BACKGROUND: Juvenile hormones (JH) and ecdysteroids control postembryonic development in insects. They serve as valuable targets for pest management. Hence, understanding the molecular mechanisms of their action is of crucial importance. CREB-binding protein (CBP) is a universal transcriptional co-regulator. It controls the expression of several genes including those from hormone signaling pathways through co-activation of many transcription factors. However, the role of CBP during postembryonic development in insects is not well understood. Therefore, we have studied the role of CBP in postembryonic development in Tribolium, a model coleopteran insect. RESULTS: CBP is ubiquitously expressed in the red flour beetle, Tribolium castaneum. RNA interference (RNAi) mediated knockdown of CBP resulted in a decrease in JH induction of Kr-h1 gene expression in Tribolium larvae and led to a block in their development. Moreover, the injection of CBP double-stranded RNA (dsRNA) showed lethal phenotypes within 8 days of injection. RNA-seq and subsequent differential gene expression analysis identified CBP target genes in Tribolium. Knockdown of CBP caused a decrease in the expression of 1306 genes coding for transcription factors and other proteins associated with growth and development. Depletion of CBP impaired the expression of several JH response genes (e.g., Kr-h1, Hairy, early trypsin) and ecdysone response genes (EcR, E74, E75, and broad complex). Further, GO enrichment analyses of the downregulated genes showed enrichment in different functions including developmental processes, pigmentation, anatomical structure development, regulation of biological and cellular processes, etc. CONCLUSION: These data suggest diverse but crucial roles for CBP during postembryonic development in the coleopteran model insect, Tribolium. It can serve as a target for RNAi mediated pest management of this stored product pest.

• MeSH
• Gene Expression MeSH
• Insect Proteins antagonists & inhibitors   genetics   metabolism   physiology   MeSH
• Juvenile Hormones pharmacology   MeSH
• Larva genetics   metabolism   MeSH
• CREB-Binding Protein antagonists & inhibitors   genetics   metabolism   physiology   MeSH
• RNA Interference MeSH
• Tribolium genetics   growth & development   metabolism   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Juvenile hormones (JH) and ecdysteroids regulate many biological and metabolic processes. CREB-binding protein (CBP) is a transcriptional co-regulator with histone acetyltransferase (HAT) activity. Therefore, CBP is involved in activation of many transcription factors that regulate expression of genes associated with postembryonic development in insects. However, the function of CBP in JH action in insects is not well understood. Hence, we studied the role of CBP in JH action in the red flour beetle, Tribolium castaneum and the Tribolium cell line. CBP knockdown caused a decrease in JH induction of genes, Kr-h1, 4EBP and G13402 in T. castaneum larvae, adults and TcA cells whereas, Trichostatin A [TSA, a histone deacetylase (HDAC) inhibitor] induced the expression of these JH-response genes. Western blot analysis with specific antibodies revealed the requirement of CBP for the acetylation of H3K18 and H3K27 in both T. castaneum and TcA cells. Chromatin immunoprecipitation (Chip) assays showed the importance of CBP-mediated acetylation of H3K27 for JH induction of Kr-h1, 4EBP, and G13402 in TcA cells. These data suggest that CBP plays an important role in JH action in the model insect, T.castaneum.

• MeSH
• Acetylation MeSH
• Gene Knockout Techniques MeSH
• Histones metabolism   MeSH
• Insect Proteins genetics   metabolism   MeSH
• Juvenile Hormones pharmacology   MeSH
• CREB-Binding Protein genetics   metabolism   MeSH
• Tribolium genetics   growth & development   metabolism   MeSH
• Gene Expression Regulation, Developmental drug effects   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

