Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

Wang, Linyuan; Luk, Cynthia T.; Schroer, Stephanie A.; Smith, Alannah M.; Xie, Li; Cai, Erica P.; Gaisano, Herbert Y.; MacDonald, Patrick E.; Zhou, Hao; Mak, Tak W.; Woo, Minna

doi:10.1007/s00125-014-3295-8

Cited by 16 publications

(10 citation statements)

References 40 publications

(57 reference statements)

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“…p53 accumulation mediated by HUWE1 inactivation has been frequently reported to induce apoptosis, for example, in U2OS cells in vitro 29 and in mouse pancreatic β-cells in vivo 46 . Nonetheless, HUWE1 inactivation in a human lung cancer cell line did not induce cellular apoptosis in vitro .…”

Section: Discussionmentioning

confidence: 99%

HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53

Yang

Cheng

et al. 2018

Theranostics

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Lung cancer is the most frequent cancer type and the leading cause of tumor-associated deaths worldwide. TP53 is an important tumor suppressor gene and is frequently inactivated in lung cancer. E3 ligases targeting p53, such as MDM2, are involved in the development of lung cancer. The E3 ligase HUWE1, which targets many tumor-associated proteins including p53, has been reported to be highly expressed in lung cancer; however, its role in lung tumorigenesis is unclear.Methods: The expression of HUWE1 and p53 in lung cancer cells was modulated and the phenotypes were assessed by performing soft agar colony forming assays, cell cycle analysis, BrdU incorporation assays, and xenograft tumor growth assays. The effect on tumorigenesis in genetically-engineered mice was also analyzed. The mechanism through which HUWE1 sustained lung cancer cell malignancy was confirmed by western blotting. HUWE1 expression in clinical lung cancer was identified by immunohistochemistry and validated by analyzing lung adenocarcinoma and lung squamous carcinoma samples from the Cancer Genome Atlas (TCGA) database. Finally, we assessed the association between HUWE1 expression and patient outcome using online survival analysis software including survival information from the caBIG, GEO, and TCGA database.Results: Inactivation of HUWE1 in a human lung cancer cell line inhibited proliferation, colony-forming capacity, and tumorigenicity. Mechanistically, this phenotype was driven by increased p53, which was due to attenuated proteasomal degradation by HUWE1. Up-regulation of p53 inhibited cancer cell malignancy, mainly through the induction of p21 expression and the down-regulation of HIF1α. Huwe1 deletion completely abolished the development of EGFRVIII-induced lung cancer in Huwe1 conditional knockout mice. Furthermore, survival analysis of lung cancer patients showed that increased HUWE1 expression is significantly associated with worse prognosis.Conclusion: Our data suggest that HUWE1 plays a critical role in lung cancer and that the HUWE1-p53 axis might be a potential target for lung cancer therapy.

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Section: Discussionmentioning

confidence: 99%

HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53

Yang

Cheng

et al. 2018

Theranostics

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“…Thus, our study broadens the spectrum of biological activities regulated by HUWE1 and highlights its involvement in lipid metabolism by regulating PPARα. Interestingly, the specific deletion of HUWE1 in pancreatic β cells leads to reduced β cell mass with aging, resulting in severe diabetes before reaching 1 year of age, indicating that HUWE1 is involved in metabolic regulation. This notion is also supported by our finding that Huwe1 knockdown up‐regulated the expression of PPARα target genes at the cellular level (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1

Zhao

Wang

et al. 2018

Hepatology

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Peroxisome proliferator‐activated receptor α (PPARα) is a key transcriptional factor that regulates hepatic lipid catabolism by stimulating fatty acid oxidation and ketogenesis in an adaptive response to nutrient starvation. However, how PPARα is regulated by posttranslational modification is poorly understood. In this study, we identified that progestin and adipoQ receptor 3 (PAQR3) promotes PPARα ubiquitination through the E3 ubiquitin ligase HUWE1, thereby negatively modulating PPARα functions both in vitro and in vivo. Adenovirus‐mediated Paqr3 knockdown and liver‐specific deletion of the Paqr3 gene reduced hepatic triglyceride levels while increasing fatty acid oxidation and ketogenesis upon fasting. PAQR3 deficiency enhanced the fasting‐induced expression of PPARα target genes, including those involved in fatty acid oxidation and fibroblast growth factor 21, a key molecule that mediates the metabolism‐modulating effects of PPARα. PAQR3 directly interacted with PPARα and increased the polyubiquitination and proteasome‐mediated degradation of PPARα. Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARα polyubiquitination. Additionally, PAQR3 enhanced the interaction between HUWE1 and PPARα. Conclusion: Ubiquitination modification through the coordinated action of PAQR3 with HUWE1 plays a crucial role in regulating the activity of PPARα in response to starvation. (Hepatology 2018;68:289‐303).

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“…HUWE1 is an E3 ubiquitin ligase targeting substrates with unshielded, hydrophobic segments [ 30 ] – befitting of MG-modified proteins. Interestingly, conditional knockout of HUWE1 in pancreatic beta-cells of mice accelerated the age-dependent decline of insulin secretion and glucose homeostasis [ 31 ], which may mimic the effect of chronic dicarbonyl stress in clinical insulin resistance [ 32 ]. CHIP, as mentioned above, is a functional partner of HSP70.…”

Section: Activation Of the Unfolded Protein Response In Dicarbonyl Stressmentioning

confidence: 99%

Dicarbonyl stress, protein glycation and the unfolded protein response

2021

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The reactive dicarbonyl metabolite, methylglyoxal (MG), is increased in obesity and diabetes and is implicated in the development of insulin resistance, type 2 diabetes mellitus and vascular complications of diabetes. Dicarbonyl stress is the metabolic state of abnormal high MG concentration. MG is an arginine-directed glycating agent and precursor of the major advanced glycation endproduct, arginine-derived hydroimidazolone MG-H1. MG-H1 is often formed on protein surfaces and an uncharged hydrophobic residue, inducing protein structural distortion and misfolding. Recent studies indicate that dicarbonyl stress in human endothelial cells and fibroblasts in vitro induced a proteomic response consistent with activation of the unfolded protein response (UPR). The response included: increased abundance of heat shock proteins and ubiquitin ligases catalysing the removal of proteins with unshielded surface hydrophobic patches and formation of polyubiquitinated chains to encapsulate misfolded proteins; and increased low grade inflammation. Activation of the UPR is implicated in insulin resistance. An effective strategy to counter increased MG is inducing increased expression of glyoxalase-1 (Glo1). An optimized inducer of Glo1 expression, trans-resveratrol and hesperetin combination, normalized increased MG concentration, corrected insulin resistance and decreased low grade inflammation in overweight and obese subjects. We propose that dicarbonyl stress, through increased formation of MG-glycated proteins, may be an important physiological stimulus of the UPR and Glo1 inducers may provide a route to effective suppression and therapy. With further investigation and validation, this may provide key new insight into physiological activators of the UPR and association with dicarbonyl stress.

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Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

Cited by 16 publications

References 40 publications

HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53

HUWE1 controls the development of non-small cell lung cancer through down-regulation of p53

Hepatic PPARα function is controlled by polyubiquitination and proteasome‐mediated degradation through the coordinated actions of PAQR3 and HUWE1

Dicarbonyl stress, protein glycation and the unfolded protein response

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