Browse
Submit Data
Databases
API
Help

Dataset Information

8 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Riboflavin transporter SLC52A1, a target of p53, suppresses cellular senescence by activating mitochondrial complex II.

ABSTRACT: Cellular senescence is a state of permanent proliferative arrest induced by a variety of stresses, such as DNA damage. The transcriptional activity of p53 has been known to be essential for senescence induction. It remains unknown, however, whether among the downstream genes of p53, there is a gene that has antisenescence function. Our recent studies have indicated that the expression of SLC52A1 (also known as GPR172B/RFVT1), a riboflavin transporter, is up-regulated specifically in senescent cells depending on p53, but the relationship between senescence and SLC52A1 or riboflavin has not been described. Here, we examined the role of SLC52A1 in senescence. We found that knockdown of SLC52A1 promoted senescence phenotypes induced by DNA damage in tumor and normal cells. The senescence suppressive action of SLC52A1 was dependent on its riboflavin transport activity. Furthermore, elevation of intracellular riboflavin led to activation of mitochondrial membrane potential (MMP) mediated by the mitochondrial electron transport chain complex II. Finally, the SLC52A1-dependent activation of MMP inhibited the AMPK-p53 pathway, a central mediator of mitochondria dysfunction-related senescence. These results suggest that SLC52A1 contributes to suppress senescence through the uptake of riboflavin and acts downstream of p53 as a negative feedback mechanism to limit aberrant senescence induction.

SUBMITTER: Nagano T

PROVIDER: S-EPMC8693961 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence.

Project description:Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the p19(Arf)-p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the p19(Arf)-p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19(Arf)-p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy.

| S-EPMC2928066 | biostudies-literature

Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence.

Project description:Dysfunctional telomeres induce p53-dependent cellular senescence and apoptosis, but it is not known which function is more important for tumour suppression in vivo. We used the p53 ( R172P ) knock-in mouse, which is unable to induce apoptosis but retains intact cell-cycle arrest and cellular senescence pathways, to show that spontaneous tumorigenesis is potently repressed in Terc -/- p53 ( R172P ) mice. Tumour suppression is accompanied by global induction of p53, p21 and the senescence marker senescence-associated-beta-galactosidase. By contrast, cellular senescence was unable to suppress chemically induced skin carcinomas. These results indicate that suppression of spontaneous tumorigenesis by dysfunctional telomeres requires the activation of the p53-dependent cellular senescence pathway.

| S-EPMC1866197 | biostudies-other

Paradoxical suppression of cellular senescence by p53.

Project description:The tumor suppressor p53 is a canonical inducer of cellular senescence (irreversible loss of proliferative potential and senescent morphology). p53 can also cause reversible arrest without senescent morphology, which has usually been interpreted as failure of p53 to induce senescence. Here we demonstrate that p53-induced quiescence actually results from suppression of senescence by p53. In previous studies, suppression of senescence by p53 was masked by p53-induced cell cycle arrest. Here, we separated these two activities by inducing senescence through overexpression of p21 and then testing the effect of p53 on senescence. We found that in p21-arrested cells, p53 converted senescence into quiescence. Suppression of senescence by p53 required its transactivation function. Like rapamycin, which is known to suppress senescence, p53 inhibited the mTOR pathway. We suggest that, while inducing cell cycle arrest, p53 may simultaneously suppress the senescence program, thus causing quiescence and that suppression of senescence and induction of cell cycle arrest are distinct functions of p53. Thus, in spite of its ability to induce cell cycle arrest, p53 can act as a suppressor of cellular senescence.

| S-EPMC2906905 | biostudies-literature

Mitochondrial peptides modulate mitochondrial function during cellular senescence.

Project description:Cellular senescence is a complex cell fate response that is thought to underlie several age-related pathologies. Despite a loss of proliferative potential, senescent cells are metabolically active and produce energy-consuming effectors, including senescence-associated secretory phenotypes (SASPs). Mitochondria play crucial roles in energy production and cellular signaling, but the key features of mitochondrial physiology and particularly of mitochondria-derived peptides (MDPs), remain underexplored in senescence responses. Here, we used primary human fibroblasts made senescent by replicative exhaustion, doxorubicin or hydrogen peroxide treatment, and examined the number of mitochondria and the levels of mitochondrial respiration, mitochondrial DNA methylation and the mitochondria-encoded peptides humanin, MOTS-c, SHLP2 and SHLP6. Senescent cells showed increased numbers of mitochondria and higher levels of mitochondrial respiration, variable changes in mitochondrial DNA methylation, and elevated levels of humanin and MOTS-c. Humanin and MOTS-c administration modestly increased mitochondrial respiration and selected components of the SASP in doxorubicin-induced senescent cells partially via JAK pathway. Targeting metabolism in senescence cells is an important strategy to reduce SASP production for eliminating the deleterious effects of senescence. These results provide insight into the role of MDPs in mitochondrial energetics and the production of SASP components by senescent cells.

| S-EPMC6046248 | biostudies-other

Serpine 1 induces alveolar type II cell senescence through activating p53-p21-Rb pathway in fibrotic lung disease.

Project description:Senescence of alveolar type 2 (ATII) cells, progenitors of the alveolar epithelium, is implicated in the pathogeneses of idiopathic pulmonary fibrosis (IPF), an aging-related progressive fatal lung disorder with unknown etiology. The mechanism underlying ATII cell senescence in fibrotic lung diseases, however, remains poorly understood. In this study, we report that ATII cells in IPF lungs express higher levels of serpine 1, also known as plasminogen activator inhibitor 1 (PAI-1), and cell senescence markers p21 and p16, compared to ATII cells in control lungs. Silencing PAI-1 or inhibition of PAI-1 activity in cultured rat ATII (L2) cells leads to decreases in p53 serine 18 phosphorylation (p53S18P ), p53 and p21 protein expressions; an increase in retinoblastoma protein phosphorylation (ppRb); and a reduction in the sensitivity to bleomycin- and doxorubicin-induced senescence. Silencing p53, on the other hand, abrogates PAI-1 protein-stimulated p21 expression and cell senescence. In vivo studies, using ATII cell-specific PAI-1 conditional knockout mouse model generated recently in this laboratory, further support the role of PAI-1 in the activation of p53-p21-Rb cell cycle repression pathway, ATII cell senescence, and lung fibrosis induced by bleomycin. This study reveals a novel function of PAI-1 in regulation of cell cycle and suggests that elevation of PAI-1 contributes importantly to ATII cell senescence in fibrotic lung diseases.

| S-EPMC5595683 | biostudies-literature

Mitochondrial and Peroxisomal Alterations Contribute to Energy Dysmetabolism in Riboflavin Transporter Deficiency.

Project description:Riboflavin transporter deficiency (RTD) is a childhood-onset neurodegenerative disorder characterized by progressive pontobulbar palsy, sensory and motor neuron degeneration, sensorineural hearing loss, and optic atrophy. As riboflavin (RF) is the precursor of FAD and FMN, we hypothesize that both mitochondrial and peroxisomal energy metabolism pathways involving flavoproteins could be directly affected in RTD, thus impacting cellular redox status. In the present work, we used induced pluripotent stem cells (iPSCs) from RTD patients to investigate morphofunctional features, focusing on mitochondrial and peroxisomal compartments. Using this model, we document the following RTD-associated alterations: (i) abnormal colony-forming ability and loss of cell-cell contacts, revealed by light, electron, and confocal microscopy, using tight junction marker ZO-1; (ii) mitochondrial ultrastructural abnormalities, involving shape, number, and intracellular distribution of the organelles, as assessed by focused ion beam/scanning electron microscopy (FIB/SEM); (iii) redox imbalance, with high levels of superoxide anion, as assessed by MitoSOX assay accompanied by abnormal mitochondrial polarization state, evaluated by JC-1 staining; (iv) altered immunofluorescence expression of antioxidant systems, namely, glutathione, superoxide dismutase 1 and 2, and catalase, as assessed by quantitatively evaluated confocal microscopy; and (v) peroxisomal downregulation, as demonstrated by levels and distribution of fatty acyl ?-oxidation enzymes. RF supplementation results in amelioration of cell phenotype and rescue of redox status, which was associated to improved ultrastructural features of mitochondria, thus strongly supporting patient treatment with RF, to restore mitochondrial- and peroxisomal-related aspects of energy dysmetabolism and oxidative stress in RTD syndrome.

| S-EPMC7443020 | biostudies-literature

Role of p53 in the Regulation of Cellular Senescence.

Project description:The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent cell-cycle arrest that has a crucial role in aging, and it also represents a robust physiological antitumor response, which counteracts oncogenic insults. In addition, senescent cells can also negatively impact the surrounding tissue microenvironment and the neighboring cells by secreting pro-inflammatory cytokines, ultimately triggering tissue dysfunction and/or unfavorable outcomes. This review focuses on the characteristics of senescence and on the recent advances in the contribution of p53 to cellular senescence. Moreover, we also discuss the p53-mediated regulation of several pathophysiological microenvironments that could be associated with senescence and its development.

| S-EPMC7175209 | biostudies-literature

YPEL3, a p53-regulated gene that induces cellular senescence.

Project description:Cellular senescence, the limited ability of cultured normal cells to divide, can result from cellular damage triggered through oncogene activation (premature senescence) or the loss of telomeres following successive rounds of DNA replication (replicative senescence). Although both processes require a functional p53 signaling pathway, relevant downstream p53 targets have been difficult to identify. Discovery of senescence activators is important because induction of tumor cell senescence may represent a therapeutic approach for the treatment of cancer. In microarray studies in which p53 was reactivated in MCF7 cells, we discovered that Yippee-like-3 (YPEL3), a member of a recently discovered family of putative zinc finger motif coding genes consisting of YPEL1-5, is a p53-regulated gene. YPEL3 expression induced by DNA damage leads to p53 recruitment to a cis-acting DNA response element located near the human YPEL3 promoter. Physiologic induction of YPEL3 results in a substantial decrease in cell viability associated with an increase in cellular senescence. Through the use of RNAi and H-ras induction of cellular senescence, we show that YPEL3 activates cellular senescence downstream of p53. Consistent with its growth suppressive activity, YPEL3 gene expression is repressed in ovarian tumor samples. One mechanism of YPEL3 downregulation in ovarian tumor cell lines seems to be hypermethylation of a CpG island upstream of the YPEL3 promoter. We believe these findings point to YPEL3 being a novel tumor suppressor, which upon induction triggers a permanent growth arrest in human tumor and normal cells.

| S-EPMC2862112 | biostudies-literature

Regulation of cellular senescence via the FOXO4-p53 axis.

Project description:Forkhead box O (FOXO) and p53 proteins are transcription factors that regulate diverse signalling pathways to control cell cycle, apoptosis and metabolism. In the last decade both FOXO and p53 have been identified as key players in aging, and their misregulation is linked to numerous diseases including cancers. However, many of the underlying molecular mechanisms remain mysterious, including regulation of ageing by FOXOs and p53. Several activities appear to be shared between FOXOs and p53, including their central role in the regulation of cellular senescence. In this review, we will focus on the recent advances on the link between FOXOs and p53, with a particular focus on the FOXO4-p53 axis and the role of FOXO4/p53 in cellular senescence. Moreover, we discuss potential strategies for targeting the FOXO4-p53 interaction to modulate cellular senescence as a drug target in treatment of aging-related diseases and morbidity.

| S-EPMC6033032 | biostudies-literature

FBXW7 inactivation induces cellular senescence via accumulation of p53.

Project description:F-box and WD repeat domain containing 7 (FBXW7) acts as a substrate receptor of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase and plays crucial roles in the regulation of several cellular processes, including cell growth, division, and differentiation, by targeting diverse key regulators for degradation. However, its role in regulating cellular senescence remains elusive. Here, we found that FBXW7 inactivation by siRNA-based knockdown or CRISPR/Cas9-based knockout induced significant cellular senescence in p53 wild-type cells, but not in p53 mutant or null cells, along with activation of both the p53/p21 and p16INK4a/Rb pathways. Simultaneous p53 inactivation abrogated senescence and cell growth arrest induced by FBXW7 deficiency as well as the alteration of both the p53/p21 and p16INK4a/Rb pathways. Moreover, Fbxw7 deletion accelerated replicative senescence of primary mouse embryonic fibroblasts in a p53-dependent manner. In addition, FBXW7 deletion induced the senescence-associated secretory phenotype to trigger secondary senescence. Importantly, in a radiation-induced senescence mouse model, simultaneous deletion of p53 rescued accelerated senescence and aging caused by Fbxw7 loss. Thus, our study uncovered a novel role for FBXW7 in the regulation of senescence by eliminating p53.

| S-EPMC9475035 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data