Estradiol Up-regulates AUF1p45 Binding to Stabilizing Regions within the 3′-Untranslated Region of Estrogen Receptor α mRNA

Ing, Nancy H.; Massuto, Dana A.; Jaeger, Laurie A.

doi:10.1074/jbc.m704745200

Cited by 31 publications

(33 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…family of ARE binding factors consisting of four different isoforms generated by alternative splicing of a common transcript. In the literature conflicting results exist concerning the role of AUF1 as stabilizer or destabilizer of ARE-containing mRNAs (22,23,26,43,44). Also, opposite effects of the individual AUF1 isoforms on mRNA decay have been reported (25,27).…”

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Similar Regulation of Human Inducible Nitric-oxide Synthase Expression by Different Isoforms of the RNA-binding Protein AUF1

Pautz

Linker

Altenhöfer

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The ARE/poly-(U) binding factor 1 (AUF1), a protein family consisting of four isoforms, is believed to mediate mRNA degradation by binding to AU-rich elements (ARE). However, evidence exists that individual AUF1 isoforms may stabilize AREcontaining mRNAs. The 3-untranslated region of the human inducible nitric-oxide synthase (iNOS) contains five AREs, which promote RNA degradation. We have recently shown that the RNA-binding protein KSRP is critically involved in the decay of the iNOS mRNA. In this study we examined the effects of the individual AUF1 isoforms on iNOS expression. Overexpression of each AUF1 isoform reduces iNOS expression on mRNA and protein levels to the same extent by modulation of mRNA stability. Accordingly, knockdown of all or individual AUF1 isoforms by an RNA interference approach enhances iNOS expression. The AUF1 effect on iNOS expression is dependent on the iNOS 3-untranslated region sequence, as demonstrated in transfection experiments with a reporter mRNA. Binding studies showed that all AUF1 isoforms interact with the same AU-rich region in the iNOS-3-untranslated region. Cytokine stimulation altered intracellular AUF1 binding activities. These data demonstrate that AUF1 is an important factor that promotes iNOS mRNA degradation. Furthermore, all individual AUF1 isoforms act in a similar manner.

show abstract

Section: Discussionmentioning

confidence: 92%

“…1A) (24). Furthermore, some evidence exists that the individual AUF1 isoforms exert different effects in the regulation of mRNA stability depending on their expressional level (25)(26)(27). In addition to these post-transcriptional effects, also AUF1-dependent transcriptional regulation mechanisms have been published (28,29).…”

mentioning

confidence: 99%

Similar Regulation of Human Inducible Nitric-oxide Synthase Expression by Different Isoforms of the RNA-binding Protein AUF1

Pautz

Linker

Altenhöfer

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…ER␣ is the more widely expressed of the two ER isoforms, and its levels are regulated by multiple mechanisms in a development-and tissue-specific manner (23). ER␣ levels are regulated at all levels of gene expression, beginning with transcriptional control by several transcription factors (48) and continuing with regulation at the posttranscriptional (26,27) and posttranslational levels (2), including the control of protein turnover (44).…”

mentioning

confidence: 99%

miR-22 Inhibits Estrogen Signaling by Directly Targeting the Estrogen Receptor α mRNA

