Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Alastair G. Stewart in AIRWAY WALL REMODELLING in ASTHMA, 2020
A number of genes contain sequences in the promoter regions called cAMP response elements (CREs) which are activated by CRE-binding protein (CREB). Increases in cAMP may cause activation and nuclear translocation of PKA, which is then able to phosphorylate CREB, increasing its transcriptional activity.147 CREB binds to a nuclear protein called CREB-binding protein (CBP)148 which is also bound by the phosphorylated (active) form of Jun. It has been suggested that limiting levels of CBP may cause competition between CREB and Jun, resulting in mutual inhibition.149 Given the importance of Jun in activating mitogen-sensitive genes (see Figure 4), it is plausible that cAMP could inhibit cell proliferation by phosphorylated CREB sequestering the available CBP and, therefore, inhibiting the transcriptional activity of Jun complexes.
Dopamine Receptors, Signaling Pathways, and Drugs
Nira Ben-Jonathan in Dopamine, 2020
Increased cAMP levels activate PKA, which acts upon several targets, including cAMP response element binding protein (CREB) and DARPP-32 (32-kDa dopamine and cAMP-regulated phosphoprotein). PKA is a tetramer, composed of two regulatory (R) and two catalytic (C) subunits. Binding of four cAMP molecules to the R subunit promotes conformational changes that result in the dissociation of the C monomers. Upon ATP binding, the C monomers become activated and can phosphorylate cytoplasmic and nuclear proteins that contain the appropriate consensus sequence. CREB is a transcription factor that is activated by PKA-induced Ser133 phosphorylation and regulates the transcription of numerous genes [50]. DARPP-32 is a multifunctional phosphoprotein with a protein phosphatase 1 (PPI) inhibitory function. DARPP-32 becomes activated upon PKA- and cyclin-dependent kinase 5-induced Thr34 phosphorylation [51]. As discussed in Chapters 11 and 12, DARPP-32 play a critical role in tumorigenesis and is overexpressed in breast, prostate, colon, and stomach cancers.
Drugs of Abuse and Addiction
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
In assorted regions of brain responsible for addiction, the CREB protein gets activated by the drugs and most prominently in the nucleus accumbens. This CREB activation represents a negative feedback mechanism as it reduces the satisfying effects of the drug by actually lessening the sensitivity of an individual and mediates dependence on drug at the time of drug withdrawal (Robison and Nestler, 2012; Nestler, 2013). This negative reinforcement leads to self-administering of drugs by the people and probably relapse. This action of CREB in the regions of amygdala and hippocampus is contemplated as a vital factor in behavioral memory. For example, in case of opioid, the initiation of dynorphin (peptides of opioid) expression in NAc neurons is regulated via CREB (Shaw-Lutchman et al., 2002; Shaw-Lutchman et al., 2003; Robison and Nestler, 2012; Nestler, 2013). CREB is associated with the increasing dynorphin activation of κ-opioid receptors present on the DA neurons which lie in the VTA region and henceforth suppressing dopamine transmission to NAc and thus impairing reward related behavior. Target genes for CREB are known only in some drugs, about its mantle in other drugs of abuse still remains undisclosed (Shaw-Lutchman et al., 2002; Shaw-Lutchman et al., 2003; Carlezon et al., 2005; Edwards et al., 2007; Altarejos and Montminy, 2011).
The potential beneficial effects of Lactobacillus plantarum GM11 on rats with chronic unpredictable mild stress- induced depression
Published in Nutritional Neuroscience, 2023
Jie Ma, Junrui Wang, Gang Wang, Yujun Wan, Nanzhen Li, Lijuan Luo, Hongmei Gou, Jianwen Gu
Brain-derived neurotrophic factor (BDNF) is an extensively researched neurotrophin vital for memory, learning and mental disorders [60,61]. Previous studies have demonstrated that the occurrence of depression is related to a decline in BDNF levels and that BDNF deficiency can lead to cognitive deficits, feelings of helplessness and anhedonia [62]. In our study, the impact of LacP GM11 treatment on BDNF was observed. LacP GM11 significantly elevated the level of BDNF in both the serum and hippocampus of CUMS rats. It has also been proven that the CREB-BDNF signaling cascade plays a crucial role in the pathogenesis of depression [63]. Consequently, reversing the decreased expression of the CREB-BDNF signaling pathway is of great significance for ameliorating depression [64]. The results demonstrated that the mRNA and protein expression of CREB and BDNF was significantly reduced in the hippocampus of depressed rats. Supplementation with LacP GM11 markedly upregulated the mRNA and protein expression of CREB and BDNF in the hippocampus of rats. Therefore, the abovementioned findings suggest a possible fact that the effect of LacP GM11 against depression might be attributed to alleviating the deficiency of monoamine neurotransmitters and hyperfunction of the HPA axis and reversing the CREB-BDNF signaling pathway downregulation in depressive rats.
Genotype-phenotype analysis of ocular findings in Rubinstein-Taybi syndrome – A case report and review of literature
Published in Ophthalmic Genetics, 2023
Eva Jin, Hong Le, Ann Jewell, Natario L. Couser
CREBBP was the first gene discovered to contribute to the etiology of RSTS (8). CREBBP has 2442 amino acids and is located on 16p13.3, with genomic coordinates of 3775055–3930121. Its genomic size is 155067 bp, with a total 31 coding exons. A haplo-insufficiency model has been proposed to underlie the mutational effects of CREBBP, where both copies of CREBBP are needed for normal functioning (8). CREBBP has various domains, including a histone acetyltransferase (HAT) domain with epigenetic regulation activities. CREBBP had been described as a transcriptional co-activator that interacts with phosphorylated CREB to facilitate cAMP-regulated gene expression (8). On the other hand, EP300 is located on chromosome 22q13.2. EP300 and CREBBP are highly homologous in function, and both have a HAT domain (9).
Mitochondrial biogenesis alteration in arsenic-induced carcinogenesis and its therapeutic interventions
Published in Toxin Reviews, 2023
Kshirod Bihari Sathua, Rakesh Kumar Singh
cAMP response element binding protein (CREB) is an omnipresent nuclear transcription factor which acts both directly and indirectly. In response to increase in energy demands, cAMP signaling pathways activated mediated by CREB. The mitochondrial function is directly regulated by CREB, and is indirectly regulated via PGC-1α resulting into cell proliferation, differentiation, homeostasis, and survival. CREB acts as proto-oncogene in different tumor types and involved in progression of carcinogenesis (Sapio et al. 2020, Herzig et al. 2001). Though CREB activation in arsenicosis is well known, but its involvement in carcinogenesis is less explored (Qu et al.2016, Srivastava et al.2018). Even the interlinking of the molecular events between CREB, mitochondrial biogenesis, and homeostasis concerning to chronic arsenic-induced carcinogenesis is yet to be resolved.
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