A novel cyclic AMP response element-binding protein-1 (CREB-1) splice product may down-regulate CREB-1 activity

1995 ◽  
Vol 14 (2) ◽  
pp. 191-198 ◽  
Author(s):  
M J C Ellis ◽  
H C Hurst ◽  
S Goodbourn
Keyword(s):  
Cyclic Amp ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Transactivation Domain ◽  
Camp Response Element ◽  
Response Element ◽  
Element Binding Protein ◽  
Dependent Protein ◽  
Cyclic Amp Response Element ◽  
Splice Product

ABSTRACT In this report we identify novel spliced forms of cyclic AMP (cAMP) response element-binding protein-1 (CREB-1) mRNA. These forms contained an additional 17 nucleotide insert, which we refer to as the β exon, located between exons 4 and 7 of the Δ, and 5 and 7 of the α forms of CREB-1 transcript (nomenclature of Ruppert et al. 1992; EMBO Journal 11, 1503-1512). The inclusion of the β exon led to the generation of mRNAs in which the frame of CREB-1 sequences 3′ to the exon was shifted such that the encoded proteins terminate after the transactivation domain, but before the target serine for cAMP-dependent protein kinase. The β exon-containing CREB-1 mRNAs were more abundant in tissues that respond poorly to cAMP, suggesting that the generation of βCREB-1 mRNAs may contribute to the down-regulation of CREB-1 activity and cAMP responsiveness.

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 Glucose-Dependent Insulinotropic Polypeptide-Mediated Up-Regulation of β-Cell Antiapoptotic Bcl-2 Gene Expression Is Coordinated by Cyclic AMP (cAMP) Response Element Binding Protein (CREB) and cAMP-Responsive CREB Coactivator 2

2007 ◽  
Vol 28 (5) ◽  
pp. 1644-1656 ◽  
Author(s):  
Su-Jin Kim ◽  
Cuilan Nian ◽  
Scott Widenmaier ◽  
Christopher H. S. McIntosh
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Β Cells ◽  
Β Cell ◽  
Camp Response Element ◽  
Response Element ◽  
Element Binding Protein ◽  
Interfering Rna

ABSTRACT The cyclic AMP (cAMP)/protein kinase A (PKA) cascade plays a central role in β-cell proliferation and apoptosis. Here, we show that the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates expression of the antiapoptotic Bcl-2 gene in pancreatic β cells through a pathway involving AMP-activated protein kinase (AMPK), cAMP-responsive CREB coactivator 2 (TORC2), and cAMP response element binding protein (CREB). Stimulation of β-INS-1 (clone 832/13) cells with GIP resulted in increased Bcl-2 promoter activity. Analysis of the rat Bcl-2 promoter revealed two potential cAMP response elements, one of which (CRE-I [GTGACGTAC]) was shown, using mutagenesis and deletion analysis, to be functional. Subsequent studies established that GIP increased the nuclear localization of TORC2 and phosphorylation of CREB serine 133 through a pathway involving PKA activation and reduced AMPK phosphorylation. At the nuclear level, phospho-CREB and TORC2 were demonstrated to bind to CRE-I of the Bcl-2 promoter, and GIP treatment resulted in increases in their interaction. Furthermore, GIP-mediated cytoprotection was partially reversed by small interfering RNA-mediated reduction in BCL-2 or TORC2/CREB or by pharmacological activation of AMPK. The antiapoptotic effect of GIP in β cells is therefore partially mediated through a novel mode of transcriptional regulation of Bcl-2 involving cAMP/PKA/AMPK-dependent regulation of CREB/TORC2 activity.

scholarly journals Aberrant expression of cAMP-response-element-binding protein (‘CREB’) induces apoptosis

1999 ◽  
Vol 343 (1) ◽  
pp. 249-255 ◽  
Author(s):  
Kumiko SAEKI ◽  
Akira YUO ◽  
Emiko SUZUKI ◽  
Yoshio YAZAKI ◽  
Fumimaro TAKAKU
Keyword(s):  
Cell Cycle ◽  
Expression Vector ◽  
Binding Protein ◽  
Camp Response Element Binding ◽  
Dependent Manner ◽  
Transactivation Domain ◽  
Camp Response Element ◽  
Response Element ◽  
Element Binding Protein ◽  
Induction Of Apoptosis

We have reported previously that cAMP-response-element-binding protein (CREB) was phosphorylated in a cell-cycle-dependent manner, showing that it was phosphorylated at early S-phase at casein kinase II target sites. To assess the possible involvement of CREB in cell cycle progression, CREB expression vector was transiently transfected into various cells. Unexpectedly we found that transfection with CREB expression vector resulted in an abundance of dead cells. Morphological examination revealed that these cells had undergone apoptosis. The coincidence of CREB overexpression and apoptosis induction at the individual cell level was confirmed by a immunohistochemical study. To confirm that overexpression of CREB was the cause of apoptosis, a dominant-negative mutant of CREB, KCREB, was co-expressed with the wild type. The co-existence of KCREB effectively rescued CREB-mediated apoptosis in a dose-dependent manner, verifying that apoptosis was truly a specific effect of overexpressed CREB and not an artifact of the transfection procedure. Deletion analysis indicates that neither the Q1 transactivation domain, which functions in transcription, nor the kinase-inducible domain, in which a cluster of various kinase targets exists, is necessary; however, the Q2 transactivation domain is required for the induction of apoptosis. A more precise study indicates that the four-residue stretch Glu-Glu-Ala-Ala at the most C-terminal region of the Q2 domain is especially important for the induction of apoptosis. Thus overexpressed CREB induces apoptosis by transmitting certain signals from the C-terminal portion of the Q2 domain. Possible roles of cell-cycle-regulated phosphorylation and also an elevation of the intracellular cAMP level in CREB-induced apoptosis are suggested.

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