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Dysfunction of circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulation of Aldh3a1 gene

ABSTRACT: Dysfunction of circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulation of Aldh3a1 gene

PROVIDER: PRJNA450537 | ENA |

REPOSITORIES: ENA

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Dysfunction of circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulation of Aldh3a1 gene

Project description:Disruption of circadian rhythms is implicated in increasing the risk of cancer development. The Period2 (Per2) gene is one of the major components of mammalian circadian clock, which plays a key role in controlling the circadian rhythms in physiology and behavior. PER2 also has tumor suppression function, but its role in the regulation of susceptibility to chemotherapeutic drugs remains unclear. In this study, we identified up-regulation of Aldehyde dehydrogenase 3a1 (Aldh3a1) gene in oncogenic transformed mouse embryo fibroblasts prepared from Per2-mutant (Per2m/m) mice, which were associated with the resistance against chemotherapeutic drugs. Co-expression of H-rasV12 and SV40 large T antigen induced malignant transformation of both wild-type and Per2m/m cells, but the cytotoxic effects of methotrexate, gemcitabine, etoposide, vincristine, and oxaliplatin were significantly alleviated in oncogenic transformed Per2m/m cells. Although introduction of oncogenes increased the expression of Aldh3a1 in both wild-type and Per2m/m cells, the levels of ALDH3A1 protein in oncogenic transformed Per2m/m cells were 10-fold higher than those in wild-type cells. Elevated ALDH3A1 levels in oncogenic transformed Per2m/m cells were sufficient to prevent chemotherapeutic drug-induced production of reactive oxygen species. Consequently, suppression of Aldh3a1 expression by siRNA relived chemoresistance of Per2m/m cells. These results suggest an uncovered role for PER2 in the development of multiple drug resistance and offers new therapeutic strategies for treatment of cancers.

2018-10-10 | GSE113242 | GEO

Mutation of the gene encoding the circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulating the Aldh3a1 gene.

Project description:Disruption of circadian rhythms has been implicated in an increased risk for cancer development. The Period2 (Per2) gene encodes one of the major components of the mammalian circadian clock, which plays a key role in controlling the circadian rhythms in physiology and behavior. PER2 has also been reported to suppress the malignant transformation of cells, but its role in the regulation of cancer susceptibility to chemotherapeutic drugs remains unclear. In this study, we found that oncogene-transformed embryonic fibroblasts prepared from Per2-mutant (Per2m/m ) mice, which are susceptible to both spontaneous and radiation-induced tumorigenesis, were resistant against common chemotherapeutic drugs and that this resistance is associated with up-regulation of the aldehyde dehydrogenase 3a1 (Aldh3a1) gene. Co-expression of the oncogenes H-rasV12 and SV40 large T-antigen induced malignant transformation of both WT and Per2m/m cells, but the cytotoxic effects of the chemotherapeutic agents methotrexate, gemcitabine, etoposide, vincristine, and oxaliplatin were significantly alleviated in the oncogene-transformed Per2m/m cells. Although introduction of the two oncogenes increased the expression of Aldh3a1 in both WT and Per2m/m cells, the ALDH3A1 protein levels in the Per2m/m cells were ?7-fold higher than in WT cells. The elevated ALDH3A1 levels in the oncogene-transformed Per2m/m cells were sufficient to prevent chemotherapeutic drug-induced accumulation of reactive oxygen species. Consequently, shRNA-mediated suppression of Aldh3a1 expression relieved the chemoresistance of the Per2m/m cells. These results suggest a role for mutated PER2 in the development of multiple drug resistance and may inform therapeutic strategies for cancer management.

| S-EPMC6333901 | biostudies-literature

Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids

Project description:Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids

| PRJNA751487 | ENA

The role of core circadian component BMAL1 or CLOCK in human bone marrow mesenchymal stem cells osteogenic capacity

Project description:To elucidate how the core circadian component BMAL1 and clock regulate the osteogenic capacity of human bone marrow MSCs, RNA-seq was performed to study the impact of diminishing core component BMAL1 or CLOCK in MSCs by lentiviruses.

