The Steroid Hormone 20-Hydroxyecdysone Enhances Gene Transcription through the cAMP Response Element-binding Protein (CREB) Signaling Pathway

Jing, Yu-Pu; Wang, Di; Han, Xiangxin; Dong, Du-Juan; Wang, Jinxing; Zhao, Xiao‐Fan

doi:10.1074/jbc.m115.706028

Cited by 29 publications

(26 citation statements)

References 73 publications

(50 reference statements)

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“…We observed that a continuous 20E signal could inhibit PKA-mediated phosphorylation of silkworm BR-C, which is similar to the findings of 20E inhibition on PKC-mediated phosphorylation of the new isoform (BrZ7) of H. armigera BR-C (11). Notably, our data reveal that the cAMP/PKA signaling pathway was enhanced by 20E treatment at the early response stage, consistent with a previous report showing that the cAMP/PKA signaling pathway is enhanced by 20E in H. armigera (39). Nevertheless, the cAMP/PKA pathway was attenuated at the late-response stage after 20E application.…”

Section: Discussionsupporting

confidence: 92%

Protein kinase A-mediated phosphorylation of the Broad-Complex transcription factor in silkworm suppresses its transcriptional activity

Qian

Gang

Zhang

et al. 2017

Journal of Biological Chemistry

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The insect-specific transcription factor Broad-Complex (BR-C) is transcriptionally activated by the steroid 20-hydroxyecdysone (20E) and regulates the expression of many target genes involved in insect growth and development. However, although the transcriptional regulation of BR-C proteins has been well studied, how BR-C is regulated at post-transcription and -translation levels is poorly understood. To this end, using liquid chromatography-tandem mass spectrometry analysis, we identified residue Ser-186 as a phosphorylation site of BR-C in silkworm. Site-directed mutagenesis and treatment with specific kinase activators and inhibitors indicated that the Ser-186 residue in silkworm BR-C is phosphorylated by protein kinase A (PKA). Immunostaining assays disclosed that PKA-mediated phosphorylation of silkworm BR-C has no effect on its nuclear import. However, luciferase reporter analysis, electrophoretic mobility shift assays, and chromatin immunoprecipitation revealed that the PKA phosphorylation event suppresses the transcriptional activation of silkworm BR-C target genes and that this inhibition was caused by repression of BR-C binding to its DNA targets. Of note, both and experiments disclosed that a continuous 20E signal inhibits the PKA-mediated BR-C phosphorylation and also the cAMP/PKA pathway, indicating that 20E's inhibitory effect on PKA-mediated phosphorylation of silkworm BR-C contributes to maintaining BR-C transcriptional activity. In conclusion, our findings indicate that PKA-mediated phosphorylation inhibits silkworm BR-C activity by interfering with its binding to DNA and that 20E signaling relieves PKA-mediated phosphorylation of BR-C, thereby maintaining its transcriptional activity.

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Section: Discussionsupporting

confidence: 92%

Protein kinase A-mediated phosphorylation of the Broad-Complex transcription factor in silkworm suppresses its transcriptional activity

Qian

Gang

Zhang

et al. 2017

Journal of Biological Chemistry

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“…A schematic representation of the mechanism by which 20E regulates PKCδ expression and EcRB1 phosphorylation. (1) 20E via ErGPCR1 and ErGPCR2, Gαq, PLC, calcium ion, and CaMKII signaling triggers USP1 phosphorylation and acetylation to modulate formation of EcRB1/USP1 transcription complex to bind on EcRE for 20E pathway gene transcription based on our previous studies (16,36). (2) 20E rapidly up-regulates PKCδ expression via EcRB1 and USP1.…”

Section: Methodsmentioning

confidence: 90%

“…A previous study showed that USP phosphorylation is necessary for it interacting with EcRB1 in H. armigera (16). In addition, acetylation of USP1 is also necessary for it interacting with EcRB1 (36). 20E induces phosphorylation of cyclin-dependent kinase 10 to promote EcRB1/USP1 complex formation (21).…”

Section: E Up-regulates Pkcδ Expression To Promote Apoptosis Duringmentioning

confidence: 98%

Protein kinase C delta phosphorylates ecdysone receptor B1 to promote gene expression and apoptosis under 20-hydroxyecdysone regulation

Chen

Pan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The nuclear receptor EcRB1, which is activated by the insect steroid hormone 20-hydroxyecdysone (20E), is reportedly phosphorylated by a protein kinase after 20E induction. However, the protein kinase has not been identified, and the significance of EcRB1 phosphorylation is unclear. In this study, we identified a protein kinase C δ (PKCδ) isoform (the E isoform) that phosphorylates EcRB1 in the lepidopteran , a serious agricultural pest worldwide, to promote apoptotic gene expression and apoptosis during metamorphosis. Through activation of the EcRB1/USP1 transcription complex by 20E, expression was up-regulated in several tissues during the metamorphic stage. Knockdown of caused failure to transition from larvae to pupae, prevented tissues from undergoing programmed cell death (PCD), and down-regulated the expression of the transcription factor and the apoptosis executors and The threonine residue at position 1343 of PKCδ was phosphorylated and was critical for its proapoptotic function. Overexpression of the PKCδ catalytic domain was localized to the nuclei in HaEpi cells, which increased caspase-3 activity and apoptosis. PKCδ directly phosphorylated a threonine residue at position 468 in the amino acid sequence of EcRB1. The phosphorylation of EcRB1 was critical for its heterodimeric interaction with the USP1 protein and for binding to the ecdysone response element. The data suggested that 20E up-regulates PKCδ expression to regulate EcRB1 phosphorylation for EcRB1/USP1 transcription complex formation, apoptotic gene transcription, and apoptosis.

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“…However, this behavior was not observed for S. littoralis larvae fed on all the other DEHP conditions as their food consumption was on contrary increased, while their body mass remained similar to that of control larvae. In vertebrates, several deleterious effects of DEHP have been reported, on gut or digestive glands, with induction of tumors (Chen et al 2017), genotoxicity (Kitamoto et al, 2015), disruption of cholesterol homeostasis, deregulation of the inflammatory response, and acceleration of atherosclerosis (Zhao et al 2016). As a result, DEHP may have induced digestive problems to S. littoralis larvae such as malabsorption or altered digestion, which could have been compensated by increased food intake.…”

Section: Effect Of Dehp On Post-embryonic Developmentmentioning

confidence: 99%

Effects of DEHP on post-embryonic development, nuclear receptor expression, metabolite and ecdysteroid concentrations of the moth Spodoptera littoralis

et al. 2019

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Di (2-ethylhexyl) phthalate (DEHP) is recognized in vertebrates as an Endocrine Disrupting Chemical (EDC). DEHP can alter steroid hormones production, development, reproduction and behavior in vertebrates. Only few studies investigated DEHP effects on insects. However, some recent studies on aquatic insects showed that DEHP could also act as an EDC by interfering with the signaling pathways of ecdysteroids, the main hormones involved in the control of insect postembryonic development and physiology. The aim of the study was to investigate (1) the fate of DEHP within a terrestrial insect species by exposing larvae to food containing a wide range of DEHP concentrations and (2) the effects of this chemical on their post-embryonic development and metamorphosis, by using a multi-level approach. DEHP was shown to be present both in larvae and resulting stages, with higher concentrations in chrysalises and adults than in larvae. DEHP concentrations also decreased at the end of the last larval instar, suggesting the metabolic transformation or excretion of this chemical during this time. Only the two highest DEHP doses induced higher insect mortality, whereas low and intermediate concentrations increased larval food consumption without affecting body weight. Metabolic profiles showed that in control insects, the last three days before metamorphosis correspond to a metabolic transition, but with time-dependent changes in treated insects. Interestingly, DEHP treatments also alter both hemolymphatic ecdysteroid titers and expression levels of ecdysteroid response genes. These results confirm that DEHP can alter insect post-embryonic development and metamorphosis, by interfering with ecdysteroid pathways.

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The Steroid Hormone 20-Hydroxyecdysone Enhances Gene Transcription through the cAMP Response Element-binding Protein (CREB) Signaling Pathway

Cited by 29 publications

References 73 publications

Protein kinase A-mediated phosphorylation of the Broad-Complex transcription factor in silkworm suppresses its transcriptional activity

Protein kinase A-mediated phosphorylation of the Broad-Complex transcription factor in silkworm suppresses its transcriptional activity

Protein kinase C delta phosphorylates ecdysone receptor B1 to promote gene expression and apoptosis under 20-hydroxyecdysone regulation

Effects of DEHP on post-embryonic development, nuclear receptor expression, metabolite and ecdysteroid concentrations of the moth Spodoptera littoralis

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