AUF1 Is a bcl-2 A + U-rich Element-binding Protein Involved in bcl-2 mRNA Destabilization during Apoptosis

Lapucci, Andrea; Donnini, Martino; Papucci, Laura; Witort, Ewa; Tempestini, Alessio; Bevilacqua, Annamaria; Nicolin, A; Brewer, Gary; Schiavone, Nicola; Capaccioli, S.

doi:10.1074/jbc.m201377200

Cited by 98 publications

(89 citation statements)

References 44 publications

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“…The binding of AUF1 to the ARE of bcl-2 is increased in apoptotic cells and inhibited by caspase inhibitors (Lapucci et al, 2002). Association of AUBPs with an ARE could promote or prevent the assembly of a decay complex necessary for the RNA turnover.…”

Section: Rate Of Rna Decay and Gene Expressionmentioning

confidence: 99%

“…Preliminary studies have shed some light on the biochemical mechanisms regulating the activity of some AUBPs (Laroia et al, 1999;Ming et al, 2001;Lapucci et al, 2002). The expression of each AUBP might be down-regulated by the use of antisense oligonucleotides, ribozyme, or siRNA , and if the AUBPs are classified as co-activators (e.g., AUF1 or TTP) or co-inhibitors (HuR), the rate of RNA degradation might be regulated accordingly.…”

Section: Aubps or The Exosome As The Targetmentioning

confidence: 99%

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Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Bevilacqua

Ceriani

Capaccioli

et al. 2003

Journal Cellular Physiology

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294

259

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Recent evidence suggests that gene expression may be regulated, at least in part, at post-transcriptional level by factors inducing the extremely rapid degradation of messenger RNAs. These factors include reactions between adenyl-uridyl-rich elements (AREs) of the relevant mRNA and either specific proteins that bind to these elements or exosomes. This review deals with examples of the proteins (AU-rich binding proteins, AUBPs) and exosomes, which have been shown to form complexes with AREs and bring about rapid degradation of the relevant mRNA, and with certain other factors, which protect the RNA from such degradation. The biochemical and physiological factors underlying the stability of messenger RNAs carrying the ARE motifs will be reviewed in the light of their emerging significance for cell physiology, human pathology, and molecular medicine. We also consider the possible application of the results of recent insights into the mechanisms to pharmacological interventions to prevent or cure disorders, especially developmental disorders, which the suppression of gene expression may bring about. Molecular targeting of specific steps in protein degradation by synthetic compounds has already been utilized for the development of pharmacological therapies.

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Section: Rate Of Rna Decay and Gene Expressionmentioning

confidence: 99%

Section: Aubps or The Exosome As The Targetmentioning

confidence: 99%

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Bevilacqua

Ceriani

Capaccioli

et al. 2003

Journal Cellular Physiology

Self Cite

294

259

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“…Both of these anti-apoptotic proteins have been shown to play a role in beta cell survival [22,40]. The effect of AUF1 on BCL2 may be mediated, at least in part, by direct association of the RNA-binding protein to the AU-rich elements present in the 3′-UTR of Bcl2 mRNA, resulting in messenger destabilisation [21,41]. Indeed, we observed that silencing of AUF1 results in a small but significant increase in Bcl2 mRNA stability.…”

Section: Discussionmentioning

confidence: 61%

“…It has been previously demonstrated that AUF1 isoforms can destabilise the mRNAs encoding the anti-apoptotic protein, BCL2 [21]. Western blotting analysis revealed that overproduction of p45 AUF1 results in a significant decrease in the production of BCL2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Involvement of the RNA-binding protein ARE/poly(U)-binding factor 1 (AUF1) in the cytotoxic effects of proinflammatory cytokines on pancreatic beta cells

et al. 2011

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Aims/hypothesis Chronic exposure of pancreatic beta cells to proinflammatory cytokines leads to impaired insulin secretion and apoptosis. ARE/poly(U)-binding factor 1 (AUF1) belongs to a protein family that controls mRNA stability and translation by associating with adenosine-and uridine-rich regions of target messengers. We investigated the involvement of AUF1 in cytokine-induced beta cell dysfunction. Methods Production and subcellular distribution of AUF1 isoforms were analysed by western blotting. To test for their role in the control of beta cell functions, each isoform was overproduced individually in insulin-secreting cells. The contribution to cytokine-mediated beta cell dysfunction was evaluated by preventing the production of AUF1 isoforms by RNA interference. The effect of AUF1 on the production of potential targets was assessed by western blotting. Results MIN6 cells and human pancreatic islets were found to produce four AUF1 isoforms (p42>p45>p37>p40). AUF1 isoforms were mainly localised in the nucleus but were partially translocated to the cytoplasm upon exposure of beta cells to cytokines and activation of the ERK pathway. Overproduction of AUF1 did not affect glucose-induced insulin secretion but promoted apoptosis. This effect was associated with a decrease in the production of the antiapoptotic proteins, B cell leukaemia/lymphoma 2 (BCL2) and myeloid cell leukaemia sequence 1 (MCL1). Silencing of AUF1 isoforms restored the levels of the anti-apoptotic proteins, attenuated the activation of the nuclear factor-κB (NFκB) pathway, and protected the beta cells from cytokineinduced apoptosis. Conclusions/interpretation Our findings point to a contribution of AUF1 to the deleterious effects of cytokines on beta cell functions and suggest a role for this RNA-binding protein in the early phases of type 1 diabetes.

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“…Bcl-2 transcript contains an ARE and is rapidly degraded during apoptosis upon binding by the AUF1 protein (see below). 182 It has been reported that CDIR, a noncoding RNA overexpressed in lung cancer, 183 sequesters AUF1 away from Bcl-2 transcript, supporting Bcl-2 overexpression. 184 A recently identified oncoprotein, CaSM, appears to act by enhancing the stability of mRNAs including cyclin B1 by inhibiting 5 0 to 3 0 mRNA degradation.…”

Section: Mrna Stability and Cancermentioning

confidence: 99%

mRNA stability control: a clandestine force in normal and malignant hematopoiesis

Steinman

2007

Leukemia

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This review addresses the scope of influence of mRNA decay on cellular functions and its potential role in normal and malignant hematopoiesis. Evidence is emerging that leukemic oncogenes and hematopoietic cytokines interact with mRNA decay pathways. These pathways can co-regulate functionally related genes through specific motifs in the 3 0 -untranslated region of targeted transcripts. The steps that link external stimuli to transcript turnover are not fully understood, but include subcellular relocalization or post-transcriptional modification of specific transcript-stabilizing or -destabilizing proteins. Improper functioning of these regulators of mRNA turnover can impede normal cellular differentiation or promote cancers. By delineating how subsets of transcripts decay in synchrony during normal hematopoiesis, it may be possible to determine whether this post-transcriptional regulatory pathway is hijacked in leukemogenesis.

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AUF1 Is a bcl-2 A + U-rich Element-binding Protein Involved in bcl-2 mRNA Destabilization during Apoptosis

Cited by 98 publications

References 44 publications

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Involvement of the RNA-binding protein ARE/poly(U)-binding factor 1 (AUF1) in the cytotoxic effects of proinflammatory cytokines on pancreatic beta cells

mRNA stability control: a clandestine force in normal and malignant hematopoiesis

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