Dataset Information

Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences.

ABSTRACT: The mammalian unfolded protein response (UPR) is propagated by three ER-resident transmembrane proteins, each of which initiates a signaling cascade that ultimately culminates in production of a transcriptional activator. The UPR was originally characterized as a pathway for upregulating ER chaperones, and a comprehensive body of subsequent work has shown that protein synthesis, folding, oxidation, trafficking, and degradation are all transcriptionally enhanced by the UPR. However, the global reach of the UPR extends to genes involved in diverse physiological processes having seemingly little to do with ER protein folding, and this includes a substantial number of mRNAs that are suppressed by stress rather than stimulated. Through multiple non-canonical mechanisms emanating from each of the UPR pathways, the cell dynamically regulates transcription and mRNA degradation. Here we highlight these mechanisms and their increasingly appreciated impact on physiological processes.

SUBMITTER: Arensdorf AM

PROVIDER: S-EPMC3844873 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences.

Arensdorf Angela M AM Diedrichs Danilo D Rutkowski D Thomas DT

Frontiers in genetics 20131202

The mammalian unfolded protein response (UPR) is propagated by three ER-resident transmembrane proteins, each of which initiates a signaling cascade that ultimately culminates in production of a transcriptional activator. The UPR was originally characterized as a pathway for upregulating ER chaperones, and a comprehensive body of subsequent work has shown that protein synthesis, folding, oxidation, trafficking, and degradation are all transcriptionally enhanced by the UPR. However, the global re ...[more]

PMID: 24348511

Similar Datasets

Project description:BackgroundThe development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation.MethodsCell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP, and 22RV1 cells, as well as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy.ResultsHerein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites.ConclusionsWe found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.

Project description:BackgroundUnder caged conditions, birds are affected more severely by environmental stressors such as dietary structure, activity space, human disturbances, and pathogens, which may be reflected in the gene expression in peripheral blood or other tissues. Elucidating the molecular mechanism of these stress responses will help improve animal welfare.ResultsIn the present study, the blood transcriptomes of six male and five female caged magpies (Pica pica) were sequenced, and a total of ~ 100 Gb in clean reads were generated using the Illumina HiSeq 2000 sequencer. A total of 420,291 unigenes were identified after assembly, of which 179,316 were annotated in five databases, 7471 were assigned to 269 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and 566 were assigned to the Clusters of Orthologous Groups (COG) functional classification "defense mechanisms". Analysis of differentially expressed genes (DEGs) showed that 2657 unigenes were differentially expressed between males and females (q < 0.1), and these DEGs were assigned to 45 KEGG pathways involving stress resistance, immunity, energy metabolism, reproduction, lifespan regulation, and diseases. Further analysis revealed that females might be more sensitive to stress through upregulation of c-Jun N-terminal kinases (JNKs) and 5'AMP-activated protein kinase (AMPK), and were also possibly more sensitive to dynamic changes in energy. Females expressed higher major histocompatibility complex (MHC) class II levels than males, enhancing resistance to pathogens, and the DEGs related to reproduction included MAPK, CaMK, CPEB, and Cdc25. The genes related to stress, energy, and immunity were also likely related to the regulation of longevity. The upregulated JNKs in females might prolong lifespan and relieve antioxidant stress. Females may also activate the AMPK pathway and implement dietary restrictions to prolong lifespan, whereas males may upregulate SIRT1 and CRAB to increase lifespan.ConclusionsFemale magpies might be more sensitive to stress and dynamic changes in energy thus enhanced resistance to pathogens, and the genes related to stress, energy, and immunity were also possibly related to the regulation of longevity. Further confirmations with techniques such as RT-qPCR and western blot are necessary to validate the above arguments.

Dataset Information

Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences.

Publications

Regulation of the transcriptome by ER stress: non-canonical mechanisms and physiological consequences.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets