Purification and Identification of p68 RNA Helicase Acting as a Transcriptional Coactivator Specific for the Activation Function 1 of Human Estrogen Receptor α

Endoh, Hideki; Maruyama, Kei; Masuhiro, Yoshikazu; Kobayashi, Yôko; Goto, Masahide; Tai, Hitoshi; Yanagisawa, Junn; Metzger, Daniel L.; Hashimoto, Seiichi; Kato, Shigeaki

doi:10.1128/mcb.19.8.5363

Cited by 333 publications

(303 citation statements)

References 53 publications

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“…Our study identified two new tyrosine phosphorylation sites for cAbl, Tyr-52 and Tyr-219 (Figures 2c-d). In general, phosphorylation of serine residues in the AF1 domain of ERa seems to influence the recruitment of coactivators, resulting in enhanced ER-mediated transcription (Deborah, 2003;Tremblay et al, 1999;Endoh et al, 1999). Phosphorylation of tyrosine 537 leads to increased ligand-independent transcriptional activation.…”

Section: Discussionmentioning

confidence: 99%

“…Most of the ERa coactivators binding to the AF-2 region of ERa have been shown to increase ERa transcriptional activity in a ligand-dependent manner. Recently, a few coactivators interact with the AF-1 or DBD region and regulate ERa transcriptional activity in a ligand-independent manner (Chakravarti et al, 1996;Yao et al, 1996;Weigel and Zhang, 1998;Alen et al, 1999;Endoh et al, 1999;Xu et al, 1999;Ding et al, 2003). Given that c-Abl does not interact with ERa P79,333A, the ligand-independent ERa transactivation by c-Abl seems to involve the AF-1 and AF-2 domains, especially the AF1 domain.…”

Section: Discussionmentioning

confidence: 99%

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c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

He¹,

Zheng²,

Song³

et al. 2010

Oncogene

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Estrogen receptors are members of the steroid hormone superfamily of nuclear receptors that act as ligandactivated transcription factors. Similar to other steroid hormone receptors, estrogen receptor a (ERa) is a substrate for protein kinases, and phosphorylation has profound effects on the function of this receptor. In this study, we show that ERa associates with c-Abl nonreceptor tyrosine kinase. The direct interaction is mediated by two PXXP motifs of ERa and the c-Abl SH3 domain. Mutational analysis and in vitro kinase assays show that ERa can be phosphorylated on two sites, tyrosine 52 (Y-52) and tyrosine 219 (Y-219). ERa phosphorylation by c-Abl stabilizes ERa, resulting in enhanced ERa transcriptional activity and increased expression of endogenous ERa target genes. Furthermore, ERa phosphorylation at the Y-219 site affects DNA binding and dimerization by ERa. Both the c-Abl inhibitor and the c-Abl kinase dead mutation abolish the c-Ablinduced accumulation of ERa and enhancement of ERa transcriptional activity, indicating that c-Abl kinase activity is required for regulation of the ERa function. Moreover, the ERa (Y52,219F) mutant shows reduced breast cancer cell growth and invasion. Taken together, these results show that c-Abl is a novel kinase that upregulates ERa expression and promotes breast cancer cell proliferation, suggesting a great potential for this kinase to function as a therapeutic target for breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

He¹,

Zheng²,

Song³

et al. 2010

Oncogene

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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%

From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

911

1,018

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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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“…Estradiol (E 2 ) modifies the effect of the IGF-1 pathway by upregulating the expression of several components of the pathway including the insulin-like growth factor 1 receptor (IGF1R), insulin receptor substrate 1 (IRS-1), and IGF binding proteins (IGFBPs) [11,[15][16][17]. Conversely, the insulin and IGF-1 pathways have been shown to induce ER phosphorylation and therefore receptor activity through a phosphatidylinositol 3-kinase (PI3-kinase) or extracellular signalregulated (ERK-mediated) mechanism [12,[18][19][20]. It also has been shown through in vitro assays, that co-administration of estrogen and growth factors to cells has synergistic effects on proliferation compared to either treatment alone [11,12]; however, the exact mechanism of this synergy has not been resolved.…”

Section: Introductionmentioning

confidence: 99%

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

Fan

McKean‐Cowdin

Bernstein

et al. 2006

Breast Cancer Res Treat

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Insulin receptor substrate-1 (IRS-1) is a key downstream signaling molecule common to both the insulin and IGF signaling pathways that can interact with the estrogen pathway to regulate breast cell growth. We investigated whether a putative functional variant for IRS-1 (G972R) influences circulating levels of sex hormones, sex hormone binding globulin (SHBG), C-peptide, and insulinlike growth factor 1 (IGF-1) levels among postmenopausal African-American and non-Hispanic white breast cancer patients enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study. Circulating levels of sex hormones and growth factors can influence breast cancer recurrence and survival. Serum estrone, estradiol, testosterone, SHBG, IGF-1 and C-peptide were measured in 468 patients at 30+ months post diagnosis. Non-protein bound hormone levels (free estradiol, free testosterone) were calculated. In African-American patients, the IRS-1 variant was associated with increased serum levels of estrone (p=0.02), free estradiol (p=0.04), total testosterone (p=0.04), free testosterone (p=0.006) and decreased levels of sex hormone-binding globulin (p=0.02). No association was present for white patients. Our findings provide suggestive evidence that IRS-1 G972R variant may be associated with circulating levels of sex hormones and SHBG in African American breast cancer survivors.

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Purification and Identification of p68 RNA Helicase Acting as a Transcriptional Coactivator Specific for the Activation Function 1 of Human Estrogen Receptor α

Cited by 333 publications

References 53 publications

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

From unwinding to clamping — the DEAD box RNA helicase family

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

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