scholarly journals Human nuclear pregnane X receptor cross-talk with CREB to repress cAMP activation of the glucose-6-phosphatase gene

2007 ◽  
Vol 407 (3) ◽  
pp. 373-381 ◽  
Author(s):  
Susumu Kodama ◽  
Rick Moore ◽  
Yukio Yamamoto ◽  
Masahiko Negishi
Keyword(s):  
Knockout Mice ◽  
Glutathione Transferase ◽  
Pregnane X Receptor ◽  
Camp Response Element Binding ◽  
Wild Type ◽  
Huh7 Cells ◽  
Genes Encoding ◽  
Element Binding Protein ◽  
Promoter Construct ◽  
Dependent Protein

The nuclear PXR (pregnane X receptor) was originally characterized as a key transcription factor that activated hepatic genes encoding drug-metabolizing enzymes. We have now demonstrated that PXR also represses glucagon-activated transcription of the G6Pase (glucose-6-phosphatase) gene by directly binding to CREB [CRE (cAMP-response element)-binding protein]. Adenoviral-mediated expression of human PXR (hPXR) and its activation by rifampicin strongly repressed cAMP-dependent induction of the endogenous G6Pase gene in Huh7 cells. Using the −259 bp G6Pase promoter construct in cell-based transcription assays, repression by hPXR of PKA (cAMP-dependent protein kinase)-mediated promoter activation was delineated to CRE sites. GST (glutathione transferase) pull-down and immunoprecipitation assays were employed to show that PXR binds directly to CREB, while gel-shift assays were used to demonstrate that this binding prevents CREB interaction with the CRE. These results are consistent with the hypothesis that PXR represses the transcription of the G6Pase gene by inhibiting the DNA-binding ability of CREB. In support of this hypothesis, treatment with the mouse PXR activator PCN (pregnenolone 16α-carbonitrile) repressed cAMP-dependent induction of the G6Pase gene in primary hepatocytes prepared from wild-type, but not from PXR-knockout, mice, and also in the liver of fasting wild-type, but not PXR-knockout, mice. Moreover, ChIP (chromatin immunoprecipitation) assays were performed to show a decreased CREB binding to the G6Pase promoter in fasting wild-type mice after PCN treatment. Thus drug activation of PXR can repress the transcriptional activity of CREB, down-regulating gluconeogenesis.

Scutellarin Mitigates Cancer-Induced Bone Pain by Suppressing CaMKII/CREB Pathway in Rat Models

2019 ◽  
Vol 17 (3) ◽  
pp. 249-253
Author(s):  
Liu Chenglong ◽  
Liu Haihua ◽  
Zhang Fei ◽  
Zheng Jie ◽  
Wei Fang
Keyword(s):  
Protein Kinase ◽  
Bone Pain ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Camp Response Element ◽  
Dependent Protein Kinase ◽  
Response Element ◽  
Protein Kinase Ii ◽  
Element Binding Protein ◽  
Dependent Protein

Cancer-induced bone pain is a severe and complex pain caused by metastases to bone in cancer patients. The aim of this study was to investigate the analgesic effect of scutellarin on cancer-induced bone pain in rat models by intrathecal injection of Walker 256 carcinoma cells. Mechanical allodynia was determined by paw withdrawal threshold in response to mechanical stimulus, and thermal hyperalgesia was indicated by paw withdrawal latency in response to noxious thermal stimulus. The paw withdrawal threshold and paw withdrawal latencies were significantly decreased after inoculation of tumor cells, whereas administration of scutellarin significantly attenuated tumor cell inoculation-induced mechanical and heat hyperalgesia. Tumor cell inoculation-induced tumor growth was also significantly abrogated by scutellarin. Ca2+/calmodulin-dependent protein kinase II is a multifunctional kinase with up-regulated activity in bone pain models. The activation of Ca2+/calmodulin-dependent protein kinase II triggers phosphorylation of cAMP-response element binding protein. Scutellarin significantly reduced the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein in cancer-induced bone pain rats. Collectively, our study demonstrated that scutellarin attenuated tumor cell inoculation-induced bone pain by down-regulating the expression of phosphorylated-Ca2+/calmodulin-dependent protein kinase II and phosphorylated-cAMP-response element binding protein. The suppressive effect of scutellarin on phosphorylated-Ca2+/calmodulin-dependent protein kinase II/phosphorylated-cAMP-response element binding protein activation may serve as a novel therapeutic strategy for CIBP management.