BACKGROUND: Glycogen synthase kinase-3β (GSK3β), cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) play critical roles in neuronal survival, synaptic plasticity and memory and participate in the pathophysiology of both depressive disorder and Alzheimer's disease (AD). METHODS: This study was designed to determine the association of GSK3β activity, CREB activity and BDNF concentration in peripheral blood of patients with AD with or without depressive symptoms and in depressive patients without AD. GSK3β activity in platelets, CREB activity in lymphocytes and BDNF concentration in plasma, platelet-rich plasma or platelets were measured in 85 AD patients (36 of whom displayed co-morbid depressive symptoms), 65 non-AD patients with depressive disorder and 96 healthy controls. AD patients were clinically assessed for stage of dementia, cognitive impairment and severity of depressive symptoms. Depressive patients were clinically assessed for severity of depression. RESULTS: We observed increased CREB activity and GSK3β activity in AD with depressive symptoms or in AD at mild stage of dementia. Decreased BDNF concentration was found in platelet-rich plasma of AD patients at moderate to severe stages of dementia or in AD without depressive symptoms. An association was revealed of the severity of cognitive impairment with the increase of GSK3β in the platelets of AD patients with mild dementia. In depressive patients, a lower concentration of phosphorylated GSK3β was associated with a higher severity of depression. Association was confirmed between severity of depression, CREB activation, and BDNF concentration in drug-naïve depressive patients. CONCLUSION: Our data demonstrated that AD is accompanied by increased CREB activity in lymphocytes and a decreased concentration of BDNF in platelet-rich plasma. The decreased BDNF concentration appears to correlate with moderate to severe stages of dementia in AD. Observation of decreased phosphorylation of GSK3β in platelets of both AD patients with depressive symptoms and depressive patients after treatment confirms the role of increased GSK3β activity in the pathophysiology of both AD and depressive disorder. Associations were confirmed between AD and platelet GSK3β activity, lymphocyte CREB activity and plasma BDNF. CREB activity and platelet BDNF concentration seems to be related to depressive disorder.

• MeSH
• Alzheimer Disease blood   complications   psychology   MeSH
• Depression blood   complications   psychology   MeSH
• Glycogen Synthase Kinase 3 blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• Brain-Derived Neurotrophic Factor blood   MeSH
• Neuropsychological Tests MeSH
• CREB-Binding Protein blood   MeSH
• Psychiatric Status Rating Scales MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• Publication type
• Meeting Abstract MeSH

Gamma-glutamyltransferase (GGT), a marker of liver disease, has been shown to be associated with increased risk of diabetes and relative insulin secretion deficiency. However, the mechanism of hepatic Ggt regulation has not been explored fully. In this study, we made a concerted effort to understand the mechanism by investigating the effects of acetylation of histones H3 and H4, and bindings of histone acetyltransferases, CREB binding protein (CBP) and p300, at the Ggt promoter on the regulation of the expression of Ggt gene in the livers of streptozotocin (STZ)-induced moderate hypoinsulinemia rat model. The rats treated with STZ showed remarkably higher serum GGT level and hepatic Ggt/GGT expression than the untreated control rats. Furthermore, the acetylation of histones H3 and H4, and the binding of CBP not p300 at the Ggt promoter regions were significantly higher in the livers of STZ rats than those of the control rats. These results suggest that an enhanced hepatic expression of Ggt is associated with increased acetylation of histones H3 and H4 and CBP binding at the Ggt promoter in STZ-induced moderate hypoinsulinemic rats.

• MeSH
• Acetylation MeSH
• Diabetes Mellitus, Experimental enzymology   genetics   MeSH
• gamma-Glutamyltransferase biosynthesis   genetics   MeSH
• Histone Acetyltransferases metabolism   MeSH
• Histones metabolism   MeSH
• Liver enzymology   MeSH
• Rats MeSH
• Rats, Wistar MeSH
• Promoter Regions, Genetic MeSH
• E1A-Associated p300 Protein metabolism   MeSH
• CREB-Binding Protein metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

PURPOSE: The purpose of our study is to examine phospho-ATF-2(Thr-69/71) (phospho-activating transcription factor-2, p-ATF-2), phospho-CREB(Ser-133) (phospho-cAMP response binding element protein, p-CREB), and phospho-c-Myc(Thr-58/Ser-62) (phosho-myelocytomatosis protooncogene, p-c-Myc) expression in irradiated rat colon transversum. MATERIALS AND METHODS: Male Wistar rats were randomly divided to 28 groups and irradiated with whole-body gamma-radiation of 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 Gy. Samples were taken 4 and 24 hours after the irradiation, immunohistochemically stained. P-ATF-2, p-CREB, and p-c-Myc expression was measured. RESULTS: We measured increased cytoplasmatic p-ATF-2 expression 4 hours after irradiation by 0.25 - 1, 10 Gy and 24 hours after irradiation by 0.5 - 1, 10 Gy. Increased cytoplasmatic p-CREB expression was found 4 hours after irradiation by 0.25 - 1, 9, 10 Gy and 24 hours after irradiation by 0.25 - 1, 4, 10 Gy. Increased p-c-Myc cytoplasmatic expression was found 4 hours after irradiation by 0.25, 0.75, 4, 5 Gy and 24 hours after irradiation by 0.75, 1, 10 Gy. Nuclear p-ATF-2, p-CREB, and p-c-Myc expressions were similar to their cytoplasmatic expressions. CONCLUSION: The detection of p-ATF-2 and p-CREB might be considered as a perspective biodosimetric tool for irradiated enterocytes in vivo. The use of p-c-Myc appears to be controversial due to the ambivalent expression values.

