Sharpin Contributes to TNFα Dependent NFκB Activation and Anti-Apoptotic Signalling in Hepatocytes

Sieber, Sabrina; Lange, Nicole; Kollmorgen, Gwendlyn; Erhardt, Annette; Quaas, Alexander; Gontarewicz, Arthur; Sass, Gabriele; Tiegs, Gisa; Kreienkamp, Hans‐Jürgen

doi:10.1371/journal.pone.0029993

Cited by 27 publications

(26 citation statements)

References 24 publications

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“…In this study, we only observed a nonsignificant delay of I-kB phosphorylation in Cpdm cultures (Fig. 4E), in contrast to what has been reported for other cell types from Cpdm mice by us (16) and by others (10)(11)(12).…”

Section: Primary Calvarial Cells From Cpdm Mice Display Impaired Ostecontrasting

confidence: 93%

“…Having established that impaired osteoblast differentiation is causative for the osteopenia of Cpdm mice, we finally addressed the question of whether TNF signaling is impaired in mesenchymal osteoprogenitor cells from Cpdm mice. We first monitored TNF-a-induced I-kB phosphorylation in primary calvarial osteoblasts and found, in contrast to our previous analysis in primary hepatocytes (16), that there was no significant difference between WT and Cpdm cultures. We also analyzed the possibility that TNF-a treatment would induce apoptosis specifically in Cpdm osteoblast cultures, similar to what has been reported for other cell types (10)(11)(12)16).…”

Section: Discussionmentioning

confidence: 62%

“…We first monitored TNF-a-induced I-kB phosphorylation in primary calvarial osteoblasts and found, in contrast to our previous analysis in primary hepatocytes (16), that there was no significant difference between WT and Cpdm cultures. We also analyzed the possibility that TNF-a treatment would induce apoptosis specifically in Cpdm osteoblast cultures, similar to what has been reported for other cell types (10)(11)(12)16). In this study, we found, unexpectedly, that TNF-a treatment significantly enhanced caspase-3/7 activity in WT, but not in Cpdm, cultures.…”

Section: Discussionmentioning

confidence: 62%

“…007599). Offspring from heterozygous matings were genotyped by sequencing of a PCR amplicon generated with the primers 59-CGGACCGTGCCTGGAG-39 and 59-CACGAA TGTGAA-AGGAAAAG-39 as described previously (16). All experiments were performed with WT littermates as a control.…”

Section: Micementioning

confidence: 99%

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Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

Jeschke

Catalá-Lehnen

Sieber

et al. 2015

The Journal of Immunology

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The cytosolic protein Sharpin is a component of the linear ubiquitin chain assembly complex, which regulates NF-κB signaling in response to specific ligands, such as TNF-α. Its inactivating mutation in chronic proliferative dermatitis mutation (Cpdm) mice causes multiorgan inflammation, yet this phenotype is not transferable into wild-type mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, and that this osteopenia is corrected by Tnf deletion. Because the cellular mechanism underlying this pathology, however, was still undefined, we performed a thorough skeletal phenotyping of Cpdm mice on the basis of nondecalcified histology and cellular and dynamic histomorphometry. We show that the trabecular and cortical osteopenia in Cpdm mice is solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. Consistently, Cpdm primary calvarial cells display reduced osteogenic capacity ex vivo, and the same was observed with CD11b− bone marrow cells. Unexpectedly, short-term treatment of these cultures with TNF-α did not reveal an impaired molecular response in the absence of Sharpin. Instead, genome-wide and gene-specific expression analyses revealed that Cpdm mesenchymal cells display increased responsiveness toward TNF-α–induced expression of specific cytokines, such as CXCL5, IL-1β, and IL-6. Therefore, our data not only demonstrate that the skeletal defects of Cpdm mice are specifically caused by impaired differentiation of osteoprogenitor cells, they also suggest that increased cytokine expression in mesenchymal bone marrow cells contributes to the inflammatory phenotype of Cpdm mice.

