Hsp27 and F-Box Protein β-TrCP Promote Degradation of mRNA Decay Factor AUF1

Li, Meiling; Defren, Jennifer; Brewer, Gary

doi:10.1128/mcb.00931-12

Cited by 29 publications

(26 citation statements)

References 56 publications

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“…TTP destabilizes mRNA via its binding to AU-rich mRNA elements and is inactivated by phosphorylation [47]. Regarding Hsp27, it has recently been described as a regulator of the stability of mRNAs containing AREs [48]. Using the database "AREsite" [49], we found ARE presence in the 3'UTR of HB-EGF mRNA.…”

Section: Discussionmentioning

confidence: 97%

Mitogen-activated protein kinase-activated protein kinase 2 mediates resistance to hydrogen peroxide-induced oxidative stress in human hepatobiliary cancer cells

Ho-Bouldoires

Clapéron

Mergey

et al. 2015

Free Radical Biology and Medicine

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The development and progression of liver cancer are characterized by increased levels of reactive oxygen species (ROS). ROS-induced oxidative stress impairs cell proliferation and ultimately leads to cell death. Although liver cancer cells are especially resistant to oxidative stress, mechanisms of such resistance remain understudied. We identified the MAPK-activated protein kinase 2 (MK2)/heat shock protein 27 (Hsp27) signaling pathway mediating defenses against oxidative stress. In addition to MK2 and Hsp27 overexpression in primary liver tumors compared to adjacent nontumorous tissues, the MK2/Hsp27 pathway is activated by hydrogen peroxide-induced oxidative stress in hepatobiliary cancer cells. MK2 inactivation or inhibition of MK2 or Hsp27 expression increases caspase-3 and PARP cleavage and DNA breaks and therefore cell death. Interestingly, MK2/Hsp27 inhibition decreases antioxidant defenses such as heme oxygenase 1 through downregulation of the transcription factor nuclear factor erythroid-derived 2-like 2. Moreover, MK2/Hsp27 inhibition decreases both phosphorylation of epidermal growth factor receptor (EGFR) and expression of its ligand, heparin-binding EGF-like growth factor. A new identified partner of MK2, the scaffold PDZ protein EBP50, could facilitate these effects through MK2/Hsp27 pathway regulation. These findings demonstrate that the MK2/Hsp27 pathway actively participates in resistance to oxidative stress and may contribute to liver cancer progression.

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Section: Discussionmentioning

confidence: 97%

Mitogen-activated protein kinase-activated protein kinase 2 mediates resistance to hydrogen peroxide-induced oxidative stress in human hepatobiliary cancer cells

Ho-Bouldoires

Clapéron

Mergey

et al. 2015

Free Radical Biology and Medicine

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“…In this study, we showed that, similar to other ARE-BPs, TIS11/TTP proteins possess high turnover rates, which ensure the setting of rapid transitions in protein levels. However, while ARE-BPs such as AUF1 or HuR are targeted to degradation by ubiquitin-dependent mechanisms (16,17), we showed that TIS11/TTP proteins enter a ubiquitin-independent degradation-by-default pathway. The Drosophila dTIS11 protein and the mammalian TTP protein are both targeted for degradation by the same mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…A positive correlation was established between AUF1 degradation by the proteasome and ARE mRNA turnover (15). More recent data have also demonstrated that ubiquitination of AUF1 by the E3 ligase b-Trcp leads to its destruction by the proteasome and to the stabilization of its target mRNAs (16). HuR ubiquitination and subsequent proteasomal degradation upon heat shock has also been described (17).…”

mentioning

confidence: 84%

Rapid Proteasomal Degradation of Posttranscriptional Regulators of the TIS11/Tristetraprolin Family Is Induced by an Intrinsically Unstructured Region Independently of Ubiquitination

Ngoc

Wauquier

Soin

et al. 2014

Molecular and Cellular Biology

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The TIS11/tristetraprolin (TTP) CCCH tandem zinc finger proteins are major effectors in the destabilization of mRNAs bearing AU-rich elements (ARE) in their 3= untranslated regions. In this report, we demonstrate that the Drosophila melanogaster dTIS11 protein is short-lived due to its rapid ubiquitin-independent degradation by the proteasome. Our data indicate that this mechanism is tightly associated with the intrinsically unstructured, disordered N-and C-terminal domains of the protein. Furthermore, we show that TTP, the mammalian TIS11/TTP protein prototype, shares the same three-dimensional characteristics and is degraded by the same proteolytic pathway as dTIS11, thereby indicating that this mechanism has been conserved across evolution. Finally, we observed a phosphorylation-dependent inhibition of dTIS11 and TTP degradation by the proteasome in vitro, raising the possibility that such modifications directly affect proteasomal recognition for these proteins. As a group, RNAbinding proteins (RNA-BPs) have been described as enriched in intrinsically disordered regions, thus raising the possibility that the mechanism that we uncovered for TIS11/TTP turnover is widespread among other RNA-BPs.

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“…Interestingly, a ~70 kDa band that was serine–threonine‐phosphorylated in AUF1 immunoprecipitates might represent HSP70, recently identified as a substrate of AMPK (Schaffer et al ., 2015). It has been observed that phosphorylation of AUF1 has been reported to regulate AUF1 protein stability and binding to target mRNAs (Wilson et al ., 2003; Li et al ., 2013). AUF1 has also been implicated in regulating cellular senescence and also targets p16 INK4a , a potent regulator of senescence (Guo et al ., 2010; Pont et al ., 2012).…”

Section: Discussionmentioning

confidence: 99%

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

et al. 2016

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SummaryMetformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age‐related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA‐processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post‐transcriptional mechanism involving the RNA‐binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life‐extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR‐20a, miR‐34a, miR‐130a, miR‐106b, miR‐125, and let‐7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1‐dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence‐associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age‐related disease.

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Hsp27 and F-Box Protein β-TrCP Promote Degradation of mRNA Decay Factor AUF1

Cited by 29 publications

References 56 publications

Mitogen-activated protein kinase-activated protein kinase 2 mediates resistance to hydrogen peroxide-induced oxidative stress in human hepatobiliary cancer cells

Mitogen-activated protein kinase-activated protein kinase 2 mediates resistance to hydrogen peroxide-induced oxidative stress in human hepatobiliary cancer cells

Rapid Proteasomal Degradation of Posttranscriptional Regulators of the TIS11/Tristetraprolin Family Is Induced by an Intrinsically Unstructured Region Independently of Ubiquitination

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

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