scholarly journals Differential Dose- and Tissue-Dependent Effects of foxo on Aging, Metabolic and Proteostatic Pathways

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3577
Author(s):  
Maria S. Manola ◽  
Sentiljana Gumeni ◽  
Ioannis P. Trougakos
Keyword(s):  
Accelerated Aging ◽  
Model Organisms ◽  
Dependent Manner ◽  
Forkhead Box ◽  
Age Related ◽  
Wide Range ◽  
Transgenic Lines ◽  
Ubiquitin Proteasome ◽  
Increased Sensitivity ◽  
Proteasome Pathway

Aging is the gradual deterioration of physiological functions that culminates in death. Several studies across a wide range of model organisms have revealed the involvement of FOXO (forkhead box, class O) transcription factors in orchestrating metabolic homeostasis, as well as in regulating longevity. To study possible dose- or tissue-dependent effects of sustained foxo overexpression, we utilized two different Drosophila transgenic lines expressing high and relatively low foxo levels and overexpressed foxo, either ubiquitously or in a tissue-specific manner. We found that ubiquitous foxo overexpression (OE) accelerated aging, induced the early onset of age-related phenotypes, increased sensitivity to thermal stress, and deregulated metabolic and proteostatic pathways; these phenotypes were more intense in transgenic flies expressing high levels of foxo. Interestingly, there is a defined dosage of foxo OE in muscles and cardiomyocytes that shifts energy resources into longevity pathways and thus ameliorates not only tissue but also organismal age-related defects. Further, we found that foxo OE stimulates in an Nrf2/cncC dependent-manner, counteracting proteostatic pathways, e.g., the ubiquitin-proteasome pathway, which is central in ameliorating the aberrant foxo OE-mediated toxicity. These findings highlight the differential dose- and tissue-dependent effects of foxo on aging, metabolic and proteostatic pathways, along with the foxo-Nrf2/cncC functional crosstalk.

scholarly journals Ubiquitin-dependent Degradation of p73 Is Inhibited by PML

2004 ◽  
Vol 199 (11) ◽  
pp. 1545-1557 ◽  
Author(s):  
Francesca Bernassola ◽  
Paolo Salomoni ◽  
Andrew Oberst ◽  
Charles J. Di Como ◽  
Michele Pagano ◽  
...  
Keyword(s):  
Nuclear Body ◽  
Promyelocytic Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Primary Cells ◽  
Tumor Suppressor P53 ◽  
Ubiquitin Proteasome Pathway ◽  
Mitogen Activated Protein ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin–proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML–nuclear body (NB)–dependent manner. p38 mitogen-activated protein kinase–mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml−/− primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression.

scholarly journals SOCS-1 Localizes to the Microtubule Organizing Complex-Associated 20S Proteasome

2004 ◽  
Vol 24 (20) ◽  
pp. 9092-9101 ◽  
Author(s):  
Bao Q. Vuong ◽  
Teresita L. Arenzana ◽  
Brian M. Showalter ◽  
Julie Losman ◽  
X. Peter Chen ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Sh2 Domain ◽  
Cytokine Signaling ◽  
20S Proteasome ◽  
Signaling Proteins ◽  
Dependent Manner ◽  
Data Link ◽  
Protein Levels ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

ABSTRACT The regulation of cytokine signaling is critical for controlling cellular proliferation and activation during an immune response. SOCS-1 is a potent inhibitor of Jak kinase activity and of signaling initiated by several cytokines. SOCS-1 protein levels are tightly regulated, and recent data suggest that SOCS-1 may regulate the protein levels of some signaling proteins by the ubiquitin proteasome pathway; however, the cellular mechanism by which SOCS-1 directs proteins for degradation is unknown. In this report, SOCS-1 is found to colocalize and biochemically copurify with the microtubule organizing complex (MTOC) and its associated 20S proteasome. The SOCS-1 SH2 domain is required for the localization of SOCS-1 to the MTOC. Overexpression of SOCS-1 targets Jak1 in an SH2-dependent manner to a perinuclear distribution resembling the MTOC-associated 20S proteasome. Analysis of MTOCs fractionated from SOCS-1-deficient cells demonstrates that SOCS-1 may function redundantly to regulate the localization of Jak1 to the MTOC. Nocodazole inhibits the protein turnover of SOCS-1, demonstrating that the minus-end transport of SOCS-1 to the MTOC-associated 20S proteasome is required to regulate SOCS-1 protein levels. These data link SOCS-1 directly with the proteasome pathway and suggest another function for the SH2 domain of SOCS-1 in the regulation of Jak/STAT signaling.

scholarly journals Cks1 is degraded via the ubiquitin-proteasome pathway in a cell cycle-dependent manner

2003 ◽  
Vol 8 (11) ◽  
pp. 889-896 ◽  
Author(s):  
Takayuki Hattori ◽  
Kyoko Kitagawa ◽  
Chiharu Uchida ◽  
Toshiaki Oda ◽  
Masatoshi Kitagawa
Keyword(s):  
Cell Cycle ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

scholarly journals Galactose-modified duocarmycin prodrugs as senolytics

2019 ◽  
Author(s):  
Ana Guerrero ◽  
Romain Guiho ◽  
Nicolás Herranz ◽  
Anthony Uren ◽  
Dominic J. Withers ◽  
...  
Keyword(s):  
Whole Body ◽  
Dependent Manner ◽  
Doxorubicin Treatment ◽  
Therapeutic Implications ◽  
Age Related ◽  
Wide Range ◽  
Selective Elimination ◽  
Elevated Activity ◽  
Stable Growth ◽  
Adamantinomatous Craniopharyngioma

SUMMARYSenescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β-galactosidase this has been exploited as a marker for senescence (senescence-associated β-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of β-catenin-positive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies.

scholarly journals The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51

PLoS Biology ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. e3001281
Author(s):  
Jung Mi Park ◽  
Seung Wook Yang ◽  
Wei Zhuang ◽  
Asim K. Bera ◽  
Yan Liu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Scaffolding Protein ◽  
Dependent Manner ◽  
Nonreceptor Tyrosine Kinase ◽  
Akt Activation ◽  
Fk506 Binding Protein ◽  
Human Cancers ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.

scholarly journals Proteasome-mediated degradation of collagen III by cortisol in amnion fibroblasts

2018 ◽  
Vol 60 (2) ◽  
pp. 45-54 ◽  
Author(s):  
Yabing Mi ◽  
Wangsheng Wang ◽  
Jiangwen Lu ◽  
Chuyue Zhang ◽  
Yawei Wang ◽  
...  
Keyword(s):  
Enzyme Inhibitor ◽  
Fetal Membranes ◽  
Protein Abundance ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Human Amnion ◽  
Collagen Iii ◽  
Transcription Inhibitor ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Rupture of fetal membranes (ROM) can initiate parturition at both term and preterm. Collagen III in the compact layer of the amnion contributes to the tensile strength of fetal membranes. However, the upstream signals triggering collagen III degradation remain mostly elusive. In this study, we investigated the role of cortisol regenerated by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in collagen III degradation in human amnion fibroblasts with an aim to seek novel targets for the prevention of preterm premature ROM (pPROM)-elicited preterm birth. Human amnion tissue and cultured amnion tissue explants and amnion fibroblasts were used to study the regulation of collagen III, which is composed of three identical 3α 1 chains (COL3A1), by cortisol. Cortisol decreased COL3A1 protein but not mRNA abundance in a concentration-dependent manner. Cortisone also decreased COL3A1 protein, which was blocked by 11β-HSD1 inhibition. The reduction in COL3A1 protein by cortisol was not affected by a transcription inhibitor but was further enhanced by a translation inhibitor. Autophagic pathway inhibitor chloroquine or siRNA-mediated knock-down of ATG7, an essential protein for autophagy, failed to block cortisol-induced reduction in COL3A1 protein abundance, whereas proteasome pathway inhibitors MG132 and bortezomib significantly attenuated cortisol-induced reduction in COL3A1 protein abundance. Moreover, cortisol increased COL3A1 ubiquitination and the reduction of COL3A1 protein by cortisol was blocked by PYR-41, a ubiquitin-activating enzyme inhibitor. Conclusively, cortisol regenerated in amnion fibroblasts may be associated with ROM at parturition by reducing collagen III protein abundance through a ubiquitin-proteasome pathway.

scholarly journals NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaozhen Zhang ◽  
Xing Huang ◽  
Jian Xu ◽  
Enliang Li ◽  
Mengyi Lao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Immunotherapy ◽  
Pancreatic Tumors ◽  
Binding Motif ◽  
Dependent Manner ◽  
Substantial Impact ◽  
Post Translational Modifications ◽  
Programmed Cell Death 1 ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

