance have not been fully elucidated. In part, this is due to the heterogeneous nature of breast cancers, resulting in multiple mechanisms of resistance. For example, past studies have demonstrated that tamoxifen resistance is mediated by differential expression of nuclear hormone receptor coregulators (2, 3), growth factor signaling crosstalk (4-7), regulation of microRNAs (8), cyclin dependent kinases (CKDs) (9), CDK inhibitors (10, 11), and more recently, acquired somatic mutations and alterations in ER (12-17). Further insight into the molecular mediators of tamoxifen and hormone therapy resistance would have great impact on the ability to target genes and pathways that could overcome drug resistance and lead to improved clinical outcomes.In this study we describe a previously unidentified gene, MACROD2, which is amplified and overexpressed in a subset of breast cancers. MACROD2 belongs to a family of genes containing a macro domain, an evolutionarily conserved protein motif (18), whose functional role until recently has been unclear. Studies have demonstrated that MACROD2 deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins (19). More recent work demonstrates that MACRO domain containing proteins are involved with mono-ADP ribosylation, and can regulate cell signaling pathways and modify proteins involved with gene transcription (20). Interestingly, MACROD1 (LRP16) has been implicated in modulating ER and androgen receptor (AR) signaling in prio...

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Estrogenically regulated LRP16 interacts with estrogen receptor α and enhances the receptor’s transcriptional activity

Cited by 45 publications

References 55 publications

Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network

Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network

Reprogramming cellular events by poly(ADP-ribose)-binding proteins

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

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