• MeSH
• Biological Assay methods   MeSH
• Whole-Body Irradiation MeSH
• Whole-Body Counting methods   MeSH
• Gene Expression radiation effects   MeSH
• Financing, Organized MeSH
• Colon metabolism   radiation effects   MeSH
• Rats MeSH
• Body Burden MeSH
• Rats, Wistar MeSH
• Cyclic AMP Response Element-Binding Protein metabolism   MeSH
• Relative Biological Effectiveness MeSH
• Activating Transcription Factor 2 metabolism   MeSH
• Gamma Rays MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH

Most behavioral and physiological processes in living organisms exhibit periodic circadian rhythmicity. In mammals, these rhythms are coordinated by the circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In order to precisely synchronize free-running circadian oscillations to the 24h solar cycle, signals from the external environment, primarily the light/dark cycle, must reach the circadian clock within the SCN. A light pulse elevates intracellular Ca(2+) levels, and activates signaling cascades, leading to transcriptional activation of the clock genes mPer1 and mPer2 via phosphorylation of extracellular-signal-regulated kinases 1/2 (ERK1/2) and cyclic AMP-responsive element binding protein (CREB). Glutamate is the primary excitatory transmitter in retinal terminals in the SCN, and NMDA receptors (NMDAR) are the principal glutamate receptors that mediate the effect of light on resetting the circadian clock. Here we show the circadian rhythm in mRNA expression and protein level of the NMDAR 2B subunit (NR2B) in the SCN, with a peak at night. Also, we demonstrate ifenprodil inhibition of glutamate-induced phosphorylation of CREB (pCREB) and ERK1/2 (pERK1/2), and support thus the evidence for NR2B role in activation of signaling cascade involved in photic resetting of the circadian clock.

• MeSH
• Excitatory Amino Acid Antagonists pharmacology   MeSH
• Phosphorylation MeSH
• In Situ Hybridization MeSH
• Rats MeSH
• Glutamic Acid metabolism   MeSH
• MAP Kinase Signaling System MeSH
• Suprachiasmatic Nucleus drug effects   metabolism   MeSH
• Piperidines pharmacology   MeSH
• Rats, Wistar MeSH
• Cyclic AMP Response Element-Binding Protein metabolism   MeSH
• Receptors, N-Methyl-D-Aspartate metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Prostate cancer (PCa) is a common and fatal type of cancer in men. Metastatic PCa (mPCa) is a major factor contributing to its lethality, although the mechanisms remain poorly understood. PTEN is one of the most frequently deleted genes in mPCa. Here we show a frequent genomic co-deletion of PTEN and STAT3 in liquid biopsies of patients with mPCa. Loss of Stat3 in a Pten-null mouse prostate model leads to a reduction of LKB1/pAMPK with simultaneous activation of mTOR/CREB, resulting in metastatic disease. However, constitutive activation of Stat3 led to high LKB1/pAMPK levels and suppressed mTORC1/CREB pathway, preventing mPCa development. Metformin, one of the most widely prescribed therapeutics against type 2 diabetes, inhibits mTORC1 in liver and requires LKB1 to mediate glucose homeostasis. We find that metformin treatment of STAT3/AR-expressing PCa xenografts resulted in significantly reduced tumor growth accompanied by diminished mTORC1/CREB, AR and PSA levels. PCa xenografts with deletion of STAT3/AR nearly completely abrogated mTORC1/CREB inhibition mediated by metformin. Moreover, metformin treatment of PCa patients with high Gleason grade and type 2 diabetes resulted in undetectable mTORC1 levels and upregulated STAT3 expression. Furthermore, PCa patients with high CREB expression have worse clinical outcomes and a significantly increased risk of PCa relapse and metastatic recurrence. In summary, we have shown that STAT3 controls mPCa via LKB1/pAMPK/mTORC1/CREB signaling, which we have identified as a promising novel downstream target for the treatment of lethal mPCa.