scholarly journals Protocatechuic Aldehyde Inhibits α-MSH-Induced Melanogenesis in B16F10 Melanoma Cells via PKA/CREB–Associated MITF Downregulation

2021 ◽  
Vol 22 (8) ◽  
pp. 3861
Author(s):  
Seok-Chun Ko ◽  
Seung-Hong Lee
Keyword(s):  
Molecular Mechanisms ◽  
3D Structure ◽  
Camp Response Element Binding ◽  
Melanoma Cells ◽  
Dependent Manner ◽  
Camp Response Element ◽  
B16f10 Cells ◽  
Protocatechuic Aldehyde ◽  
Element Binding Protein ◽  
Dependent Protein

Protocatechuic aldehyde (PA) is a naturally occurring phenolic compound that is a potent inhibitor of mushroom tyrosinase. However, the molecular mechanisms of the anti-melanogenesis activity of PA have not yet been reported. The aim of the current study was to clarify the melanogenesis inhibitory effects of PA and its molecular mechanisms in murine melanoma cells (B16F10). We first predicted the 3D structure of tyrosinase and used a molecular docking algorithm to simulate binding between tyrosinase and PA. These molecular modeling studies calculated a binding energy of −527.42 kcal/mol and indicated that PA interacts with Cu400 and 401, Val283, and His263. Furthermore, PA significantly decreased α-MSH-induced intracellular tyrosinase activity and melanin content in a dose-dependent manner. PA also inhibited key melanogenic proteins such as tyrosinase, tyrosinase-related protein 1 (TRP-1), and TRP-2 in α-MSH-stimulated B16F10 cells. In addition, PA decreased MITF expression levels by inhibiting phosphorylation of cAMP response element-binding protein (CREB) and cAMP-dependent protein kinase A (PKA). These results demonstrate that PA can effectively suppress melanin synthesis in melanoma cells. Taken together, our results show that PA could serve as a potential inhibitor of melanogenesis, and hence could be explored as a possible skin-lightening agent.

Stimulation by lithium of the interaction between the transcription factor CREB and its co-activator TORC

2009 ◽  
Vol 29 (2) ◽  
pp. 77-87 ◽  
Author(s):  
Annette Heinrich ◽  
Ulrike Böer ◽  
Mladen Tzvetkov ◽  
Elke Oetjen ◽  
Willhart Knepel
Keyword(s):  
Transcription Factor ◽  
Gene Transcription ◽  
Glutathione Transferase ◽  
Nuclear Translocation ◽  
Camp Response Element Binding ◽  
Lithium Salts ◽  
Camp Response Element ◽  
Element Binding Protein ◽  
A Cell ◽  
Novel Target

Lithium salts are clinically important drugs used to treat bipolar mood disorder. The mechanisms accounting for the clinical efficacy are not completely understood. Chronic treatment with lithium is required to establish mood stabilization, suggesting the involvement of neuronal plasticity processes. CREB (cAMP-response-element-binding protein) is a transcription factor known to mediate neuronal adaptation. Recently, the CREB-co-activator TORC (transducer of regulated CREB) has been identified as a novel target of lithium and shown to confer an enhancement of cAMP-induced CREB-directed gene transcription by lithium. TORC is sequestered in the cytoplasm and its nuclear translocation controls CREB activity. In the present study, the effect of lithium on TORC function was investigated. Lithium affected neither the nuclear translocation of TORC nor TORC1 transcriptional activity, but increased the promoter occupancy by TORC1 as revealed by chromatin immunoprecipitation assay. In a mammalian two-hybrid assay, as well as in a cell-free GST (glutathione transferase) pull-down assay, lithium enhanced the CREB–TORC1 interaction. Magnesium ions strongly inhibited the interaction between GST–CREB and TORC1 and this effect was reversed by lithium. Thus our results suggest that, once TORC has entered the nucleus, lithium as a cation stimulates directly the binding of TORC to CREB, leading to an increase in cAMP-induced CREB target-gene transcription. This novel mechanism of lithium action is likely to contribute to the clinical mood-stabilizing effect of lithium salts.

scholarly journals Long-Term Potentiation of Exocytosis and Cell Membrane Repair in Fibroblasts

2003 ◽  
Vol 14 (1) ◽  
pp. 93-106 ◽  
Author(s):  
Tatsuru Togo ◽  
Janet M. Alderton ◽  
Richard A. Steinhardt
Keyword(s):  
Long Term Potentiation ◽  
Camp Response Element Binding ◽  
Membrane Repair ◽  
Regulated Exocytosis ◽  
3T3 Fibroblasts ◽  
Term Potentiation ◽  
Element Binding Protein ◽  
Dependent Protein ◽  
Membrane Resealing

We previously found that a microdisruption of the plasma membrane evokes Ca2+-regulated exocytosis near the wound site, which is essential for membrane resealing. We demonstrate herein that repeated membrane disruption reveals long-term potentiation of Ca2+-regulated exocytosis in 3T3 fibroblasts, which is closely correlated with faster membrane resealing rates. This potentiation of exocytosis is cAMP-dependent protein kinase A dependent in the early stages (minutes), in the intermediate term (hours) requires protein synthesis, and for long term (24 h) depends on the activation of cAMP response element-binding protein (CREB). We were able to demonstrate that wounding cells activated CREB within 3.5 h. In all three phases, the increase in the amount of exocytosis was correlated with an increase in the rate of membrane resealing. However, a brief treatment with forskolin, which is effective for short-term potentiation and which could also activate CREB, was not sufficient to induce long-term potentiation of resealing. These results imply that long-term potentiation by CREB required activation by another, cAMP-independent pathway.

scholarly journals CaMKII locally encodes L-type channel activity to signal to nuclear CREB in excitation–transcription coupling

2008 ◽  
Vol 183 (5) ◽  
pp. 849-863 ◽  
Author(s):  
Damian G. Wheeler ◽  
Curtis F. Barrett ◽  
Rachel D. Groth ◽  
Parsa Safa ◽  
Richard W. Tsien
Keyword(s):  
Surface Membrane ◽  
Camp Response Element Binding ◽  
Membrane Depolarization ◽  
Surface Proteins ◽  
Excitable Cells ◽  
Camp Response Element ◽  
Dependent Protein Kinase ◽  
Natural Stimulus ◽  
Element Binding Protein ◽  
Dependent Protein

Communication between cell surface proteins and the nucleus is integral to many cellular adaptations. In the case of ion channels in excitable cells, the dynamics of signaling to the nucleus are particularly important because the natural stimulus, surface membrane depolarization, is rapidly pulsatile. To better understand excitation–transcription coupling we characterized the dependence of cAMP response element–binding protein phosphorylation, a critical step in neuronal plasticity, on the level and duration of membrane depolarization. We find that signaling strength is steeply dependent on depolarization, with sensitivity far greater than hitherto recognized. In contrast, graded blockade of the Ca2+ channel pore has a remarkably mild effect, although some Ca2+ entry is absolutely required. Our data indicate that Ca2+/CaM-dependent protein kinase II acting near the channel couples local Ca2+ rises to signal transduction, encoding the frequency of Ca2+ channel openings rather than integrated Ca2+ flux—a form of digital logic.

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