Pro-inflammatory cytokines IL-6 and CCL2 suppress expression of circadian gene Period2 in mammary epithelial cells

Yu, Chun; Cheng, Kuo-Chih; Chen, Ling-Chih; Lin, Meng-Xuan; Chang, Yi‐Cheng; Hwang‐Verslues, Wendy W.

doi:10.1016/j.bbagrm.2018.09.003

Cited by 11 publications

(8 citation statements)

References 49 publications

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“…In addition to its circadian role, PER2 exhibits tumor suppressive functions as a transcriptional suppressor in many cancers [58][59][60] . Suppression of PER2 at both gene expression and protein levels facilitates tumor growth, invasion and cancer malignancy [60][61][62][63] . Since PER2 protein level oscillates and PER2 shuttles between nucleus and cytoplasm, its protein stability and subcellular localization may also determine its tumor suppression function.…”

Section: Discussionmentioning

confidence: 99%

“…Depending on the experiments, these PER2 cDNAs were sub-cloned into various tagged vectors including pcDNA3.0.HA (Thermo Fisher Scientific, Waltham, MA), 3XFLAG-CMV-7.1-2 (Sigma-Aldrich, St. Louis, MO) and pcDNA3.1.Myc.HisA/pcDNA3.1.Myc.HisC (Thermo Fisher Scientific) for transient expression in mammalian cells. pGL3.PER2.Luc promoter (− 948 ~ + 424) was generated as previously described 63 . All cloned and mutated genes were verified by sequencing.…”

Section: Methodsmentioning

confidence: 99%

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Differential effects of SUMO1 and SUMO2 on circadian protein PER2 stability and function

Chen

Hsieh

Tan

et al. 2021

Sci Rep

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Posttranslational modification (PTM) of core circadian clock proteins, including Period2 (PER2), is required for proper circadian regulation. PER2 function is regulated by casein kinase 1 (CK1)-mediated phosphorylation and ubiquitination but little is known about other PER2 PTMs or their interaction with PER2 phosphorylation. We found that PER2 can be SUMOylated by both SUMO1 and SUMO2; however, SUMO1 versus SUMO2 conjugation had different effects on PER2 turnover and transcriptional suppressor function. SUMO2 conjugation facilitated PER2 interaction with β-TrCP leading to PER2 proteasomal degradation. In contrast, SUMO1 conjugation, mediated by E3 SUMO-protein ligase RanBP2, enhanced CK1-mediated PER2S662 phosphorylation, inhibited PER2 degradation and increased PER2 transcriptional suppressor function. PER2 K736 was critical for both SUMO1- and SUMO2-conjugation. A PER2K736R mutation was sufficient to alter PER2 protein oscillation and reduce PER2-mediated transcriptional suppression. Together, our data revealed that SUMO1 versus SUMO2 conjugation acts as a determinant of PER2 stability and function and thereby affects the circadian regulatory system and the expression of clock-controlled genes.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Differential effects of SUMO1 and SUMO2 on circadian protein PER2 stability and function

Chen

Hsieh

Tan

et al. 2021

Sci Rep

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“…Per2 is also related to inflammation response, like myocardial inflammation [31] and dermatitis [32]. Previous research has demonstrated that Per2 expression was reduced in non-tumourigenic breast epithelial cells stimulated by IL-6 [33]. Further, immunoblotting analysis showed the Per2 protein expression was inhibited in LPS-treated rheumatoid arthritis synovial cells [34].…”

Section: Discussionmentioning

confidence: 99%

Per2 attenuates LPS-induced chondrocyte injury through the PTEN/PI3K/Akt signalling pathway

Zhao¹,

Ma²,

Dong³

et al. 2020

Bioscience Reports

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This research aimed to explore the role of period circadian clock 2 (Per2) in the evolution of osteoarthritis (OA) and the relevant mechanisms. Per2 messenger RNA (mRNA) and protein levels were markedly reduced in NHAC-kn cells treated with 5 µg/ml lipopolysaccharide (LPS) for 12 h. Then, pcDNA3.1-Per2 and si-Per2 were recruited to boost and reduce the expression of Per2, respectively. MTT assay, apoptosis analysis and enzyme-linked immunosorbent assay (ELISA) results showed that Per2 increased cell proliferation, while inhibited apoptosis and inflammation. Furthermore, the PTEN/PI3K/Akt signalling pathway was activated by Per2 overexpression; the CO-IP data confirmed that Per2 specifically bound to PTEN. Through employing IGF-1, a PI3K activator, we determined that Per2-mediated inflammation response in LPS-stimulated NHAC-kn cells through the PTEN/PI3K/Akt signalling pathway. In summary, the present study indicates that Per2 may serve as a novel therapeutic target through activating the PTEN/PI3K/Akt signalling pathway.

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“…22 Fisher Scientific) for transient expression in mammalian cells. pGL3.PER2.Luc promoter (-10 948~+424) was generated as previously described (Yu et al, 2018). All cloned and mutated genes 11…”

Section: Sumoylation Acts Upstream Of Per2 S662 Phosphorylation Whichmentioning

confidence: 99%

“…In addition to its circadian role, PER2 exhibits tumor suppressive functions in many cancers [17][18][19]. Suppression of PER2 at both gene expression and protein levels facilitates tumor growth, invasion and cancer malignancy [19][20][21][22]. Since PER2 protein level oscillates and PER2 shuttles between nucleus and cytoplasm, PTMs that affect PER2 stability and subcellular localization can determine both its circadian transcriptional suppression activity and tumor suppressor activity.…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of SUMO1/2 on Circadian Protein PER2 Stability and Function

Chen

Hsieh

Kuo

et al. 2019

Preprint

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Keywords: Period2/SUMO/phosphorylation/ubiquitination/circadian/post-translational modification 26,461 characters without space, excluding references and materials and methods. AbstractCircadian rhythm control by clock proteins, including Period 2 (PER2), is strongly impacted by posttranslational modifications (PTMs) controlling clock protein stability, localization and activity. PER2 function is regulated by casein kinase 1 (CK1)-mediated phosphorylation and ubiquitination but little is known about other PER2 PTMs. We found that PER2 can be SUMOylated by both SUMO1 and SUMO2; however, SUMO1 versus SUMO2 conjugation had dramatically different effects on PER2 turnover and subcellular localization. PER2-SUMO2 conjugation facilitated PER2 ubiquitination and degradation. In contrast, SUMO1 conjugation mediated by the E3 SUMO-protein ligase RanBP2 led to enhanced CK1-mediated PER2 S662 phosphorylation and also increased PER2 nuclear accumulation, chromatin association and suppression function. PER2 K736 was an important determinant of both SUMO1-and SUMO2-conjugation. A PER2 K736R mutation was sufficient to alter circadian periodicity, reduce PER2 interaction with β-TrCP or CRY1, decrease PER2 nuclear entry and abolish PER2-mediated transcriptional suppression of REV-ERBα, REV-ERBβ and RORγ.Together, our data revealed differential effects of SUMO isoforms on PER2 function and demonstrated the effect of SUMOylation on PER2 coordination of the circadian regulatory system.

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Pro-inflammatory cytokines IL-6 and CCL2 suppress expression of circadian gene Period2 in mammary epithelial cells

Cited by 11 publications

References 49 publications

Differential effects of SUMO1 and SUMO2 on circadian protein PER2 stability and function

Differential effects of SUMO1 and SUMO2 on circadian protein PER2 stability and function

Per2 attenuates LPS-induced chondrocyte injury through the PTEN/PI3K/Akt signalling pathway

Differential Effects of SUMO1/2 on Circadian Protein PER2 Stability and Function

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