Pandey

Picard

2009

Molecular and Cellular Biology

231

107

View full text Add to dashboard Cite

Estrogen receptor ␣ (ER␣) is a ligand-regulated transcription factor with a broad range of physiological functions and one of the most important classifiers in breast cancer. MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as important regulators of gene expression in a plethora of physiological and pathological processes. Upon binding the 3 untranslated region (UTR) of target mRNAs, miRNAs typically reduce their stability and/or translation. The ER␣ mRNA has a long 3 UTR of about 4.3 kb which has been reported to reduce mRNA stability and which bears evolutionarily conserved miRNA target sites, suggesting that it might be regulated by miRNAs. We have performed a comprehensive and systematic assessment of the regulatory role of all miRNAs that are predicted to target the 3 UTR of the ER␣ mRNA. We found that miR-22 represses ER␣ expression most strongly and by directly targeting the ER␣ mRNA 3 UTR. Of the three predicted miR-22 target sites in the 3 UTR, the evolutionarily conserved one is the primary target. miR-22 overexpression leads to a reduction of ER␣ levels, at least in part by inducing mRNA degradation, and compromises estrogen signaling, as exemplified by its inhibitory impact on the ER␣-dependent proliferation of breast cancer cells.The steroid hormone 17␤-estradiol (E2) regulates a number of developmental and physiological processes, such as growth and differentiation, in a range of tissues, including the male and female reproductive tracts, breast epithelium, and a plethora of other organs (9, 23). These physiological effects are mediated, at least in part, by two nuclear receptors, estrogen receptor ␣ (ER␣) and ER␤. Upon binding E2, they are activated as transcription factors and regulate target genes by binding directly to specific regulatory sequences or indirectly to other DNA-bound transcription factors (23). In addition, rapid nongenomic effects of E2 can be elicited by the same ERs as membrane-associated receptors (22). ER␣ is the more widely expressed of the two ER isoforms, and its levels are regulated by multiple mechanisms in a development-and tissue-specific manner (23). ER␣ levels are regulated at all levels of gene expression, beginning with transcriptional control by several transcription factors (48) and continuing with regulation at the posttranscriptional (26, 27) and posttranslational levels (2), including the control of protein turnover (44).Breast cancer is the most frequent form of cancer in women, and ER␣ is still the most important classifier of breast tumors. ER␣-positive tumors, which represent nearly 70% of all breast tumors, respond to E2 for growth and survival, and consequently, ER␣-positive tumors can be inhibited with antiestrogens such as tamoxifen. Why and how most tumors eventually become resistant to antiestrogen therapy and why some tumors do not express ER␣ from the outset remain hotly debated questions. Multiple mechanisms have been invoked to explain

show abstract

“…Third, some stimuli have been reported to modulate the cellular levels of specific AUF1 isoforms. In sheep uterus, estradiol increased expression of p45 AUF1 but not other isoforms (29). Similarly, prostaglandin A 2 specifically increased levels of p45 AUF1 in H1299 nonsmall-cell lung carcinoma cells (30).…”

mentioning

confidence: 98%

Alternatively Expressed Domains of AU-rich Element RNA-binding Protein 1 (AUF1) Regulate RNA-binding Affinity, RNA-induced Protein Oligomerization, and the Local Conformation of Bound RNA Ligands

Zucconi¹,

Ballin²,

Brewer

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

AU-rich element RNA-binding protein 1 (AUF1) binding to AU-rich elements (AREs) in the 3-untranslated regions of mRNAs encoding many cytokines and other regulatory proteins modulates mRNA stability, thereby influencing protein expression. AUF1-mRNA association is a dynamic paradigm directed by various cellular signals, but many features of its function remain poorly described. There are four isoforms of AUF1 that result from alternative splicing of exons 2 and 7 from a common pre-mRNA. Preliminary evidence suggests that the different isoforms have varied functional characteristics, but no detailed quantitative analysis of the properties of each isoform has been reported despite their differential expression and regulation. Using purified recombinant forms of each AUF1 protein variant, we used chemical cross-linking and gel filtration chromatography to show that each exists as a dimer in solution. We then defined the association mechanisms of each AUF1 isoform for ARE-containing RNA substrates and quantified relevant binding affinities using electrophoretic mobility shift and fluorescence anisotropy assays. Although all AUF1 isoforms generated oligomeric complexes on ARE substrates by sequential dimer association, sequences encoded by exon 2 inhibited RNA-binding affinity. By contrast, the exon 7-encoded domain enhanced RNA-dependent protein oligomerization, even permitting cooperative RNA-binding activity in some contexts. Finally, fluorescence resonance energy transfer-based assays showed that the different AUF1 isoforms remodel bound RNA substrates into divergent structures as a function of protein:RNA stoichiometry. Together, these data describe isoform-specific characteristics among AUF1 ribonucleoprotein complexes, which likely constitute a mechanistic basis for differential functions and regulation among members of this protein family.

show abstract

Estradiol Up-regulates AUF1p45 Binding to Stabilizing Regions within the 3′-Untranslated Region of Estrogen Receptor α mRNA

Cited by 31 publications

References 80 publications

Similar Regulation of Human Inducible Nitric-oxide Synthase Expression by Different Isoforms of the RNA-binding Protein AUF1

Similar Regulation of Human Inducible Nitric-oxide Synthase Expression by Different Isoforms of the RNA-binding Protein AUF1

miR-22 Inhibits Estrogen Signaling by Directly Targeting the Estrogen Receptor α mRNA

Alternatively Expressed Domains of AU-rich Element RNA-binding Protein 1 (AUF1) Regulate RNA-binding Affinity, RNA-induced Protein Oligomerization, and the Local Conformation of Bound RNA Ligands

Contact Info

Product

Resources

About