The mRNA-stabilizing Factor HuR Protein Is Targeted by β-TrCP Protein for Degradation in Response to Glycolysis Inhibition

Chu, Po-Chen; Chuang, Hsiao-Ching; Kulp, Samuel K.; Chen, Ching‐Shih

doi:10.1074/jbc.m112.393678

Cited by 50 publications

(56 citation statements)

References 36 publications

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“…Abdelmohsen et al 22 showed that HuR protein reduction following heat shock involved HuR ubiquitination of lysine residue 182, nucleocytoplasmic transport and check-point kinase 2-mediated phosphorylation. Chu et al 28 also showed that, following the treatment of glucose transport inhibitor (CG-5), HuR was ubiquitinated and degraded via a mechanism involving the beta-transducing repeat-containing protein (β-TrCP1) complex, PKCα-mediated phosphorylation and HuR nucleocytoplamsic translocation. In both of these studies, HuR ubiquitination was shown to lead to protein degradation; however, the exact mechanisms including the E3 ligase(s) involved in HuR ubiquitination were not revealed.…”

Section: Discussionmentioning

confidence: 95%

“…The ECRG2 V30E mutant failed to induce cell death and neither activated caspases nor suppressed XIAP and HuR (Figures 4 and 5). The information gathered in our study (Table 1) indicates that ECRG2 mutations could be found in various human malignancies and their distributions appear to be largely localize within a small region (a.a. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. This information could suggest that this region (a.a.27-44) may be commonly targeted by mutations and is important for ECRG2's function and/or regulation.…”

Section: Discussionmentioning

confidence: 96%

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Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2

2015

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Esophageal cancer-related gene 2 (ECRG2) is a newer tumor suppressor whose function in the regulation of cell growth and apoptosis remains to be elucidated. Here we show that ECRG2 expression was upregulated in response to DNA damage, and increased ECRG2 expression induced growth suppression in cancer cells but not in non-cancerous epithelial cells. ECRG2-mediated growth suppression was associated with activation of caspases and marked reduction in the levels of apoptosis inhibitor, X chromosome-linked inhibitor of apoptosis protein (XIAP). ECRG2, via RNA-binding protein human antigen R (HuR), regulated XIAP mRNA stability and expression. Furthermore, ECRG2 increased HuR ubiquitination and degradation but was unable to modulate the non-ubiquitinable mutant form of HuR. We also identified missense and frame-shift ECRG2 mutations in various human malignancies and noted that, unlike wild-type ECRG2, one cancer-derived ECRG2 mutant harboring glutamic acid instead of valine at position 30 (V30E) failed to induce cell death and activation of caspases. This naturally occurring V30E mutant also did not suppress XIAP and HuR. Importantly, the V30E mutant overexpressing cancer cells acquired resistance against multiple anticancer drugs, thus suggesting that ECRG2 mutations appear to have an important role in the acquisition of anticancer drug resistance in a subset of human malignancies.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 96%

Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2

2015

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“…Migration and invasion were also impaired in cancer cells expressing the nonphosphorylatable HuR mutant S318A and enhanced in cells expressing the phosphomimetic mutant S318D . In breast cancer cells undergoing apoptosis in response to doxorubicin, HuR was phosphorylated at S221 and S318; in prostate cancer cells, PKC‐mediated phosphorylation on HuR S318 triggered the cytoplasmic export of HuR, which permitted the recognition of HuR by the E3 ubiquitin ligase βTrCP1 and its subsequent ubiquitin‐dependent degradation …”

Section: Hur Phosphorylationmentioning

confidence: 99%

Posttranslational control of HuR function

2016

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The RNA-binding protein HuR (human antigen R) associates with numerous transcripts, coding and noncoding, and controls their splicing, localization, stability, and translation. Through its regulation of target transcripts, HuR has been implicated in cellular events including proliferation, senescence, differentiation, apoptosis, and the stress and immune responses. In turn, HuR influences processes such as cancer and inflammation. HuR function is primarily regulated through posttranslational modifications that alter its subcellular localization and its ability to bind target RNAs; such modifications include phosphorylation, methylation, ubiquitination, NEDDylation, and proteolytic cleavage. In this review, we describe the modifications that impact upon HuR function on gene expression programs and disease states.

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“…In addition, over-expression of deubiquinating enzymes of the UBP family also altered the half-life of a GM-CSF ARE containing mRNA reporter, suggesting that the degradation of RNA and AUF1 protein components of an mRNP may be temporally correlated [115]. Since then several RNA binding proteins such as HuR [116], TTP [117], and SLBP [47] have been shown to be polyubiquitinated.…”

Section: Ubiquitin-dependent Pathwaysmentioning

confidence: 99%

Signaling pathways that control mRNA turnover

Thapar

Denmon

2013

Cellular Signalling

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Cells regulate their genomes mainly at the level of transcription and at the level of mRNA decay. While regulation at the level of transcription is clearly important, the regulation of mRNA turnover by signaling networks is essential for a rapid response to external stimuli. Signaling pathways result in posttranslational modification of RNA binding proteins by phosphorylation, ubiquitination, methylation, acetylation etc. These modifications are important for rapid remodeling of dynamic ribonucleoprotein complexes and triggering mRNA decay. Understanding how these posttranslational modifications alter gene expression is therefore a fundamental question in biology. In this review we highlight recent findings on how signaling pathways and cell cycle checkpoints involving phosphorylation, ubiquitination, and arginine methylation affect mRNA turnover.

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The mRNA-stabilizing Factor HuR Protein Is Targeted by β-TrCP Protein for Degradation in Response to Glycolysis Inhibition

Cited by 50 publications

References 36 publications

Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2

Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2

Posttranslational control of HuR function

Signaling pathways that control mRNA turnover

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