The Yin and Yang of hsa-miR-1244 expression levels during activation of the UPR control cell fate.

Regulation of endoplasmic reticulum (ER) homeostasis plays a critical role in maintaining cell survival. When ER stress occurs, a network of three pathways called the unfolded protein response (UPR) is activated to reestablish homeostasis. While it is known that there is cross-talk between these pathways, how this complex network is regulated is not entirely clear.

Induced Attenuation of Scleral TGF-β Signaling in Mutant Mice Increases Susceptibility to IOP-Induced Optic Nerve Damage.

Purpose: Axonal optic nerve (ON) damage in glaucoma is characteristically associated with increased amounts of active transforming growth factor-beta 2 (TGF-β2) in the ON head. Here we investigated the functional role of scleral TGF-β signaling in glaucoma.

Methods: A deficiency of Tgfbr2, which encodes for TGF-β receptor type II (TGF-βRII), the essential receptor for canonical TGF-β signaling, was induced in fibroblasts (including those of the sclera) of mutant mice.

VDR and PDIA3 Are Essential for Activation of Calcium Signaling and Membrane Response to 1,25(OH)D in Squamous Cell Carcinoma Cells.

The genomic activity of 1,25(OH)D is mediated by vitamin D receptor (VDR), whilst non-genomic is associated with protein disulfide isomerase family A member 3 (PDIA3). Interestingly, our recent studies documented that PDIA3 is also involved, directly or indirectly, in the modulation of genomic response to 1,25(OH)D. Moreover, PDIA3 was also shown to regulate cellular bioenergetics, possibly through the modulation of STAT signaling.

IRE1-mediated degradation of pre-miR-301a promotes apoptosis through upregulation of GADD45A.

The unfolded protein response is a survival signaling pathway that is induced during various types of ER stress. Here, we determine IRE1's role in miRNA regulation during ER stress. During induction of ER stress in human bronchial epithelial cells, we utilized next generation sequencing to demonstrate that pre-miR-301a and pre-miR-106b were significantly increased in the presence of an IRE1 inhibitor.

The Unfolded Protein Response: A Double-Edged Sword for Brain Health.

Efficient brain function requires as much as 20% of the total oxygen intake to support normal neuronal cell function. This level of oxygen usage, however, leads to the generation of free radicals, and thus can lead to oxidative stress and potentially to age-related cognitive decay and even neurodegenerative diseases. The regulation of this system requires a complex monitoring network to maintain proper oxygen homeostasis.

EPAS1 resistance to miRNA-based regulation contributes to prolonged expression of HIF-2 during hypoxia in human endothelial cells.

The cellular adaptation to hypoxia is regulated by hypoxia inducible factors: HIF-1 and HIF-2. HIF-1 mediates response to acute hypoxia, whereas HIF-2 allows adaptation to chronic oxygen deprivation. The hypoxic transition from HIF-1 to HIF-2 is possible due to the low stability of HIF-1α subunit transcript (HIF1A) and the stable mRNA of HIF-2α (EPAS1).

The hypoxia-induced changes in miRNA-mRNA in RNA-induced silencing complexes and HIF-2 induced miRNAs in human endothelial cells.

The cellular adaptive response to hypoxia relies on the expression of hypoxia-inducible factors (HIFs), HIF-1 and HIF-2. HIFs regulate global gene expression changes during hypoxia that are necessary for restoring oxygen homeostasis and promoting cell survival. In the early stages of hypoxia, HIF-1 is elevated, whereas at the later stages, HIF-2 becomes the predominant form.

Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor.

Accumulation of misfolded proteins in ER activates the unfolded protein response (UPR), a multifunctional signaling pathway that is important for cell survival. The UPR is regulated by three ER transmembrane sensors, one of which is inositol-requiring protein 1 (IRE1). IRE1 activates a transcription factor, X-box-binding protein 1 (XBP1), by removing a 26-base intron from XBP1 mRNA that generates spliced XBP1 mRNA (XBP1s).

The Effects of Single Nucleotide Polymorphisms in Cancer RNAi Therapies.

Tremendous progress in RNAi delivery methods and design has allowed for the effective development of siRNA-based therapeutics that are currently under clinical investigation for various cancer treatments. This approach has the potential to revolutionize cancer therapy by providing the ability to specifically downregulate or upregulate the mRNA of any protein of interest. This exquisite specificity, unfortunately, also has a downside.

Genome-wide mRNA profiling identifies RCAN1 and GADD45A as regulators of the transitional switch from survival to apoptosis during ER stress.

Endoplasmic reticulum (ER) stress conditions promote a cellular adaptive mechanism called the unfolded protein response (UPR) that utilizes three stress sensors, inositol-requiring protein 1, protein kinase RNA-like ER kinase, and activating transcription factor 6. These sensors activate a number of pathways to reduce the stress and facilitate cell survival. While much is known about the mechanisms involved that modulate apoptosis during chronic stress, less is known about the transition between the prosurvival and proapoptotic factors that determine cell fate.

PIWI proteins contribute to apoptosis during the UPR in human airway epithelial cells.

Small noncoding microRNAs (miRNAs) post-transcriptionally regulate a large portion of the human transcriptome. miRNAs have been shown to play an important role in the unfolded protein response (UPR), a cellular adaptive mechanism that is important in alleviating endoplasmic reticulum (ER) stress and promoting cell recovery. Another class of small noncoding RNAs, the Piwi-interacting RNAs (piRNAs) together with PIWI proteins, was originally shown to play a role as repressors of germline transposable elements.

SNPs in microRNA target sites and their potential role in human disease.

In the post-genomic era, the goal of personalized medicine is to determine the correlation between genotype and phenotype. Developing high-throughput genotyping technologies such as genome-wide association studies (GWAS) and the 1000 Genomes Project (http://www.internationalgenome.