scholarly journals Multiple ribonuclease A family members cleave transfer RNAs in response to stress

2019 ◽  
Author(s):  
Yasutoshi Akiyama ◽  
Shawn Lyons ◽  
Marta M. Fay ◽  
Takaaki Abe ◽  
Paul Anderson ◽  
...  
Keyword(s):  
Cell Survival ◽  
Family Members ◽  
Rnase A ◽  
Transfer Rnas ◽  
Cellular Processes ◽  
Stress Changes ◽  
Response To Stress ◽  
Rnase A Superfamily

ABSTRACTDuring stress, changes in gene expression are critical for cell survival. Stress-induced tRNA cleavage has been implicated in various cellular processes, where tRNA fragments play diverse regulatory roles. Angiogenin (ANG), a member of the RNase A superfamily, induces cleavage of tRNAs resulting in the formation of tRNA-derived stress-induced RNAs (tiRNAs) that contribute to translational reprogramming aiming at cell survival. The role of other stress-induced RNases in tRNA cleavage is poorly understood. Using gene editing and biochemical approaches, we show that other members of the RNase A family are capable of targeting tRNAs in stress-responsive manner. We show that in the absence of ANG, these RNases also promote the production of tiRNAs. Moreover, specific stresses (such as treatment with sodium arsenite) activate cleavage of universal 3’-CCA termini of tRNAs in ANG-independent fashion in living cells. We conclude that multiple RNase A family members are capable of targeting tRNAs in a stress-specific manner in vivo.

scholarly journals The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae

2009 ◽  
Vol 185 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Debrah M. Thompson ◽  
Roy Parker
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cell Survival ◽  
Cellular Response ◽  
Cellular Damage ◽  
Transfer Rnas ◽  
Endonucleolytic Cleavage ◽  
Response To Stress ◽  
Rnase T2

The cellular response to stress conditions involves a decision between survival or cell death when damage is severe. A conserved stress response in eukaryotes involves endonucleolytic cleavage of transfer RNAs (tRNAs). The mechanism and significance of such tRNA cleavage is unknown. We show that in yeast, tRNAs are cleaved by the RNase T2 family member Rny1p, which is released from the vacuole into the cytosol during oxidative stress. Rny1p modulates yeast cell survival during oxidative stress independently of its catalytic ability. This suggests that upon release to the cytosol, Rny1p promotes cell death by direct interactions with downstream components. Thus, detection of Rny1p, and possibly its orthologues, in the cytosol may be a conserved mechanism for assessing cellular damage and determining cell survival, analogous to the role of cytochrome c as a marker for mitochondrial damage.

Comprehensive analysis of yeast ESCRT-III composition in single ESCRT-III deletion mutants

2019 ◽  
Vol 476 (14) ◽  
pp. 2031-2046 ◽  
Author(s):  
Christian Heinzle ◽  
Lara Mücke ◽  
Thomas Brune ◽  
Ralf Kölling
Keyword(s):  
Family Members ◽  
Cell Fractionation ◽  
Endosomal Sorting ◽  
Cellular Processes ◽  
Associated Proteins ◽  
Bona Fide ◽  
Main Component ◽  
The Impact

Abstract The endosomal sorting complex required for transport (ESCRT)-III is associated with a multitude of cellular processes involving membrane remodeling and abscission. The exact composition of ESCRT-III and the contribution of individual ESCRT-III family members to these diverse functions is unclear. Most of the currently available information about ESCRT-III was obtained with tagged, largely non-functional proteins, which may not correctly reflect the in vivo situation. Here, we performed a comprehensive biochemical analysis of ESCRT-III localization and composition in yeast under purely native conditions. Most of our findings are in line with the current concepts about ESCRT-III, but some findings are unexpected and call for adjustments to the model. In particular, our data suggest that the distinction between bona fide ESCRT-III components and ESCRT-III associated proteins is not justified. We detected a single complex containing all ESCRT-III members (except of Chm7) with Did2 as its main component. The classical core components were present in equimolar amounts. Our analysis of the impact of single deletions on the composition of ESCRT-III confirmed the central role of Snf7 for ESCRT-III assembly. For the other ESCRT-III family members predictions could be made about their role in ESCRT-III assembly. Furthermore, our cell fractionation points to a role of Vps20 at the endoplasmic reticulum.

