Hyperglycemia stimulates p62/PKCζ interaction, which mediates NF‐κB activation, increased Nox4 expression, and inflammatory cytokine activation in vascular smooth muscle

Xu, Gang; Shen, Xinchun; Wai, Christine; Vilas, Caroline K.; Clemmons, David R.

doi:10.1096/fj.15-275453

Cited by 32 publications

(26 citation statements)

References 42 publications

(70 reference statements)

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“…Our previous work suggested that p62 accumulation may activate transcription factor Nrf2 to confer cancer cells resistance to chemotherapy . Recent advances in the understanding of p62 function suggest that it increases the activity of the nuclear factor kappa B (NF‐κB) pathway in many cell systems . High NF‐κB activity may trigger several pro‐survival genes expression that contributes to chemotherapeutic resistance.…”

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confidence: 99%

“…(10) Recent advances in the understanding of p62 function suggest that it increases the activity of the nuclear factor kappa B (NF-jB) pathway in many cell systems. (9,(16)(17)(18) High NF-jB activity may trigger several pro-survival genes expression that contributes to chemotherapeutic resistance. Thus, identifying the role of p62 in the activation of NF-jB may improve the understanding of the mechanism of drug resistance.…”

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confidence: 99%

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p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Yan

Zhang

et al. 2017

Cancer Science

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Platinum‐based therapeutic strategies have been widely used in ovarian cancer treatment. However, drug resistance has greatly limited therapeutic efficacy. Recently, tolerance to cisplatin has been attributed to other factors unrelated to DNA. p62 (also known as SQSTM1) functions as a multifunctional hub participating in tumorigenesis and may be a therapeutic target. Our previous study showed that p62 was overexpressed in drug‐resistant ovarian epithelial carcinoma and its inhibition increased the sensitivity to cisplatin. In this study, we demonstrate that the activity of the NF‐κB signaling pathway and K63‐linked ubiquitination of RIP1 was higher in cisplatin‐resistant ovarian (SKOV3/DDP) cells compared with parental cells. In addition, cisplatin resistance could be reversed by inhibiting the expression of p62 using siRNA. Furthermore, deletion of the ZZ domain of p62 that interacts with RIP1 in SKOV3 cells markedly decreased K63‐linked ubiquitination of RIP1 and inhibited the activation of the NF‐κB signaling pathway. Moreover, loss of the ZZ domain from p62 led to poor proliferative capacity and high levels of apoptosis in SKOV3 cells and made them more sensitive to cisplatin treatment. Collectively, we provide evidence that p62 is implicated in the activation of NF‐κB signaling that is partly dependent on RIP1. p62 promotes cell proliferation and inhibits apoptosis thus mediating drug resistance in ovarian cancer cells.

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confidence: 99%

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confidence: 99%

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Yan

Zhang

et al. 2017

Cancer Science

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“…The NF-κB signal pathway plays an important role in the growth, proliferation, and signal transduction of different cell types. Previous studies (Burkitt et al, 2015;Cheng et al, 2015;Tsubaki et al, 2015;Xi et al, 2015) have suggested that the NF-κB pathway is activated in vascular smooth muscle cells, and that these cells show abnormal growth and proliferation during the occur-rence of heart disease. Therefore, the activation of the NF-κB signal pathway in vascular smooth muscle cells was analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have indicated that heart disease results in the activation of the NF-κB pathway in, and abnormal growth or proliferation of, vascular smooth muscle cells; however, the underlying molecular mechanisms remain unclear (Burkitt et al, 2015;Cheng et al, 2015;Lee et al, 2015;Tsubaki et al, 2015;Xi et al, 2015). We also attempted to determine the role of the NF-κB pathway in the vascular smooth muscle cells of a coronary heart disease rat model, and its related molecular mechanism.…”

Section: Introductionmentioning

confidence: 99%

miRNA-146a induces vascular smooth muscle cell apoptosis in a rat model of coronary heart disease via NF-κB pathway