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Section: Primary Calvarial Cells From Cpdm Mice Display Impaired Ostecontrasting

confidence: 93%

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 62%

Section: Micementioning

confidence: 99%

See 2 more Smart Citations

Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

Jeschke

Catalá-Lehnen

Sieber

et al. 2015

The Journal of Immunology

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“…The NZF domain of SHARPIN seems to be indispensable for NF-κB activation, but not for linear ubiquitination [5] . SHARPIN may also contribute to the anti-apoptotic signaling induced by TNF-α, either through a NF-kB-dependent [14] or -independent pathway [10] .…”

Section: Research Highlightmentioning

confidence: 99%

Emerging role of SHARPIN in hepatocellular carcinoma progression

Tanaka

Tateishi²,

Koike³

2017

Can Cell Microenviron

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and the leading cause of cancer-related death, especially in less economically developed regions. Despite recent progress in the diagnosis and therapy of HCC, the long-term survival rate of HCC patients is unacceptably low, in part due to the frequent development of vascular invasion or distant metastasis. The cellular functions of shank-associated RH domain-interacting protein (SHARPIN, also known as SIPL1) include the regulation of inflammation, apoptosis, immune signaling, and cell motility. SHARPIN is up-regulated in various types of cancers including HCC and has been implicated in the genesis and progression of malignant tumors, but its exact role in tumorigenesis is largely unknown. Here we present evidence supporting a role for SHARPIN in HCC invasion and progression. We also discuss the potential of SHARPIN and related genes as therapeutic targets for this currently incurable cancer.

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Activation of nuclear factor κB pathway and downstream targets survivin and livin by SHARPIN contributes to the progression and metastasis of prostate cancer

Zhang

Huang

Zhou

et al. 2014

Cancer

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BACKGROUND: Nuclear factor jB (NFjB) signaling is strongly associated with tumor progression, and studies have shown that SHANK-associated RH domain interacting protein (SHARPIN) is crucial for NFjB pathway activation. However, the expression and functions of SHARPIN in prostate cancer (PCa) have not yet been defined. METHODS: The expression of SHARPIN in PCa cell lines and tissues was evaluated with western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. After SHARPIN was silenced in the PCa cell lines, western blots were used to confirm that SHARPIN physically associated with components of the NFjB pathway and the downstream targets (survivin and livin). The functions of SHARPIN in cell proliferation, migration, and invasion in vitro were measured with 5-(3-carboxymethoxyphenyl)-2-(4,5-dimenthylthiazoly)-3-(4-sulfophenyl)tetrazolium, inner salt (MTS), Transwell, and invasion assays, respectively. Flow cytometry was employed to evaluate cell apoptosis. Furthermore, tumorigenesis in vivo was examined with tumorigenicity assays. RESULTS: SHARPIN expression was upregulated in PCa cell lines and tissues. The knockdown of SHARPIN or incubation with Bay 11-7082 (an NFjB inhibitor) led to dramatically decreased levels of phosphorylated IjBa and phosphorylated p65 in comparison with the control group. Downregulation of survivin and livin due to SHARPIN inhibition was attributable to transcriptional repression (P <.05). Decreases in cell viability, migration, invasion, and survival with a higher sensitivity to docetaxel in vitro and with repressed tumorigenesis in vivo were observed upon SHARPIN silencing, and this was consistent with the results from inhibition of the NFjB pathway and its downstream targets. CONCLUSION: The current study demonstrates that overexpression of SHARPIN promotes activation of the NFjB pathway and downstream targets survivin and livin, which potentially contributes to PCa development. Cancer 2014;120:3208-18.

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Sharpin Contributes to TNFα Dependent NFκB Activation and Anti-Apoptotic Signalling in Hepatocytes

Cited by 27 publications

References 24 publications

Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

Emerging role of SHARPIN in hepatocellular carcinoma progression

Activation of nuclear factor κB pathway and downstream targets survivin and livin by SHARPIN contributes to the progression and metastasis of prostate cancer

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