Molecular Components of a Cell Death Pathway Activated by Endoplasmic Reticulum Stress

Rao, Rammohan V.; Poksay, Karen S.; Castro-Obregón, Susana; Schilling, Birgit; Row, Richard H.; Río, Gabriel del; Gibson, Bradford W.; Ellerby, H. Michael; Bredesen, Dale E.

doi:10.1074/jbc.m304490200

Cited by 134 publications

(115 citation statements)

References 84 publications

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“…Treatment of colon cancer cells with rom4 extract was found to induce a number of signature ER stress markers including (PPP1R15A, DDIT3, and TRIB3) suggesting the induction of ER stress. Furthermore, the increased expression of the transcriptional regulator DDIT3 is often associated with RE stressinduced apoptosis (Rao et al 2004). This transcription factor is known to regulate the expression of a set of genes including pro-apoptotic genes, including BAK and BIM, to originate mitochondrial cell death.…”

Section: Discussionmentioning

confidence: 99%

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

et al. 2012

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In this work, the effect of rosemary extracts rich on polyphenols obtained using pressurized fluids was investigated on the gene expression of human SW480 and HT29 colon cancer cells. The application of transcriptomic profiling and functional enrichment analysis was done via two computational approaches, Ingenuity Pathway Analysis and Gene Set Enrichment Analysis. These two approaches were used for functional enrichment analysis as a previous step for a reliable interpretation of the data obtained from microarray analysis. Reverse transcription quantitative-PCR was used to confirm relative changes in mRNA levels of selected genes from microarrays. The selection of genes was based on their expression change, adjusted p value, and known biological function. According to genome-wide transcriptomics analysis, rosemary polyphenols altered the expression of *4 % of the genes covered by the Affymetrix Human Gene 1.0ST chip in both colon cancer cells. However, only *18 % of the differentially expressed genes were common to both cell lines, indicating markedly different expression profiles in response to the treatment. Differences in induction of G2/ M arrest observed by rosemary polyphenols in the two colon adenocarcinoma cell lines suggest that the extract may be differentially effective against tumors with specific mutational pattern. From our results, it is also concluded that rosemary polyphenols induced a low degree of apoptosis indicating that other multiple signaling pathways may contribute to colon cancer cell death.

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Section: Discussionmentioning

confidence: 99%

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

et al. 2012

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“…The proteasome contributes to ERAD by relieving the ER stress. Accumulation of unfolded protein within the lumen of the ER leads to prolonged UPR activation, which in turn causes oxidative stress and finally cell death (47). To target the oxidative stress, we inhibited the major stress-inducible transcription factor CHOP/GADD153, which serves as a pro-apoptotic signal in response to the UPR (Fig.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of Endoplasmic Reticulum-associated Degradation Rescues ΔF508-Cystic Fibrosis Transmembrane Regulator and Suppresses Interleukin-8 Levels

Vij¹,

Fang

Zeitlin³

2006

Journal of Biological Chemistry

153

128

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Endoplasmic reticulum (ER)-associated degradation (ERAD)is the major quality control pathway of the cell. The most common diseasecausing protein folding mutation, ⌬F508-cystic fibrosis transmembrane regulator (CFTR), is destroyed by ERAD to cause cystic fibrosis (CF). p97/valosin-containing protein (VCP) physically interacts with gp78/autocrine motility factor receptor to couple ubiquitination, retrotranslocation, and proteasome degradation of misfolded proteins. We show here that p97/VCP and gp78 form complexes with CFTR during translocation from the ER for degradation by the cytosolic proteasome. Interference in the VCP-CFTR complex promoted accumulation of immature CFTR in the ER and partial rescue of functional chloride channels to the cell surface. Moreover, under these conditions, interleukin-8 (IL8), the expression of which is regulated by the proteasome, was reduced. Inhibition of the proteasome with bortezomib (PS-341/Velcade) also rescued CFTR, but with less efficiency, and suppressed NFB-mediated IL8 activation. The inhibition of the major stress-inducible transcription factor CHOP (CCAAT/enhancerbinding protein homologous protein)/GADD153 together with bortezomib was most effective in repressing NFB-mediated IL8 activation compared with interference of VCP, MLN-273 (proteasome inhibitor), or 4-phenylbutyrate (histone deacetylase inhibitor). Immunoprecipitation of ⌬F508-CFTR from primary CF bronchial epithelial cells confirmed the interaction with VCP and associated chaperones in CF. We conclude that VCP is an integral component of ERAD and cellular stress pathways induced by the unfolded protein response and may be central to the efficacy of CF drugs that target the ubiquitin-proteasome pathway.

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“…Caspase-12 has also been detected in high molecular weight complex with apoptosis-linked gene-2 protein and p97 (also referred to as valosin-containing protein), the ERAD mediator. 165 Interference with the formation of this complex protects cells from ER stress-induced apoptosis, presumably by blocking the activation of caspase-12 or caspase-9. 165 Because p97 is also involved in ERAD, it may also mediate crosstalk between the prosurvival and proapoptotic pathways induced by ER stress.…”

Section: Esr and Apoptosismentioning

confidence: 99%

Cellular response to endoplasmic reticulum stress: a matter of life or death

2006

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The proper functioning of the endoplasmic reticulum (ER) is critical for numerous aspects of cell physiology. Accordingly, all eukaryotes react rapidly to ER dysfunction through a set of adaptive pathways known collectively as the ER stress response (ESR). Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger programmed cell death, or apoptosis. ER stress and the apoptotic program coupled to it have been implicated in many important pathologies but the regulation and execution of ER stressinduced apoptosis in mammals remain incompletely understood. Here, we review what is known about the ESR in both yeast and mammals, and highlight recent findings on the mechanism and pathophysiological importance of ER stressinduced apoptosis.

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Molecular Components of a Cell Death Pathway Activated by Endoplasmic Reticulum Stress

Cited by 134 publications

References 84 publications

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

Selective Inhibition of Endoplasmic Reticulum-associated Degradation Rescues ΔF508-Cystic Fibrosis Transmembrane Regulator and Suppresses Interleukin-8 Levels

Cellular response to endoplasmic reticulum stress: a matter of life or death

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