scholarly journals Essential Role of AKT-1/Protein Kinase Bα in PTEN-Controlled Tumorigenesis

2002 ◽  
Vol 22 (11) ◽  
pp. 3842-3851 ◽  
Author(s):  
Bangyan Stiles ◽  
Valeriya Gilman ◽  
Natalya Khanzenzon ◽  
Ralf Lesche ◽  
Annie Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Survival ◽  
Essential Role ◽  
Es Cells ◽  
Familial Cancer ◽  
Embryonic Stem ◽  
Cellular Processes ◽  
Downstream Effectors

ABSTRACT PTEN is mutated at high frequency in many primary human cancers and several familial cancer predisposition disorders. Activation of AKT is a common event in tumors in which the PTEN gene has been inactivated. We previously showed that deletion of the murine Pten gene in embryonic stem (ES) cells led to increased phosphatidylinositol triphosphate (PIP3) accumulation, enhanced entry into S phase, and better cell survival. Since PIP3 controls multiple signaling molecules, it was not clear to what degree the observed phenotypes were due to deregulated AKT activity. In this study, we mutated Akt-1 in Pten −/− ES cells to directly assess the role of AKT-1 in PTEN-controlled cellular processes, such as cell proliferation, cell survival, and tumorigenesis in nude mice. We showed that AKT-1 is one of the major downstream effectors of PTEN in ES cells and that activation of AKT-1 is required for both the cell survival and cell proliferation phenotypes observed in Pten −/− ES cells. Deletion of Akt-1 partially reverses the aggressive growth of Pten −/− ES cells in vivo, suggesting that AKT-1 plays an essential role in PTEN-controlled tumorigenesis.

scholarly journals Topoisomerase II is regulated by translationally controlled tumor protein for cell survival during organ growth in Drosophila

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Dae-Wook Yang ◽  
Jung-Wan Mok ◽  
Stephanie B. Telerman ◽  
Robert Amson ◽  
Adam Telerman ◽  
...  
Keyword(s):  
Cell Survival ◽  
Topoisomerase Ii ◽  
Wing Disc ◽  
Organ Development ◽  
Translationally Controlled Tumor Protein ◽  
Protein Levels ◽  
Eye Disc ◽  
Mutual Regulation

AbstractRegulation of cell survival is critical for organ development. Translationally controlled tumor protein (TCTP) is a conserved protein family implicated in the control of cell survival during normal development and tumorigenesis. Previously, we have identified a human Topoisomerase II (TOP2) as a TCTP partner, but its role in vivo has been unknown. To determine the significance of this interaction, we examined their roles in developing Drosophila organs. Top2 RNAi in the wing disc leads to tissue reduction and caspase activation, indicating the essential role of Top2 for cell survival. Top2 RNAi in the eye disc also causes loss of eye and head tissues. Tctp RNAi enhances the phenotypes of Top2 RNAi. The depletion of Tctp reduces Top2 levels in the wing disc and vice versa. Wing size is reduced by Top2 overexpression, implying that proper regulation of Top2 level is important for normal organ development. The wing phenotype of Tctp RNAi is partially suppressed by Top2 overexpression. This study suggests that mutual regulation of Tctp and Top2 protein levels is critical for cell survival during organ development.

The role of hypoxia in endometrial cancer

2021 ◽  
Vol 22 ◽  
Author(s):  
Yarely M. Salinas-Vera ◽  
Dolores Gallardo-Rincón ◽  
Erika Ruíz-García ◽  
Macrina B. Silva-Cázares ◽  
Carmen Sol de la Peña-Cruz ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Targeted Therapies ◽  
Current Knowledge ◽  
Vasculogenic Mimicry ◽  
Cellular Processes ◽  
Corpus Uteri

: Endometrial cancer represents the most frequent neoplasia from the corpus uteri, and comprises the 14th leading cause of death in women worldwide. Risk factors that contribute to the disease include early menarche, late menopause, nulliparity, and menopausal hormone use, as well as hypertension and obesity comorbidities. The clinical effectiveness of chemotherapy is variable, suggesting that novel molecular targeted therapies against specific cellular processes associated with the maintenance of cancer cell survival and therapy resistance urged to ameliorate the rates of success in endometrial cancer treatment. In the course of tumor growth, cancer cells must adapt to decreased oxygen availability in the microenvironment by upregulation of hypoxia-inducible factors, which orchestrate the activation of a transcriptional program leading to cell survival. During this adaptative process, the hypoxic cancer cells may acquire invasive and metastatic properties as well as increased cell proliferation and resistance to chemotherapy, enhanced angiogenesis, vasculogenic mimicry, and maintenance of cancer cell stemness, which contribute to more aggressive cancer phenotypes. Several studies have shown that hypoxia-inducible factor 1 alpha (HIF-1α) protein is aberrantly overexpressed in many solid tumors from breast, prostate, ovarian, bladder, colon, brain, and pancreas. Thus, it has been considered an important therapeutic target. Here, we reviewed the current knowledge of the relevant roles of cellular hypoxia mechanisms and HIF-1α functions in diverse processes associated with endometrial cancer progression. In addition, we also summarize the role of microRNAs in the posttranscriptional regulation of protein-encoding genes involved in the hypoxia response in endometrial cancer. Finally, we pointed out the need for urgent targeted therapies to impair the cellular processes activated by hypoxia in the tumor microenvironment.

scholarly journals Autophagy is activated in the ovarian tissue of polycystic ovary syndrome

Reproduction ◽  
2018 ◽  
Vol 155 (1) ◽  
pp. 85-92 ◽  
Author(s):  
Da Li ◽  
Yue You ◽  
Fang-Fang Bi ◽  
Tie-Ning Zhang ◽  
Jiao Jiao ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Potential Role ◽  
Polycystic Ovary ◽  
Ovarian Tissue ◽  
Ovary Syndrome ◽  
Cellular Processes ◽  
Transmission Electron ◽  
Wide Range ◽  
Response To Stress

The importance of autophagy in polycystic ovary syndrome (PCOS)-related metabolic disorders is increasingly being recognized, but few studies have investigated the role of autophagy in PCOS. Here, transmission electron microscopy demonstrated that autophagy was enhanced in the ovarian tissue from both humans and rats with PCOS. Consistent with this, ovarian granulosa cells from PCOS rats showed increases in the autophagy marker protein light chain 3B (LC3B), whereas levels of the autophagy substrate SQSTM1/p62 were decreased. In addition, the ratio of LC3-II/LC3-I was markedly elevated in human PCOS ovarian tissue compared with normal ovarian tissue. Real-time PCR arrays indicated that 7 and 34 autophagy-related genes were down- and up-regulated in human PCOS , Signal-Net, and regression analysis suggested that there are a wide range of interactions among these 41 genes, and a potential network based on EGFR, ERBB2, FOXO1, MAPK1, NFKB1, IGF1, TP53 and MAPK9 may be responsible for autophagy activation in PCOS. Systematic functional analysis of 41 differential autophagy-related genes indicated that these genes are highly involved in specific cellular processes such as response to stress and stimulus, and are linked to four significant pathways, including the insulin, ERBB, mTOR signaling pathways and protein processing in the endoplasmic reticulum. This study provides evidence for a potential role of autophagy disorders in PCOS in which autophagy may be an important molecular event in the pathogenesis of PCOS.

Functional analysis of the SUMOylation pathway in Drosophila

2008 ◽  
Vol 36 (5) ◽  
pp. 868-873 ◽  
Author(s):  
Ana Talamillo ◽  
Jonatan Sánchez ◽  
Rosa Barrio
Keyword(s):  
Functional Analysis ◽  
Fine Tuning ◽  
Model Systems ◽  
Post Translational Modification ◽  
Reversible Process ◽  
Cellular Processes ◽  
Tuning Mechanism ◽  
Sumo Conjugation

SUMOylation, a reversible process used as a ‘fine-tuning’ mechanism to regulate the role of multiple proteins, is conserved throughout evolution. This post-translational modification affects several cellular processes by the modulation of subcellular localization, activity or stability of a variety of substrates. A growing number of proteins have been identified as targets for SUMOylation, although, for many of them, the role of SUMO conjugation on their function is unknown. The use of model systems might facilitate the study of SUMOylation implications in vivo. In the present paper, we have compiled what is known about SUMOylation in Drosophila melanogaster, where the use of genetics provides new insights on SUMOylation's biological roles.

scholarly journals Functional genetic encoding of sulfotyrosine in mammalian cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xinyuan He ◽  
Yan Chen ◽  
Daisy Guiza Beltran ◽  
Maia Kelly ◽  
Bin Ma ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Biochemical Characterization ◽  
Trna Synthetase ◽  
Functional Verification ◽  
Cellular Processes ◽  
Genetic Encoding ◽  
Efficient Expression

Abstract Protein tyrosine O-sulfation (PTS) plays a crucial role in extracellular biomolecular interactions that dictate various cellular processes. It also involves in the development of many human diseases. Regardless of recent progress, our current understanding of PTS is still in its infancy. To promote and facilitate relevant studies, a generally applicable method is needed to enable efficient expression of sulfoproteins with defined sulfation sites in live mammalian cells. Here we report the engineering, in vitro biochemical characterization, structural study, and in vivo functional verification of a tyrosyl-tRNA synthetase mutant for the genetic encoding of sulfotyrosine in mammalian cells. We further apply this chemical biology tool to cell-based studies on the role of a sulfation site in the activation of chemokine receptor CXCR4 by its ligand. Our work will not only facilitate cellular studies of PTS, but also paves the way for economical production of sulfated proteins as therapeutic agents in mammalian systems.

scholarly journals Dynamic measurement of cytosolic pH and [NO3−] uncovers the role of the vacuolar transporter AtCLCa in cytosolic pH homeostasis

2020 ◽  
Vol 117 (26) ◽  
pp. 15343-15353 ◽  
Author(s):  
Elsa Demes ◽  
Laetitia Besse ◽  
Paloma Cubero-Font ◽  
Béatrice Satiat-Jeunemaitre ◽  
Sébastien Thomine ◽  
...  
Keyword(s):  
Chloride Channel ◽  
Loss Of Function ◽  
Ion Transporters ◽  
Ph Homeostasis ◽  
Cytosolic Ph ◽  
Cellular Processes ◽  
Plasma Membrane Proton Pump ◽  
Cytosolic Acidification

Ion transporters are key players of cellular processes. The mechanistic properties of ion transporters have been well elucidated by biophysical methods. Meanwhile, the understanding of their exact functions in cellular homeostasis is limited by the difficulty of monitoring their activity in vivo. The development of biosensors to track subtle changes in intracellular parameters provides invaluable tools to tackle this challenging issue. AtCLCa (Arabidopsis thalianaChloride Channel a) is a vacuolar NO3−/H+exchanger regulating stomata aperture inA.thaliana. Here, we used a genetically encoded biosensor, ClopHensor, reporting the dynamics of cytosolic anion concentration and pH to monitor the activity of AtCLCa in vivo inArabidopsisguard cells. We first found that ClopHensor is not only a Cl−but also, an NO3−sensor. We were then able to quantify the variations of NO3−and pH in the cytosol. Our data showed that AtCLCa activity modifies cytosolic pH and NO3−. In an AtCLCa loss of function mutant, the cytosolic acidification triggered by extracellular NO3−and the recovery of pH upon treatment with fusicoccin (a fungal toxin that activates the plasma membrane proton pump) are impaired, demonstrating that the transport activity of this vacuolar exchanger has a profound impact on cytosolic homeostasis. This opens a perspective on the function of intracellular transporters of the Chloride Channel (CLC) family in eukaryotes: not only controlling the intraorganelle lumen but also, actively modifying cytosolic conditions.

scholarly journals The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins

2009 ◽  
Vol 186 (3) ◽  
pp. 355-362 ◽  
Author(s):  
Delphine Mérino ◽  
Maybelline Giam ◽  
Peter D. Hughes ◽  
Owen M. Siggs ◽  
Klaus Heger ◽  
...  
Keyword(s):  
Family Members ◽  
Binding Specificity ◽  
In Vitro Studies ◽  
Genetic Approach ◽  
Activation Model ◽  
Bh3 Domain ◽  
Indirect Activation

Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models.

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