A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor α coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA

Watanabe, Michiko; Yanagisawa, Junn; Kitagawa, Hirochika; Takeyama, Ken-ichi; Ogawa, Shinpei; Arao, Yukitomo; Suzawa, Miyuki; Kobayashi, Yôko; Yano, Tetsu; Yoshikawa, Hiroyuki; Masuhiro, Yoshikazu; Kato, Shigeaki

doi:10.1093/emboj/20.6.1341

Cited by 257 publications

(286 citation statements)

References 41 publications

(109 reference statements)

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“…DDX20 represses transcription, probably through the recruitment of histone deacetylases 134 . p68 and p72 are transcriptional coactivator s for nuclear oestrogen receptor-α (ERα) 135,136 , and p68 also acts as a potent co-activator of the tumour suppressor p53 (REF. 137).…”

Section: Next-generation Sequencingmentioning

confidence: 99%

“…137). Although the interacting region between p68 and p72 and ERα includes part of the conserved helicase core and RNA binding is important for ERα co-activation, p68 helicase activity per se is not required 135,136 . Clearly, these activities are not the general rule and further work is required to elucidate how these roles are fulfilled and whether other DEAD box proteins display similar activities.…”

Section: Next-generation Sequencingmentioning

confidence: 99%

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From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

911

1,019

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Nearly all aspects of RNA metabolism, from transcription and translation to mRNA decay, involve RNA helicases, which are enzymes that use ATP to bind or remodel RNA and RNA-protein complexes (ribonucleoprotein (RNP) complexes) 1 . RNA helicases are found in all three domains of life, and many viruses also encode one or more of these proteins 2,3 . Together with the structurally related DNA helicases that function in replication, recombination and repair, the RNA helicases are classified into superfamilies and families, based on sequence and structural features 3,4 . DEAD box proteins form the largest helicase family, with 37 members in humans and 26 in Saccharomyces cerevisiae 3 , and are characterized by the presence of an Asp-Glu-Ala-Asp (DEAD) motif.DEAD box helicases have central and, in many cases, essential physiological roles in cellular RNA metabolism 5 (FIG. 1). The proteins generally function as part of larger multicomponent assemblies, such as the spliceosom e or the eukaryotic translation initiation machinery 6 . Mutations and deregulation of several DEAD box proteins have been linked to disease states, including cancer 7 . Although all DEAD box proteins contain a structurally highly conserved core with conserved ATP-binding and RNA-binding sites, different proteins have been associated with diverse and seemingly unrelated functions, including the disassembly of RNPs, chaperoning during RNA folding and even stabil ization of protein complexes on RNA 5,6 . How these highly conserved proteins fulfil such an array of different functions has been a long-standing question.Research has now started to illuminate the molecular basis for this functional diversity. In this Review, we summarize how structural data, together with biochemical and biophysical studies, have revealed unexpected modes by which these proteins function. We also discuss how novel molecular and cell biological approaches have better defined the cellular roles of DEAD box helicases. We outline our current view on common structural and mechan istic themes that have emerged, and on physical models of how these 'unusual' RNA helicases work.Structures of DEAD box RNA helicases A number of structural studies have universally shown that members of the DEAD box family contain a highly conserved helicase core that harbours the binding sites for ATP and RNA 3,4,8 . The core is surrounded by variable auxiliary domains, which are thought to be critical for the diverse functions of these enzymes.Structure of the helicase core. DEAD box proteins belong to helicase superfamily 2 (SF2) 2 . Similarly to all SF2 helicases, DEAD box proteins are built around a highly conserved helicase core of two virtually identical domains that resemble the bacterial recombination protein recombinase A (RecA) 3,4,8 (FIG. 2a,b). Within this helicase core, at least 12 characteristic sequence motifs are located at conserved positions (FIG. 2a,b). Some of these motifs are conserved across the entire SF2 family, whereas others are found only in the DEAD box family 3 ....

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Section: Next-generation Sequencingmentioning

confidence: 99%

Section: Next-generation Sequencingmentioning

confidence: 99%

From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

911

1,019

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“…This is the case of the highly related ddx5 and ddx17 RNA helicases (also known as p68 and p72, respectively) that act both in transcription and splicing. Indeed, ddx5 and ddx17 are transcriptional coregulators of the estrogen receptor alpha, p53, betacatenin and MyoD transcription factors among others (Watanabe et al, 2001;Bates et al, 2005;Caretti et al, 2006;Fuller-Pace and Ali, 2008). It is believed that ddx5 and ddx17 are recruited on target gene promoters by these transcriptional factors and in turn recruit the RNA polymerase II or enzymes with histone acetylase or deacetylase activities (Metivier et al, 2003;Rossow and Janknecht, 2003;Wilson et al, 2004;Janknecht, 2010;Dutertre et al, 2010a;Fuller-Pace and Moore, 2011).…”

Section: Introductionmentioning

confidence: 99%

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsensemediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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“…SRA was shown to contain a core RNA sequence necessary and sufficient to mediate steroid receptor activity 6 through interactions with several proteins including the coactivator/corepressor SHARP, 7 SRC1, 5 and the AF-1-specific activator p72/p68 protein. 8 Post-transcriptional modifications of SRA have also been shown to participate in the ability of this RNA to modulate receptor activity. 9 We established that SRA RNA was differentially expressed in normal and in breast tumor tissue and suggested that SRA RNA could be involved in mechanisms underlying breast tumorigenesis and breast tumor progression.…”

mentioning

confidence: 99%

The steroid receptor RNA activator protein is expressed in breast tumor tissues

Chooniedass-Kothari

Hamedani

Troup

et al. 2005

Intl Journal of Cancer

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The steroid receptor RNA activator (SRA) was originally described as the first functional non-coding RNA able to specifically coactivate the activity of steroid receptors. We previously demonstrated the existence in breast cancer cell lines of new SRA isoforms that, as opposed to the first cloned SRA RNA, encode for a 236-amino acid protein, SRAP. To investigate the possible implications of the coding SRA RNA and SRAP expression on breast cancer progression, we examined by Western blot analysis 74 primary breast tumors of patients subsequently treated with tamoxifen. Patients whose primary tumors were positive for SRAP expression (n 5 24) had a significantly (Kaplan-Meier survival curve p 5 0.047) lower likelihood of dying from recurrent disease than SRAP-negative patients (n 5 50). We generated 2 cell lines, SRAP-V5-High.A and SRAP-V5-High.B, by stably overexpressing SRAP in the estrogen receptor-positive MCF-7 breast cancer cell line. Transient transfection experiments, performed using a luciferase reporter gene under the control of an estrogen-responsive element, revealed decreased sensitivity to estradiol but no additional sensitivity to tamoxifen in SRAP-overexpressing cells. Overall, our data suggest that the presence of both coding SRA RNA and its corresponding SRAP modifies the activity of estrogen receptor in breast cancer cells and that SRAP could be a new clinical marker for breast cancer. Further studies are needed to define the respective mechanisms of action and the roles of SRA RNA and protein in breast tumorigenesis and tumor progression. ' 2005 Wiley-Liss, Inc.Key words: steroid receptor coactivator; human breast tumor; steroid receptor coactivator protein Through its action on breast epithelial cells, estrogen not only controls the growth and the development of normal mammary gland but also promotes breast tumorigenesis and breast cancer progression. 1 The biological action of estrogen is mainly mediated through two ERs, a and b, which act as ligand-dependent transcription factors. 2,3 While estrogen initially plays a pivotal role in the activation of ERs, the transcriptional activation of target genes is ultimately determined by interactions between receptors and regulatory molecules known as coactivators and corepressors, which respectively stimulate or inhibit ER activity. 4 SRA differs from all previously characterized coactivators as it was originally identified as a functional non-coding RNA molecule. 5 SRA mechanisms of action have since become the focus of extensive investigation. SRA was shown to contain a core RNA sequence necessary and sufficient to mediate steroid receptor activity 6 through interactions with several proteins including the coactivator/corepressor SHARP, 7 SRC1, 5 and the AF-1-specific activator p72/p68 protein. 8 Post-transcriptional modifications of SRA have also been shown to participate in the ability of this RNA to modulate receptor activity. 9 We established that SRA RNA was differentially expressed in normal and in breast tumor tissue and suggested that SRA R...

show abstract

A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor α coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA

Cited by 257 publications

References 41 publications

From unwinding to clamping — the DEAD box RNA helicase family

From unwinding to clamping — the DEAD box RNA helicase family

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

The steroid receptor RNA activator protein is expressed in breast tumor tissues

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