Wu¹,

Liu²,

Wang³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to investigate the role of miRNA146a in modulating the function of vascular smooth muscle cells in a rat model of coronary heart disease. Vascular smooth muscle cells were isolated and cultured from the rat coronary heart disease model and normal rats (controls). miRNA-146a levels were measured in vascular smooth muscle cells obtained from rats with coronary heart disease and control rats. The proliferation, growth, apoptosis, and activation of the NF-κB pathway in the vascular smooth muscle cells were detected using the MTT assay and flow cytometry, respectively. The role of the NF-κB pathway in modulating the apoptosis of vascular smooth muscle cells was investigated by measuring the reactivity of the cells to an NF-κB pathway inhibitor (TPCA-1). Vascular smooth muscle cells from the disease model exhibited higher levels of miRNA-146a than that by the normal controls (P = 0.0024). The vascular smooth muscle cells obtained from rats with Z.W. Wu et al. 18704©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 18703-18712 (2015) coronary heart disease showed decreased proliferation and growth and increased apoptosis. miRNA-146a overexpression elevated the rate of cell apoptosis. The NF-κB pathway was activated in vascular smooth muscle cells obtained from rats with coronary heart disease. Inhibition of the NF-κB pathway significantly decreased the rate of vascular smooth muscle cell apoptosis in coronary heart disease rats (P = 0.0038). In conclusion, miRNA146a was found to induce vascular smooth muscle cell apoptosis in rats with coronary heart disease via the activation of the NF-κB signal pathway.

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“…Additionally, insulin stimulates increased binding of PKC to p62 (27) and subsequent PKC engagement to IRS-1 through p62, also shown through co-IP (48). To investigate these interactions in real time translocation assays, we examined combinations of various YFP, CFP, and mCherry-tagged versions of p62, PKC, and IRS-1 in CHO-IR cells serum-starved overnight.…”

Section: Scaffold Proteins Differentially Regulate the Phosphorylatiomentioning

confidence: 99%

Protein Scaffolds Control Localized Protein Kinase Cζ Activity

Tobias

Newton²

2016

Journal of Biological Chemistry

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Atypical protein kinase C (aPKC) isozymes modulate insulin signaling and cell polarity, but how their activity is controlled in cells is not well understood. These enzymes are constitutively phosphorylated, insensitive to second messengers, and have relatively low activity. Here we show that protein scaffolds not only localize but also differentially control the catalytic activity of the aPKC PKC, thus promoting activity toward localized substrates and restricting activity toward global substrates. Using cellular substrate readouts and scaffolded activity reporters in live cell imaging, we show that PKC has highly localized and differentially controlled activity on the scaffolds p62 and Par6. Both scaffolds tether aPKC in an active conformation as assessed through pharmacological inhibition of basal activity, monitored using a genetically encoded reporter for PKC activity. However, binding to Par6 is of higher affinity and is more effective in locking PKC in an active conformation. FRETbased translocation assays reveal that insulin promotes the association of both p62 and aPKC with the insulin-regulated scaffold IRS-1. Using the aPKC substrate MARK2 as another readout for activity, we show that overexpression of IRS-1 reduces the phosphorylation of MARK2 and enhances its plasma membrane localization, indicating sequestration of aPKC by IRS-1 away from MARK2. These results are consistent with scaffolds serving as allosteric activators of aPKCs, tethering them in an active conformation near specific substrates. Thus, signaling of these intrinsically low activity kinases is kept at a minimum in the absence of scaffolding interactions, which position the enzymes for stoichiometric phosphorylation of substrates co-localized on the same protein scaffold.

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Hyperglycemia stimulates p62/PKCζ interaction, which mediates NF‐κB activation, increased Nox4 expression, and inflammatory cytokine activation in vascular smooth muscle

Cited by 32 publications

References 42 publications

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

miRNA-146a induces vascular smooth muscle cell apoptosis in a rat model of coronary heart disease via NF-κB pathway

Protein Scaffolds Control Localized Protein Kinase Cζ Activity

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