• MeSH
• Diabetes Mellitus, Type 2 * MeSH
• Humans MeSH
• Neoplasm Recurrence, Local MeSH
• Metformin * pharmacology   MeSH
• Mechanistic Target of Rapamycin Complex 1 metabolism   MeSH
• Mice MeSH
• Prostatic Neoplasms * genetics   pathology   MeSH
• AMP-Activated Protein Kinases metabolism   MeSH
• STAT3 Transcription Factor genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Chronic exposure to low dose of T-2 toxin causes growth retardation and reduced body weight, resulting in economic losses. Excessive inflammatory cytokines and GH deficiency are important mechanisms that contribute to growth inhibition induced by T-2 toxin. However, the regulation of the inflammatory cytokines expecially IL-6, IL-1β, and TNF-α induced by T-2 toxin still remained unclear. The new transcription factor AKNA, belonging to AT-hook protein family, is closely associated with inflammation. However, it was unclear how AKNA regulate the expression of inflammatory cytokines, and there was no report on the role of AKNA in T-2 toxin mediated toxicity. Here, we investigated the role of AKNA in T-2 toxin-mediated inflammatory response and GH deficiency and the signal transduction pathway of AKNA. We showed that AKNA regulated by PKA/CREB and NF-κB pathway is a novel downstream molecular target in T-2 toxin-mediated inflammation and GH deficiency. T-2 toxin activates the PKA/CREB and NF-κB/p65 pathways, thereby promoting the direct binding of phospho-CREB and phospho-p65 to the AKNA promoter, thus inhibiting AKNA expression. GH and inflammatory cytokines (TNF-α, IL-1β, and IL-6) expression were significantly downregulated after AKNA silencing. Furthermore, the expression of differential genes induced by T-2 toxin in the rat pituitary was further confirmed by acute toxicity tests in rats, which was consistent with the results in GH3 cells. By histopathological analysis, we confirmed the pituitary might be a novel direct target organ of T-2 toxin. These findings provided new insights into the significant role of AKNA in T-2 toxin-induced inflammatory response and growth inhibition.

• MeSH
• Cell Line MeSH
• DNA-Binding Proteins genetics   metabolism   MeSH
• Down-Regulation MeSH
• Phosphorylation MeSH
• Interleukin-1beta genetics   metabolism   MeSH
• Interleukin-6 genetics   metabolism   MeSH
• Nuclear Proteins genetics   metabolism   MeSH
• Rats MeSH
• NF-kappa B metabolism   MeSH
• Promoter Regions, Genetic MeSH
• Cyclic AMP Response Element-Binding Protein metabolism   MeSH
• Cyclic AMP-Dependent Protein Kinases metabolism   MeSH
• T-2 Toxin toxicity   MeSH
• Tumor Necrosis Factor-alpha genetics   metabolism   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Gene Silencing MeSH
• Inflammation chemically induced   genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Prenatal exposure to caffeine can cause developmental problems. This study determined chronic influence of prenatal caffeine at relatively higher doses on cognitive functions in the rat offspring. Pregnant Sprague-Dawley rats (4-month-old) were exposed to caffeine (20 mg/kg, twice a day) for whole pregnancy from gestational day 4. Fetal and offspring body and brain weight was measured. Learning and memory were tested in adult offspring with Morris water maze. Learning and memory-related receptors were measured. The exposure to prenatal caffeine not only caused fetal growth restriction, but also showed long-term effects on learning and memory in the offspring. The caffeine offspring exhibited longer escape latency and path length in navigation testing. The number of passing the target was significantly reduced in those offspring. The expression of adenosine A(1) and A(2A) receptors, nuclear PKA C(alpha), C(beta) subunits, and pCREB were significantly increased in the fetal and neonatal brain, and suppressed in the hippocampus of the adult offspring. The expression of BDNF and TrkB were reduced regardless of various ages. The results suggest that intrauterine programming dysfunction of adenosine receptors and the down-stream of cAMP/PKA/pCREB system may play an important role in prenatal caffeine induced cognition disorders in the adult offspring.

• MeSH
• Maze Learning drug effects   physiology   MeSH
• Caffeine toxicity   MeSH
• Rats MeSH
• Brain-Derived Neurotrophic Factor metabolism   MeSH
• Memory drug effects   physiology   MeSH
• Memory Disorders chemically induced   diagnosis   metabolism   MeSH
• Rats, Sprague-Dawley MeSH
• Cyclic AMP Response Element-Binding Protein metabolism   MeSH
• Cyclic AMP-Dependent Protein Kinases metabolism   MeSH
• Receptors, Purinergic P1 metabolism   MeSH
• Signal Transduction drug effects   physiology   MeSH
• Pregnancy MeSH
• Prenatal Exposure Delayed Effects chemically induced   diagnosis   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH