The retinoic acid derivative, ABPN, inhibits pancreatic cancer through induction of Nrdp1

Byun, Sun‐Sig; Shin, Seung Ho; Lee, Eunjung; Lee, Jihoon; Lee, Sung‐Young; Farrand, Lee; Jung, Sung Keun; Cho, Yong‐Yeon; Um, Soo‐Jong; Sin, Hong‐Sig; Kwon, Youn-Ja; Zhang, Chengjuan; Tsang, Benjamin K.; Bode, Ann M.; Lee, Hyong Joo; Lee, Ki Won; Dong, Zigang

doi:10.1093/carcin/bgv148

Cited by 6 publications

(8 citation statements)

References 38 publications

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“…Alternatively, there may be Clec16a-independent effects to Nrdp1 activity that regulate β-cell function. Notably, the endoplasmic reticulum structural protein reticulon 4A (Rtn4a or Nogo-A) and retinoic acid derivatives modulate Nrdp1 activity (44,45) in non-β-cells, and they do not intersect with the Clec16a pathway in our previous interactome studies (5). Rtn4a has also been implicated in the regulation of GSIS (46).…”

Section: Discussionmentioning

confidence: 76%

Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy

et al. 2017

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Mitophagy is a cellular quality-control pathway, which is essential for elimination of unhealthy mitochondria. While mitophagy is critical to pancreatic β-cell function, the posttranslational signals governing β-cell mitochondrial turnover are unknown. Here, we report that ubiquitination is essential for the assembly of a mitophagy regulatory complex, comprised of the E3 ligase Nrdp1, the deubiquitinase enzyme USP8, and Clec16a, a mediator of β-cell mitophagy with unclear function. We discover that the diabetes gene encodes an E3 ligase, which promotes nondegradative ubiquitin conjugates to direct its mitophagy effectors and stabilize the Clec16a-Nrdp1-USP8 complex. Inhibition of the Clec16a pathway by the chemotherapeutic lenalidomide, a selective ubiquitin ligase inhibitor associated with new-onset diabetes, impairs β-cell mitophagy, oxygen consumption, and insulin secretion. Indeed, patients treated with lenalidomide develop compromised β-cell function. Moreover, the β-cell Clec16a-Nrdp1-USP8 mitophagy complex is destabilized and dysfunctional after lenalidomide treatment as well as after glucolipotoxic stress. Thus, the Clec16a-Nrdp1-USP8 complex relies on ubiquitin signals to promote mitophagy and maintain mitochondrial quality control necessary for optimal β-cell function.

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Section: Discussionmentioning

confidence: 76%

Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy

et al. 2017

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“…The E3 ligase Nrdp1 has been extensively investigated on cell growth, apoptosis and inflammation in cancer cells and other cell types (Qiu et al, 2004 ; Wang et al, 2009 ; Ingalla et al, 2010 ; Byun et al, 2015 ). In the present study, we investigated Nrdp1’s role in ischemic neuronal injury.…”

Section: Discussionmentioning

confidence: 99%

Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein

Zhang

Yang

Wang

et al. 2017

Front. Cell. Neurosci.

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Neuregulin receptor degradation protein-1 (Nrdp1) is an E3 ubiquitin ligase that targets proteins for degradation and regulates cell growth, apoptosis and oxidative stress in various cell types. We have previously shown that Nrdp1 is implicated in ischemic cardiomyocyte death. In this study, we investigated the change of Nrdp1 expression in ischemic neurons and its role in ischemic neuronal injury. Primary rat cerebral cortical neurons and pheochromocytoma (PC12) cells were infected with adenoviral constructs expressing Nrdp1 gene or its siRNA before exposing to oxygen-glucose deprivation (OGD) treatment. Our data showed that Nrdp1 was upregulated in ischemic brain tissue 3 h after middle cerebral artery occlusion (MCAO) and in OGD-treated neurons. Of note, Nrdp1 overexpression by Ad-Nrdp1 enhanced OGD-induced neuron apoptosis, while knockdown of Nrdp1 with siRNA attenuated this effect, implicating a role of Nrdp1 in ischemic neuron injury. Moreover, Nrdp1 upregulation is accompanied by increased protein ubiquitylation and decreased protein levels of ubiquitin-specific protease 8 (USP8) in OGD-treated neurons, which led to a suppressed interaction between USP8 and HIF-1α and subsequently a reduction in HIF-1α protein accumulation in neurons under OGD conditions. In conclusion, our data support an important role of Nrdp1 upregulation in ischemic neuronal death, and suppressing the interaction between USP8 and HIF-1α and consequently the hypoxic adaptive response of neurons may account for this detrimental effect.

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“…RNF41 exerts differential ubiquitination functions towards Myd88 (poly-lys48) and TBK1 (poly-lys63) and regulates TLR-mediated production of type-I interferon 23. Loss of RNF41 has been reported in human cancers, such as breast cancer 24, prostate cancer 25, pancreatic cancer 26, glioma 27 and recently HCC 28. Though RNF41 regulates a broad range of physiological processes, its relationship with CACYBP and the underlying mechanism in HCC progression remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

Lian¹,

Huang²,

Zhang³

et al. 2019

Theranostics

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Calcyclin-binding protein (CACYBP) is a multi-ligand protein implicated in the progression of various human cancers. However, its function in hepatocellular carcinoma (HCC) remains unknown.Methods: The expression of CACYBP and RNF41 (RING finger protein 41) in HCC cancer and adjacent non-tumor tissues was detected by immunohistochemistry. CCK-8 assays, colony formation assays, flow cytometry detection and xenograft models were used to evaluate the impact of CACYBP expression on HCC cell growth, apoptosis and cell cycle regulation. Immunoprecipitation and ubiquitination assays were performed to determine how RNF41 regulates CACYBP. The regulatory mechanism of RNF41-CACYBP signaling axis on P27Kip1 was investigated by western blotting and immunofluorescence.Results: CACYBP was highly expressed and associated with poor prognosis in HCC. CACYBP expression was required for HCC cell growth in vitro and in vivo. Moreover, we identified RNF41 as a specific binding partner of CACYBP at exogenous and endogenous levels. RNF41 recruited CACYBP by its C-terminal substrate binding domain, subsequently ubiquitinating CACYBP and promoting its degradation in both proteasome- and lysosome-dependent pathways. In HCC tissues, RNF41 expression was reduced and conferred a negative correlation with CACYBP expression. Mechanistically, CACYBP overexpression stimulated the Ser10, Thr157 and Thr198 phosphorylation of P27Kip1 and its cytoplasmic retention, and RNF41 co-expression attenuated this phenomenon. CACYBP depletion led to decreased levels of cyclin D1, cyclin A2, CDK2 and CDK4, causing a typical cell cycle arrest at G1/S phase and increasing apoptosis in HCC cells. P27Kip1-S10D but not P27Kip1-S10A reconstitution rescued partially the cell cycle function and apoptotic feature after CACYBP depletion.Conclusion: Our findings provide novel insights into the functional role and regulatory mechanism of CACYBP in HCC.

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The retinoic acid derivative, ABPN, inhibits pancreatic cancer through induction of Nrdp1

Cited by 6 publications

References 38 publications

Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy

Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy

Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein

CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

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The retinoic acid derivative, ABPN, inhibits pancreatic cancer through induction of Nrdp1

Cited by 6 publications

References 38 publications

Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy

Clec16a, Nrdp1, and USP8 Form a Ubiquitin-Dependent Tripartite Complex That Regulates β-Cell Mitophagy

Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein

CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

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CACYBP Enhances Cytoplasmic Retention of P27^Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation