bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2021‒04‒11
sixteen papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital
  1. The Role of Unfolded Protein Response in Human Intervertebral Disc Degeneration: Perk and IRE1-α as Two Potential Therapeutic Targets.
  2. Cyclin-dependent kinase inhibitors (CDKIs) and the DNA damage response: The link between signaling pathways and cancer.
  3. The Role of the Signaling Pathways Involved in the Effects of Hydrogen Sulfide on Endoplasmic Reticulum Stress.
  4. Early nucleolar responses differentiate mechanisms of cell death induced by oxaliplatin and cisplatin.
  5. Connections between endoplasmic reticulum stress-associated unfolded protein response, mitochondria, and autophagy in arsenic-induced carcinogenesis.
  6. Consumption of vitamin A-deficient diet elevates endoplasmic reticulum stress marker and suppresses high fructose-induced orexigenic gene expression in the brain of male Wistar rats.
  7. Diabetes Mellitus due to Toxic Misfolding of Proinsulin Variants.
  8. Oldest DNA from a Homo sapiens reveals surprisingly recent Neanderthal ancestry.
  9. DNA damage response and repair in osteosarcoma: Defects, regulation and therapeutic implications.
  10. Elucidation of the mechanism of NEFA-induced PERK-eIF2α signaling pathway regulation of lipid metabolism in bovine hepatocytes.
  11. Connecting TDP-43 Pathology with Neuropathy.
  12. Spatiotemporal coordination of Greatwall-Endos-PP2A promotes mitotic progression.
  13. Impact of Delaying Antiretroviral Treatment during Primary HIV Infection on Telomere Length.
  14. Astragalus Polysaccharides Protects Thapsigargin-induced Endoplasmic Reticulum Stress in HT29 Cells.
  15. Robust p53 Stabilization Is Dispensable for Its Activation and Tumor Suppressor Function.
  16. α-Syntrophin alleviates ER stress to maintain protein homeostasis during myoblast differentiation.
  1. Oxid Med Cell Longev. 2021 ;2021 6492879
    The Role of Unfolded Protein Response in Human Intervertebral Disc Degeneration: Perk and IRE1-α as Two Potential Therapeutic Targets.
    Tianyong Wen, Peng Xue, Jinwei Ying, Shi Cheng, Yue Liu, Dike Ruan.
      Inflammation plays a key role in intervertebral disc degeneration (IDD). The association between inflammation and endoplasmic reticulum (ER) stress has been observed in many diseases. However, whether ER stress plays an important role in IDD remains unclear. Therefore, this study is aimed at investigating the expression of ER stress in IDD and at exploring the underlying mechanisms of IDD, ER stress, and inflammation. The expression of ER stress was activated in nucleus pulposus cells from patients who had IDD (D-NPCs) compared with patients without IDD (N-NPCs); and both the proliferation and synthesis capacity were decreased by inducer tunicamycin (Tm) and proinflammatory cytokines. Pretreatment of NPCs with 4-phenyl butyric acid (4-PBA) prevented the inflammatory cytokine-induced upregulation of unfolded protein response- (UPR-) related proteins and recovered cell synthetic ability. Furthermore, proinflammatory cytokine treatment significantly upregulated the expression of inositol-requiring protein 1 (IRE1-α) and protein kinase RNA-like ER kinase (PERK), but not activating transcription factor 6 (ATF6). Finally, knockdown of IRE1-α and PERK also restored the biological activity of NPCs. Our findings identified that IRE1-α and PERK might be the potential targets for IDD treatment, which may help illustrate the underlying mechanism of ER stress in IDD.
    DOI:  https://doi.org/10.1155/2021/6492879
  2. DNA Repair (Amst). 2021 Mar 26. pii: S1568-7864(21)00059-8. [Epub ahead of print]102 103103
    Cyclin-dependent kinase inhibitors (CDKIs) and the DNA damage response: The link between signaling pathways and cancer.
    Jafar Amani, Nassim Gorjizadeh, Simin Younesi, Mojtaba Najafi, Arash M Ashrafi, Saeed Irian, Negar Gorjizadeh, Khalil Azizian.
      At the cellular level, DNA repair mechanisms are crucial in maintaining both genomic integrity and stability. DNA damage appears to be a central culprit in tumor onset and progression. Cyclin-dependent kinases (CDKs) and their regulatory partners coordinate the cell cycle progression. Aberrant CDK activity has been linked to a variety of cancers through deregulation of cell-cycle control. Besides DNA damaging agents and chromosome instability (CIN), disruptions in the levels of cell cycle regulators including cyclin-dependent kinase inhibitors (CDKIs) would result in unscheduled proliferation and cell division. The INK4 and Cip/Kip (CDK interacting protein/kinase inhibitor protein) family of CDKI proteins are involved in cell cycle regulation, transcription regulation, apoptosis, and cell migration. A thorough understanding of how these CDKIs regulate the DNA damage response through multiple signaling pathways may provide an opportunity to design efficient treatment strategies to inhibit carcinogenesis.
    Keywords:  Cell cycle; Cyclin-dependent kinase inhibitors; DNA damage response
    DOI:  https://doi.org/10.1016/j.dnarep.2021.103103
  3. Front Cell Dev Biol. 2021 ;9 646723
    The Role of the Signaling Pathways Involved in the Effects of Hydrogen Sulfide on Endoplasmic Reticulum Stress.
    Shizhen Zhao, Xinping Li, Ping Lu, Xiaotian Li, Mingfei Sun, Honggang Wang.
      Endoplasmic reticulum (ER) is a kind of organelle with multiple functions including protein synthesis, modification and folding, calcium storage, and lipid synthesis. Under stress conditions, ER homeostasis is disrupted, which is defined as ER stress (ERS). The accumulation of unfolded proteins in the ER triggers a stable signaling network named unfolded protein response (UPR). Hydrogen sulfide is an important signal molecule regulating various physiological and pathological processes. Recent studies have shown that H2S plays an important role in many diseases by affecting ERS, but its mechanism, especially the signaling pathways, is not fully understood. Therefore, in this review, we summarize the recent studies about the signaling pathways involved in the effects of H2S on ERS in diseases to provide theoretical reference for the related in-depth researches.
    Keywords:  disease treatment; endoplasmic reticulum stress; hydrogen sulfide; signaling pathway; unfolded protein response
    DOI:  https://doi.org/10.3389/fcell.2021.646723
  4. J Biol Chem. 2021 Apr 02. pii: S0021-9258(21)00419-1. [Epub ahead of print] 100633
    Early nucleolar responses differentiate mechanisms of cell death induced by oxaliplatin and cisplatin.
    Emily C Sutton, Victoria J DeRose.
      Recent reports provide evidence that the platinum chemotherapeutic oxaliplatin causes cell death via ribosome biogenesis stress, while cisplatin causes cell death via the DNA damage response (DDR). Underlying differences in mechanisms that might initiate disparate routes to cell death by these two broadly used platinum compounds have not yet been carefully explored. Additionally, prior studies had demonstrated that cisplatin can also inhibit ribosome biogenesis. Therefore, we sought to directly compare the initial influences of oxaliplatin and cisplatin on nucleolar processes and on the DDR. Using pulse-chase experiments, we found that at equivalent doses, oxaliplatin but not cisplatin significantly inhibited ribosomal RNA (rRNA) synthesis by Pol I, but neither compound affected rRNA processing. Inhibition of rRNA synthesis occurred as early as 90 minutes after oxaliplatin treatment in A549 cells, concurrent with the initial redistribution of the nucleolar protein nucleophosmin (NPM1). We observed that the nucleolar protein fibrillarin began to redistribute by 6 hours after oxaliplatin treatment, and formed canonical nucleolar caps by 24 hours. In cisplatin-treated cells, DNA damage, as measured by γH2AX immunofluorescence, was more extensive, whereas nucleolar organization was unaffected. Taken together, our results demonstrate that oxaliplatin causes early nucleolar disruption via inhibition of rRNA synthesis accompanied by NPM1 relocalization, and subsequently causes extensive nucleolar reorganization, while cisplatin causes early DNA damage without significant nucleolar disruption. These data support a model in which, at clinically relevant doses, cisplatin kills cells via the canonical DDR, and oxaliplatin kills cells via ribosome biogenesis stress, specifically via rapid inhibition of rRNA synthesis.
    Keywords:  DNA damage response; Nucleolus; anticancer drug; nucleolar stress; pre-rRNA; ribosomal RNA; ribosome biogenesis; stress response
    DOI:  https://doi.org/10.1016/j.jbc.2021.100633
  5. Semin Cancer Biol. 2021 Apr 06. pii: S1044-579X(21)00105-X. [Epub ahead of print]
    Connections between endoplasmic reticulum stress-associated unfolded protein response, mitochondria, and autophagy in arsenic-induced carcinogenesis.
    Priya Wadgaonkar, Fei Chen.
      Arsenic exposure in contaminated drinking water is a global health issue, as more than 200 million people are affected globally. Arsenic has been known to cause skin, liver, lung, bladder and prostate cancers. Accordingly, it has been categorized as a group I human carcinogen by the International Agency for Research on Cancer (IARC). Various natural and anthropogenic activities lead to the release of arsenic in the environment, contaminating air, water and food sources. Traditionally, genetic mutations have been the center of cancer research. However, emerging studies have now focused on the importance of epigenetics, metabolism and endoplasmic reticulum (ER) stress in cancer. Arsenic is highly capable of inducing stress in the cells via the generation of free radicals causing oxidative stress, epigenetic and genetic alterations, mitochondrial dysfunction, activation of intracellular signaling pathways, and impairment of autophagy and DNA repair systems. The cancer cells are able to utilize the unfolded protein response (UPR) to overcome these internal stresses in various stages of arsenic-induced carcinogenesis, from cancer growth to immune responses. The UPR is an evolutionarily conserved stress response that has both survival and apoptotic outcomes. PERK, IRE1α and ATF6α are the three ER stress sensors that are activated to maintain cellular proteostasis, which can also promote apoptosis on prolonged ER stress. The dual nature of UPR in different cancer types and stages is a challenge for researchers. We must investigate the role and the connections among ER stress-associated UPR, mitochondrial dysfunction and autophagy in arsenic malignancies to identify key targets for cancer prevention and therapeutics.
    Keywords:  Arsenic; Autophagy; Cancer stem cells; ER stress; UPR
    DOI:  https://doi.org/10.1016/j.semcancer.2021.04.004
  6. Nutr Neurosci. 2021 Apr 08. 1-9
    Consumption of vitamin A-deficient diet elevates endoplasmic reticulum stress marker and suppresses high fructose-induced orexigenic gene expression in the brain of male Wistar rats.
    Mooli Raja Gopal Reddy, Shanmugam Murugaiha Jeyakumar, Ayyalasomayajula Vajreswari.
      OBJECTIVE: Here, we assessed the impact of vitamin A deficiency (both alone and in combination with fructose) on the retinol status, phospholipids fatty acid composition and pathways associated with the endoplasmic reticulum (ER) stress and energy homeostasis of the brain. For this purpose, weanling male Wistar rats were divided into four groups consisting of 8 rats each, except 16 for the second group and they received one of the following diets; control, vitamin A-deficient (VAD), high fructose (HFr) and HFr with VAD for 16 weeks, except half of the VAD diet-fed rats, were shifted to HFr diet, after 8 weeks period.RESULTS: The retinol content of the whole brain remained comparable across the groups, despite a significant reduction in the plasma at the end of VAD diet feeding. However, it suppressed the HFr-induced neuropeptide Y and agouti-related peptide, while rescuing the leptin receptor mRNA. Among ER stress markers, CCAAT/Enhancer-binding protein homologues protein levels were elevated significantly in the VAD diet-fed group. Further, the long-chain polyunsaturated fatty acid levels showed an increase in the brain phospholipids across the experimental groups, compared to that of the control.
    CONCLUSION: Vitamin A deficiency causes ER stress in the brain, and retinol seems to play a regulatory role in the fructose-mediated transcriptional regulation of the genes involved in energy homeostasis.
    Keywords:  DHA; Lipids; cognition; diet; energy homeostasis; fatty acid; metabolic syndrome; neurodegeneration
    DOI:  https://doi.org/10.1080/1028415X.2021.1911048
  7. Mol Metab. 2021 Apr 03. pii: S2212-8778(21)00074-0. [Epub ahead of print] 101229
    Diabetes Mellitus due to Toxic Misfolding of Proinsulin Variants.
    Balamurugan Dhayalan, Deepak Chatterjee, Yen-Shan Chen, Michael A Weiss.
      Dominant mutations in the human insulin gene (INS) lead to pancreatic β-cell dysfunction and diabetes mellitus (DM) due to toxic misfolding of a mutant proinsulin. Analogous to a classical mouse model of monogenic DM ("Akita"), this syndrome highlights the susceptibility of β-cells to endoreticulum (ER) stress due to protein misfolding and aberrant aggregation. Diverse clinical mutations directly or indirectly perturb native disulfide pairing. Whereas most introduce or remove a cysteine (Cys; leading in either case to an unpaired thiol group), non-Cys-related mutations identify key determinants of folding efficiency. Studies of such mutations suggest that the hormone's evolution has been constrained not only by structure-function relationships, but also by the susceptibility of its single-chain precursor to impaired foldability. An intriguing hypothesis posits that INS overexpression in response to peripheral insulin resistance likewise leads to chronic ER stress and β-cell dysfunction in the natural history of non-syndromic Type 2 DM. Cryptic contributions of conserved residues to folding efficiency, as uncovered by rare genetic variants, define molecular links between biophysical principles and the emerging paradigm of Darwinian medicine: Biosynthesis of proinsulin at the edge of non-foldability provides a key determinant of "diabesity" as a pandemic disease of civilization.
    Keywords:  folding efficiency; hormone; human genetics; metabolism; protein folding
    DOI:  https://doi.org/10.1016/j.molmet.2021.101229
  8. Nature. 2021 Apr 07.
    Oldest DNA from a Homo sapiens reveals surprisingly recent Neanderthal ancestry.
    Ewen Callaway.
      
    Keywords:  Anthropology; Genomics; Palaeontology
    DOI:  https://doi.org/10.1038/d41586-021-00916-0
  9. DNA Repair (Amst). 2021 Mar 24. pii: S1568-7864(21)00061-6. [Epub ahead of print]102 103105
    DNA damage response and repair in osteosarcoma: Defects, regulation and therapeutic implications.
    Fatemeh Sadoughi, Parisa Maleki Dana, Zatollah Asemi, Bahman Yousefi.
      Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents which has the survival rate of 20% in its advanced stages. Osteosarcomas are mostly resistance to our common treatments. DNA damage response (DDR) is a specialized multistep process containing abundant proteins which are necessary for the survival of any cell and organism. DDR machinery detects a diversity of DNA lesions and inhibits the cell cycle progression if these lesions are not repairable. DDR is involved in aging, age-related diseases, and cancer. In recent years, DDR inhibitors have gained the attention of researches due to their potentials in offering novel therapeutic targets and improving the response of many cancers to either chemo- or radio-therapy. In this regard, we tried to gather a great body of evidence about the role of DDR ingredients in osteosarcoma's initiation/progression, prognosis, and treatment.
    Keywords:  DNA damage response; Malignancy; Osteosarcoma; Radio-residence
    DOI:  https://doi.org/10.1016/j.dnarep.2021.103105
  10. J Steroid Biochem Mol Biol. 2021 Apr 02. pii: S0960-0760(21)00086-8. [Epub ahead of print] 105893
    Elucidation of the mechanism of NEFA-induced PERK-eIF2α signaling pathway regulation of lipid metabolism in bovine hepatocytes.
    Yan Huang, Chenxu Zhao, Yezi Kong, Panpan Tan, Siqi Liu, Yaoquan Liu, Fangyuan Zeng, Yang Yuan, Baoyu Zhao, Jianguo Wang.
      During the periparturient transition period, negative energy balance (NEB) characterized by high concentrations of non-esterified fatty acids (NEFA) may cause fatty liver and ketosis in dairy cows. Previous studies have shown that the protein kinase R-like endoplasmic reticulum kinase (PERK) branch of the endoplasmic reticulum stress (ERS) response plays an important role in lipid metabolism in hepatocytes. This study, therefore, investigated the role of the PERK-branch in NEFA-induced fatty liver. Different concentrations of NEFA or GSK2656157 (a novel catalytic inhibitor of PERK) were used to treat hepatocytes isolated from calves. The NEFA treatment significantly increased the triacylglycerol (TG) content, the phosphorylation level of PERK and eukaryotic initiation factor 2α (eIF2α), and the abundance of glucose-regulated protein 78 (Grp78), C/EBP homologous protein (CHOP), sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FASN), peroxisome proliferator-activated receptor-α (PPARα), carnitine palmitoyltransferase 1A (CPT1A), apolipoprotein B (APOB), and the low-density lipoprotein receptor (LDLR). Compared with the 1.2 mM NEFA group, inhibition of PERK activity further increased the TG content in hepatocytes, the very-low-density lipoprotein (VLDL) content in the supernatant and the protein abundance of APOB while reducing the expression and nuclear levels of SREBP-1c and PPARα, as well as the expression of CPT1A and CPT2. In conclusion, the results showed that the NEFA-induced PERK-eIF2α signaling pathway promotes lipid synthesis, lipid oxidation, but inhibits the assembly and secretion of VLDL. Therefore, during the transition period, the activation of the PERK-eIF2α signaling pathway in the liver of dairy cows could defeat the acid-induced lipotoxicity and provide energy to alleviate NEB.
    Keywords:  Dairy cows; Lipid metabolism; Non-esterified fatty acids; Protein kinase R-like endoplasmic reticulum kinase
    DOI:  https://doi.org/10.1016/j.jsbmb.2021.105893
  11. Trends Neurosci. 2021 Apr 05. pii: S0166-2236(21)00040-0. [Epub ahead of print]
    Connecting TDP-43 Pathology with Neuropathy.
    Joseph R Klim, Greta Pintacuda, Leslie A Nash, Irune Guerra San Juan, Kevin Eggan.
      Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP, its encoding gene, are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we review established and emerging roles of TDP-43 and consider how its dysfunction impinges on RNA homeostasis in the nervous system, thereby contributing to neural degeneration. Notably, improper splicing of the axonal growth-associated factor STMN2 has recently been connected to TDP-43 dysfunction, providing a mechanistic link between TDP-43 proteinopathies and neuropathy. This review highlights how a deep understanding of the function of TDP-43 in the brain might be leveraged to develop new targeted therapies for several neurological disorders.
    Keywords:  RNA binding protein; SCG10; Stathmin2; amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD); motor neuron disease
    DOI:  https://doi.org/10.1016/j.tins.2021.02.008
  12. J Cell Biol. 2021 Jun 07. pii: e202008145. [Epub ahead of print]220(6):
    Spatiotemporal coordination of Greatwall-Endos-PP2A promotes mitotic progression.
    Myreille Larouche, David Kachaner, Peng Wang, Karine Normandin, Damien Garrido, Changfu Yao, Maxime Cormier, Kristen M Johansen, Jørgen Johansen, Vincent Archambault.
      Mitotic entry involves inhibition of protein phosphatase 2A bound to its B55/Tws regulatory subunit (PP2A-B55/Tws), which dephosphorylates substrates of mitotic kinases. This inhibition is induced when Greatwall phosphorylates Endos, turning it into an inhibitor of PP2A-Tws. How this mechanism operates spatiotemporally in the cell is incompletely understood. We previously reported that the nuclear export of Greatwall in prophase promotes mitotic progression. Here, we examine the importance of the localized activities of PP2A-Tws and Endos for mitotic regulation. We find that Tws shuttles through the nucleus via a conserved nuclear localization signal (NLS), but expression of Tws in the cytoplasm and not in the nucleus rescues the development of tws mutants. Moreover, we show that Endos must be in the cytoplasm before nuclear envelope breakdown (NEBD) to be efficiently phosphorylated by Greatwall and to bind and inhibit PP2A-Tws. Disrupting the cytoplasmic function of Endos before NEBD results in subsequent mitotic defects. Evidence suggests that this spatiotemporal regulation is conserved in humans.
    DOI:  https://doi.org/10.1083/jcb.202008145
  13. J Infect Dis. 2021 Apr 05. pii: jiab186. [Epub ahead of print]
    Impact of Delaying Antiretroviral Treatment during Primary HIV Infection on Telomere Length.
    Marieke Raffenberg, Tanja Engel, Isabella C Schoepf, Neeltje A Kootstra, Peter Reiss, Dominique L Braun, Christian W Thorball, Jacques Fellay, Roger D Kouyos, Bruno Ledergerber, Huldrych F Günthard, Philip E Tarr, .
      BACKGROUND: Telomere length (TL) shortens during aging, HIV-seroconversion and untreated chronic HIV infection. It is unknown whether early antiretroviral therapy (ART) start is associated with less TL shortening during primary HIV infection (PHI).METHODS: We measured TL in peripheral blood mononuclear cells by quantitative PCR in participants of the Zurich PHI Study with samples available for >6 years. We obtained uni-/multivariable estimates from mixed-effects models and evaluated the association of delaying ART start or interrupting ART with baseline and longitudinal TL.
    RESULTS: In 105 participants with PHI (median age 36 years, 9% women), median ART delay was 25, 42, and 60 days, respectively, in the 1 st (shortest), 2 nd, and 3 rd (longest) ART delay tertile. First ART delay tertile was associated with longer baseline TL (p for trend=0.034), and longer TL over 6 years, but only with continuous ART (p<0.001), not if ART was interrupted >12 months (p=0.408). In multivariable analysis, participants in the 2 nd and 3 rd ART delay tertile had 17.6% (5.4-29.7%; p=0.004) and 21.5% (9.4-33.5%; p<0.001) shorter TL, after adjustment for age, with limited effect modification by clinical variables.
    DISCUSSION: In PHI, delaying ART start for even a matter of weeks was associated with significant and sustained TL shortening.
    Keywords:  HIV infection; antiretroviral therapy; multivariable analysis; primary HIV infection; telomere length
    DOI:  https://doi.org/10.1093/infdis/jiab186
  14. Open Life Sci. 2019 Jan;14 494-501
    Astragalus Polysaccharides Protects Thapsigargin-induced Endoplasmic Reticulum Stress in HT29 Cells.
    Lie Zheng, Ya-Li Zhang, Xuan Chen, De-Liang Chen, Yan-Cheng Dai, Zhi-Peng Tang.
      Aim: This study investigates the effect of astragalus polysaccharides (APS) in protecting against thapsigargin-induced endoplasmic reticulum (ER) stress in HT29 cells by suppressing the PERK-eIF2a signaling pathway.Methods: HT29 cells were induced by thapsigargin for 12 hours, then treated with APS for 24 hours, and the gene expressions of GRP78, CHOP and eIF2a were quantified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The expression of GRP78, CHOP, PERK, p-PERK, eIF2a, and p-eIF2a were detected by Western blot.
    Results: The ER stress caused by thapsigargin strongly up-regulated the expression of GRP78 and CHOP in HT29 cells, which activated the PERK-eIF2a pathway. There was an increase in PERK phosphorylation, and induction of eIF2a in HT29 cells. Thapsigargin caused significant ER expansion in HT29 cells due to the 12-hour ER stress. Importantly, Astragalus polysaccharide significantly inhibited the phosphorylation of PERK and eIF2a, which reduced the mRNA levels of GRP78, CHOP, PERK and eIF2a, and inhibited the ER expansion in HT29 cells after 24 hours of treatment.
    Conclusion: The results indicate that APS reduces the expression of GRP78 and CHOP in HT29 cells, at least in part, by preventing the activation of the PERK-eIF2a signaling pathway.
    Keywords:  Astragalus polysaccharides; ER stress; HT29 cells; PERK-eIF2a signaling; Thapsigargin
    DOI:  https://doi.org/10.1515/biol-2019-0055
  15. Cancer Res. 2021 Feb 15. 81(4): 935-944
    Robust p53 Stabilization Is Dispensable for Its Activation and Tumor Suppressor Function.
    Ning Kon, Michael Churchill, Huan Li, Siddhartha Mukherjee, James J Manfredi, Wei Gu.
      p53 is a short-lived protein with low basal levels under normal homeostasis conditions. However, upon DNA damage, levels of p53 dramatically increase for its activation. Although robust stabilization of p53 serves as a "trademark" for DNA damage responses, the requirement for such dramatic protein stabilization in tumor suppression has not been well addressed. Here we generated a mutant p53KQ mouse where all the C-terminal domain lysine residues were mutated to glutamines (K to Q mutations at K367, K369, K370, K378, K379, K383, and K384) to mimic constitutive acetylation of the p53 C-terminus. Because of p53 activation, p53KQ/KQ mice were perinatal lethal, yet this lethality was averted in p53KQ/- mice, which displayed normal postnatal development. Nevertheless, p53KQ/- mice died prematurely due to anemia and hematopoiesis failure. Further analyses indicated that expression of the acetylation-mimicking p53 mutant in vivo induces activation of p53 targets in various tissues without obviously increasing p53 levels. In the well-established pancreatic ductal adenocarcinoma (PDAC) mouse model, expression of the acetylation-mimicking p53-mutant protein effectively suppressed K-Ras-induced PDAC development in the absence of robust p53 stabilization. Together, our results provide proof-of-principle evidence that p53-mediated transcriptional function and tumor suppression can be achieved independently of its robust stabilization and reveal an alternative approach to activate p53 function for therapeutic purposes. SIGNIFICANCE: Although robust p53 stabilization is critical for acute p53 responses such as DNA damage, this study underscores the important role of low basal p53 protein levels in p53 activation and tumor suppression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1804
  16. FEBS Lett. 2021 Apr 08.
    α-Syntrophin alleviates ER stress to maintain protein homeostasis during myoblast differentiation.
    Jae Yun Moon, Hye Sun Kim.
      We have previously shown evidence that α-syntrophin plays an important role in myoblast differentiation. In this study, we focused on abnormal myotube formation of the α-syntrophin-knockdown C2 cell line (SNKD). The overall amount of intracellular protein as well as muscle-specific proteins in SNKD cells were significantly lower than those in the control. Akt-mTOR signaling, an important pathway for protein synthesis and muscle hypertrophy, was downregulated. In addition, the levels of endoplasmic reticulum (ER) stress markers increased in SNKD cells. The decrease in intracellular protein synthesis and reduction of the myotube diameter in SNKD cells were restored by 4-phenylbutyric acid, a chemical chaperone, or overexpression of α-syntrophin. These results suggest a novel role for α-syntrophin in protein homeostasis during myoblast differentiation.
    Keywords:  Endoplasmic reticulum stress; Muscle differentiation; Protein homeostasis; Protein synthesis; α-Syntrophin
    DOI:  https://doi.org/10.1002/1873-3468.14088
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:19:42.