More than half of human genes use alternative cleavage and polyadenylation (ApA) to generate mRNA transcripts that differ in the lengths of their 3' untranslated regions (UTRs), thus altering the post-transcriptional fate of the message and likely the protein output. The extent of 3' UTR variation across tissues and the functional role of ApA remain poorly understood. We developed a sequencing method called 3'-seq to quantitatively map the 3' ends of the transcriptome of diverse human tissues and isogenic transformation systems. We found that cell type-specific gene expression is accomplished by two complementary programs. Tissue-restricted genes tend to have single 3' UTRs, whereas a majority of ubiquitously transcribed genes generate multiple 3' UTRs. During transformation and differentiation, single-UTR genes change their mRNA abundance levels, while multi-UTR genes mostly change 3' UTR isoform ratios to achieve tissue specificity. However, both regulation programs target genes that function in the same pathways and processes that characterize the new cell type. Instead of finding global shifts in 3' UTR length during transformation and differentiation, we identify tissue-specific groups of multi-UTR genes that change their 3' UTR ratios; these changes in 3' UTR length are largely independent from changes in mRNA abundance. Finally, tissue-specific usage of ApA sites appears to be a mechanism for changing the landscape targetable by ubiquitously expressed microRNAs.

/pdf/ubiquitously-transcribed-genes-use-alternative-2l4l74s6g2.pdf

Ubiquitously transcribed genes use alternative polyadenylation to achieve tissue-specific expression

Iron has been shown to trigger oxidative stress by elevating reactive oxygen species (ROS) and to participate in different modes of cell death, such as ferroptosis, apoptosis and necroptosis. However, whether iron-elevated ROS is also linked to pyroptosis has not been reported. Here, we demonstrate that iron-activated ROS can induce pyroptosis via a Tom20-Bax-caspase-GSDME pathway. In melanoma cells, iron enhanced ROS signaling initiated by CCCP, causing the oxidation and oligomerization of the mitochondrial outer membrane protein Tom20. Bax is recruited to mitochondria by oxidized Tom20, which facilitates cytochrome c release to cytosol to activate caspase-3, eventually triggering pyroptotic death by inducing GSDME cleavage. Therefore, ROS acts as a causative factor and Tom20 senses ROS signaling for iron-driven pyroptotic death of melanoma cells. Since iron activates ROS for GSDME-dependent pyroptosis induction and melanoma cells specifically express a high level of GSDME, iron may be a potential candidate for melanoma therapy. Based on the functional mechanism of iron shown above, we further demonstrate that iron supplementation at a dosage used in iron-deficient patients is sufficient to maximize the anti-tumor effect of clinical ROS-inducing drugs to inhibit xenograft tumor growth and metastasis of melanoma cells through GSDME-dependent pyroptosis. Moreover, no obvious side effects are observed in the normal tissues and organs of mice during the combined treatment of clinical drugs and iron. This study not only identifies iron as a sensitizer amplifying ROS signaling to drive pyroptosis, but also implicates a novel iron-based intervention strategy for melanoma therapy.

/pdf/tom20-senses-iron-activated-ros-signaling-to-promote-3zu63icitb.pdf

Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis

Autophagy is a tightly-regulated catabolic process of cellular self-digestion by which cellular components are targeted to lysosomes for their degradation. Key functions of autophagy are to provide energy and metabolic precursors under conditions of starvation and to alleviate stress by removal of damaged proteins and organelles, which are deleterious for cell survival. Therefore, autophagy appears to serve as a pro-survival stress response in most settings. However, the role of autophagy in modulating cell death is highly dependent on the cellular context and its extent. There is an increasing evidence for cell death by autophagy, in particular in developmental cell death in lower organisms and in autophagic cancer cell death induced by novel cancer drugs. The death-promoting and -executing mechanisms involved in the different paradigms of autophagic cell death (ACD) are very diverse and complex, but a draft scenario of the key molecular targets involved in ACD is beginning to emerge. This review provides an up-to-date and comprehensive report on the molecular mechanisms of drug-induced autophagy-dependent cell death and highlights recent key findings in this exciting field of research.

Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy.

Apoptosis is a primary characteristic in the pathogenesis of liver disease. Hepatic apoptosis is regulated by autophagic activity. However, mechanisms mediating their interaction remain to be determined. Basal level of autophagy ensures the physiological turnover of old and damaged organelles. Autophagy also is an adaptive response under stressful conditions. Autophagy can control cell fate through different cross-talk signals. A complex interplay between hepatic autophagy and apoptosis determines the degree of hepatic apoptosis and the progression of liver disease as demonstrated by pre-clinical models and clinical trials. This review summarizes recent advances on roles of autophagy that plays in pathophysiology of liver. The autophagic pathway can be a novel therapeutic target for liver disease.

https://www.tandfonline.com/doi/pdf/10.1080/15384101.2015.1038685

Autophagy and apoptosis in liver injury.

3' untranslated regions (3' UTRs) of messenger RNAs (mRNAs) are best known to regulate mRNA-based processes, such as mRNA localization, mRNA stability, and translation In addition, 3' UTRs can establish 3' UTR-mediated protein-protein interactions (PPIs), and thus can transmit genetic information encoded in 3' UTRs to proteins This function has been shown to regulate diverse protein features, including protein complex formation or posttranslational modifications, but is also expected to alter protein conformations Therefore, 3' UTR-mediated information transfer can regulate protein features that are not encoded in the amino acid sequence This review summarizes both 3' UTR functions-the regulation of mRNA and protein-based processes-and highlights how each 3' UTR function was discovered with a focus on experimental approaches used and the concepts that were learned This review also discusses novel approaches to study 3' UTR functions in the future by taking advantage of recent advances in technology

/pdf/what-are-3-utrs-doing-2s1tm9aq0l.pdf

What Are 3′ UTRs Doing?

Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.

Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway

Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.

Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation

Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity

Clinical Significance of PAC-1, CD62P, and Platelet-Leukocyte Aggregates in Acute Ischemic Stroke

The invention discloses application of 1-(3,4,5-trihydroxy) phenyl-1-dinone in preparation of a medicament for preventing or treating melanoma, and relates to an organic small molecular compound 1-(3,4,5-trihydroxy) phenyl-1-dinone can be used as a medicinal composition of a medicinal carrier or an excipient or an additive, and the medicinal composition has the effect of preventing and treating the melanoma Various medicinal excipients, additives or carriers can be added in the medicinal composition for treating the melanoma The medicament and the medicinal composition can be prepared into other dosage forms of enteric or non-enteric administration such as tablets, capsules, granules and injection according to the known methods in the field The application range of 1-(3,4,5-trihydroxy) phenyl-1-dinone in disease treatment is expanded

Yong-zhen Xing

Papers

Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway

Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation

Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity

Clinical Significance of PAC-1, CD62P, and Platelet-Leukocyte Aggregates in Acute Ischemic Stroke

Application of 1-(3,4,5-trihydroxy) phenyl-1-dinone in preparation of medicament for preventing or treating melanoma