2022-07-26 | GSE208729 | GEO

Elevated PAF1-RAD52 Axis Confers Chemoresistance to Human Cancers

Project description:To identify a common protein that interacts with PAF1 in ovarian cancer, lung Cancer, and pancreatic cancer to mediate chemoresistance.

2024-01-26 | PXD039281 | Pride

Interactome of the circadian clock protein PERIOD2 in human U2OS osteosarcoma cells after the resetting of the circadian clock

Project description:Circadian rhythms are a series of endogenous autonomous 24-hour oscillations generated by the circadian clock. At the molecular level, the circadian clock is generated by a transcription-translation feedback loop, where BMAL1 and CLOCK transcription factors of the positive arm activate the expression of CRYPTOCHROME and PERIOD (PER) genes of the negative arm as well as the circadian clock-regulated genes. In this project, we aimed at finding the interactome of PER2 protein in human U2OS osteosarcoma cell line using proximity-dependent biotin identification (BioID) technique. U2OS clones overexpressing PER2-BioID2 or BioID2 were treated with dexamethasone in order to reset the circadian rhythm, and cells were then incubated in biotin-containing media for 12 hours to label the proteins in close proximity of PER2-BioID2. Samples were collected after 36 and 48 hours of the resetting to identify the labeled proteins by mass spectrometry. In addition to known interactors such as CRY1 and CRY2, many novel interactors were identified. In summary, we obtained a network of PER2 interactome and confirmed some of the novel interactions using classical the co-immunoprecipitation method.

2022-04-22 | PXD025179 | Pride

Mammalian PERIOD2 regulates H2A.Z incorporation into chromatin to orchestrate circadian negative feedback [Mnase-Seq]

Project description:We report the interdependance of PERIOD and H2A.Z to orchestrated the circadian negative feedback. H2A.Z is required for the circadian rhythm, it allows the binding of Bmal1 and PERIOD2 to the chromatin. And reciprocally, PERIOD2 aid H2A.Z deposition by interacting with the specific chaperone YL1.

2022-02-17 | GSE153936 | GEO

Mammalian PERIOD2 regulates H2A.Z incorporation into chromatin to orchestrate circadian negative feedback [Mnase-seq]

2022-02-17 | GSE190862 | GEO

Mammalian PERIOD2 regulates H2A.Z incorporation into chromatin to orchestrate circadian negative feedback [RNA-Seq]

2022-02-17 | GSE153937 | GEO

SKIP Is a Component of the Spliceosome Linking Alternative Splicing and the Circadian Clock in Arabidopsis

Project description:Circadian clocks generate endogenous rhythms in most organisms from cyanobacteria to humans and facilitate entrainment to environmental diurnal cycles, thus conferring a fitness advantage. Both transcriptional and posttranslational mechanisms are prominent in the basic network architecture of circadian systems. Posttranscriptional regulation, including mRNA processing, is emerging as a critical step for the clock function. However, little is known about the molecular mechanisms linking RNA metabolism to the circadian clock network. Here we report that a conserved SNW/SKIP domain protein, SKIP, a splicing factor and component of the spliceosome, is involved in the posttranscriptional regulation of circadian clock genes in Arabidopsis. Mutation in SKIP lengthens the circadian period in a temperature sensitive manner, affects light input and the sensitivity of light resetting to the clock. SKIP physically interacts with the spliceosomal splicing factor SR45 and associates with the pre-mRNA of clock genes, such as PRR7 and PRR9, and is necessary for the regulation of their alternative splicing and mRNA maturation. Genome-wide investigations reveal that SKIP functions in regulating alternative splicing of many genes, presumably through modulating recognition or cleavage of 5' and 3' splicing site. Our study addresses a fundamental question on how the mRNA splicing machinery contributes to circadian clock functions at a posttranscriptional level. Our findings revealed that AtSKIP is a splicing factor and a component of spliceosome. To further investigate effects of mutation in SKIP on the genome-wide changes of alternative splicing, we performed ultra-highthroughput RNA sequencing, using 10-day old seedlings. Two biological replicates for both wild type (Col-0) and skip-2 were designed.

2012-12-13 | E-GEOD-32216 | biostudies-arrayexpress

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