The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress

Austgen, Kathryn; Johnson, Emily T.; Park, Tae‐Ju; Curran, Tom; Oakes, Scott A.

doi:10.1038/ncb2395

Cited by 29 publications

(27 citation statements)

References 40 publications

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“…In fact, opposing activity has been observed depending on different cell types and stimuli . Autophagy has mostly been described to be a cytoprotective and pro‐survival event, while cytotoxic autophagy, also called type II programmed cell death, has been found in some cases . Most of the treatment‐induced autophagy was identified to be pro‐survival, thus, mediating resistance to the respective drugs (for review see Refs.…”

Section: Discussionmentioning

confidence: 99%

The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer

Dyshlovoy

Menchinskaya

Venz

et al. 2016

Intl Journal of Cancer

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Despite recent advances in the treatment of metastatic castration-resistant prostate cancer (CRPC), outcome of patients remains poor due to the development of drug resistance. Thus, new drugs are urgently needed. We investigated efficacy, toxicity and mechanism of action of marine triterpene glycoside frondoside A (FrA) using CRPC cell lines in vitro and in vivo. FrA revealed high efficacy in human prostate cancer cells, while non-malignant cells were less sensitive. Remarkably, proliferation and colony formation of cells resistant to enzalutamide and abiraterone (due to the androgen receptor splice variant AR-V7) were also significantly inhibited by FrA. The marine compound caused cell type specific cell cycle arrest and induction of caspase-dependent or -independent apoptosis. Up-regulation or induction of several pro-apoptotic proteins (Bax, Bad, PTEN), cleavage of PARP and caspase-3 and down-regulation of anti-apoptotic proteins (survivin and Bcl-2) were detected in treated cells. Global proteome analysis revealed regulation of proteins involved in formation of metastases, tumor cell invasion, and apoptosis, like keratin 81, CrkII, IL-1b and cathepsin B. Inhibition of pro-survival autophagy was observed following FrA exposure. In vivo, FrA inhibited tumor growth of PC-3 and DU145 cells with a notable reduction of lung metastasis, as well as circulating tumor cells in the peripheral blood. Increased lymphocyte counts of treated animals might indicate an immune

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Section: Discussionmentioning

confidence: 99%

The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer

Dyshlovoy

Menchinskaya

Venz

et al. 2016

Intl Journal of Cancer

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“…ER stress signals facilitate BAX and BAK oligomerization by inducing the expression of BH3-only proteins, including BIM, NOXA, PUMA, DR5 and CRK (Austgen et al, 2011;Cunha et al, 2012;Li et al, 2006;Puthalakath et al, 2007;Wali et al, 2014) and by repressing BCL2 (McCullough et al, 2001). Furthermore, the BH3-only protein BID is truncated or activated in response to ER stress in a pathway downstream of caspase-8 (Namba et al, 2013) or caspase-2 (Upton et al, 2008) -although the role of caspase-2 is debated (Sandow et al, 2014).…”

Section: The Er-stress-mitochondrial Signaling Axismentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

152

137

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In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

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“…It is well established that dysfunction of the nucleus, ER, and mitochondria induce cell death and pro-apoptotic signals [1–3]. Several studies have analyzed stimuli (stress) that induce cell death and the expression of apoptosis-related molecules via mitochondrial and nuclear dysfunction [4–7].…”

Section: Introductionmentioning

confidence: 99%

The Endoplasmic Reticulum-Resident Chaperone Heat Shock Protein 47 Protects the Golgi Apparatus from the Effects of O-Glycosylation Inhibition

et al. 2013

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The Golgi apparatus is important for the transport of secretory cargo. Glycosylation is a major post-translational event. Recognition of O-glycans on proteins is necessary for glycoprotein trafficking. In this study, specific inhibition of O-glycosylation (Golgi stress) induced the expression of endoplasmic reticulum (ER)-resident heat shock protein (HSP) 47 in NIH3T3 cells, although cell death was not induced by Golgi stress alone. When HSP47 expression was downregulated by siRNA, inhibition of O-glycosylation caused cell death. Three days after the induction of Golgi stress, the Golgi apparatus was disassembled, many vacuoles appeared near the Golgi apparatus and extended into the cytoplasm, the nuclei had split, and cell death assay-positive cells appeared. Six hours after the induction of Golgi stress, HSP47-knockdown cells exhibited increased cleavage of Golgi-resident caspase-2. Furthermore, activation of mitochondrial caspase-9 and ER-resident unfolded protein response (UPR)-related molecules and efflux of cytochrome c from the mitochondria to the cytoplasm was observed in HSP47-knockdown cells 24 h after the induction of Golgi stress. These findings indicate that (i) the ER-resident chaperon HSP47 protected cells from Golgi stress, and (ii) Golgi stress-induced cell death caused by the inhibition of HSP47 expression resulted from caspase-2 activation in the Golgi apparatus, extending to the ER and mitochondria.

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The adaptor protein CRK is a pro-apoptotic transducer of endoplasmic reticulum stress

Cited by 29 publications

References 40 publications

The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer

The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer

Redox controls UPR to control redox

The Endoplasmic Reticulum-Resident Chaperone Heat Shock Protein 47 Protects the Golgi Apparatus from the Effects of O-Glycosylation Inhibition

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