AbstractDespite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically “hot” pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.

scholarly journals Serum-dependent and independent regulation of PARP2

2018 ◽  
Author(s):  
Qizhi Sun ◽  
Mohamed I. Gatie ◽  
Gregory M. Kelly
Keyword(s):  
Cell Differentiation ◽  
Insoluble Fraction ◽  
Dependent Manner ◽  
Damage Repair ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Serum Dependent ◽  
T Cell Maturation ◽  
Serum Response

AbstractPARP2 belongs to a family of proteins involved in cell differentiation, DNA damage repair, cellular energy expenditure, chromatin modeling and cell differentiation. In addition to these overlapping functions with PARP1, PARP2 participates in spermatogenesis, T-cell maturation, extraembryonic endoderm formation and adipogenesis. The function(s) of PARP2 is far from complete, and the mechanism(s) by which the gene and protein are regulated are unknown. In this study, we found that two different mechanisms are used in vitro to regulate PARP2 levels. In the presence of serum, PARP2 is degraded through the ubiquitin-proteasome pathway, however, when serum is removed, PARP2 is rapidly sequestered into an SDS- and urea-insoluble fraction. This sequestration is relieved by serum in a dose-dependent manner, and again PARP2 is detected by immunoblotting. Furthermore, and despite the presence of a putative serum response element in the PARP2 gene, transcription is not affected by serum deprivation. These observations that PARP2 is tightly regulated by distinct pathways highlights the critical roles PARP2 plays under different physiological conditions.

scholarly journals BECN1 F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner

2022 ◽  
Author(s):  
Salwa Sebti ◽  
Zhongju Zou ◽  
Michael U Shiloh
Keyword(s):  
Skeletal Muscle ◽  
Model Organisms ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Multiple Model ◽  
Wild Type ◽  
Age Related ◽  
Organ Specific ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

Autophagy is necessary for lifespan extension in multiple model organisms and autophagy dysfunction impacts age-related phenotypes and diseases. Introduction of an F121A mutation into the essential autophagy protein BECN1 constitutively increases basal autophagy in young mice and reduces cardiac and renal age-related changes in longer-lived Becn1F121A mutant mice. However, both autophagic and lysosomal activity have been described to decline with age. Thus, whether autophagic flux is maintained during aging and whether it is enhanced in Becn1F121A mice is unknown. Here we demonstrate that old wild type mice maintained functional autophagic flux in heart, kidney and skeletal muscle but not liver, and old Becn1F121A mice had increased autophagic flux in those same organs compared to wild type. In parallel, Becn1F121A mice were not protected against age-associated hepatic phenotypes but demonstrated reduced skeletal muscle fiber atrophy. These findings identify an organ-specific role for the ability of autophagy to impact organ aging phenotypes.

The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner

2000 ◽  
Vol 113 (23) ◽  
pp. 4363-4371 ◽  
Author(s):  
J. Zhao ◽  
T. Tenev ◽  
L.M. Martins ◽  
J. Downward ◽  
N.R. Lemoine
Keyword(s):  
Cell Cycle ◽  
Proteasome Inhibitors ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Apoptosis Protein ◽  
Ubiquitin Proteasome ◽  
A Cell ◽  
Proteasome Pathway ◽  
Cycle Dependent

Survivin, a human inhibitor of apoptosis protein (IAP), plays an important role in both cell cycle regulation and inhibition of apoptosis. Survivin is expressed in cells during the G(2)/M phase of the cell cycle, followed by rapid decline of both mRNA and protein levels at the G(1) phase. It has been suggested that cell cycle-dependent expression of survivin is regulated at the transcriptional level. In this study we demonstrate involvement of the ubiquitin-proteasome pathway in post-translational regulation of survivin. Survivin is a short-lived protein with a half-life of about 30 minutes and proteasome inhibitors greatly stabilise survivin in vivo. Expression of the survivin gene under the control of the CMV promoter cannot block cell cycle-dependent degradation of the protein. Proteasome inhibitors can block survivin degradation during the G(1) phase and polyubiquitinated derivatives can be detected in vivo. Mutation of critical amino acid residues within the baculovirus IAP repeat (BIR) domain or truncation of the N terminus or the C terminus sensitises survivin to proteasome degradation. Together, these results indicate that the ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner and structural changes greatly destabilise the survivin protein.

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