Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

UCPs (uncoupling proteins) can regulate cellular ATP production by uncoupling oxidative phosphorylation. UCP2 is expressed in islet beta-cells and its induction reduces glucose-stimulated insulin secretion. Under physiological conditions, superoxide, formed as a by-product of respiration, activates UCP2. This leads to reduced ATP production, which impairs closure of the ATP-dependent K+ channels to prevent insulin secretion. It is suggested that the physiological role of UCP2 is to prevent excessive superoxide generation through a feedback loop. UCP2 induction may also alter fatty acid metabolism by altering NAD/NADH or by facilitating cycling of fatty acid anions. Recently, UCP2 has been proposed to keep insulin secretion low during starvation, a function under the control of the transcription co-repressor, surtuin-1, which has been shown to bind to the UCP2 promoter. Pathological UCP2 expression or activation may suppress glucose-stimulated insulin secretion to the extent that diabetes onset is hastened. In ob/ob mice, induction of UCP2 at age 5 weeks precedes development of insulin secretion defects and hyperglycaemia. Activating protein kinase A-dependent pathways can normalize insulin secretion in UCP2-overexpressing islets. Conversely, lowering UCP2 expression may promote increased insulin secretion. UCP2 knockout mice were protected from the diabetogenic effects of a high-fat diet and their islets exhibited increased sensitivity to glucose and elevated ATP/ADP. These results support a role for UCP2 as a gene contributing to the pathogenesis of Type 2 diabetes.
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PMID:Regulation of insulin secretion by uncoupling protein. 1705 2

The activity of Rb (retinoblastoma protein) is regulated by phosphorylation and acetylation events. Active Rb is hypophosphorylated and acetylated on multiple residues. Inactivation of Rb involves concerted hyper-phosphorylation by cyclin-CDK (cyclin-dependent kinase) complexes combined with deacetylation of appropriate lysine residues within Rb. In the present study, using in vivo co-immunoprecipitation experiments, we identified mammalian SIRT1 (sirtuin 1) as a binding partner for Rb and its family members p107 and p130. Formation of Rb-SIRT1 complexes required the pocket domain of Rb. p300 catalysed the acetylation of Rb, and SIRT1 was a potent deacetylase for Rb. The ability of SIRT1 to catalyse the deacetylation of Rb was dependent on NAD and was inhibited by the SIRT1 inhibitor nicotinamide. Deacetylated lysine residues within Rb formed a domain similar to the SIRT1-targeted domain of the p53 tumour suppressor protein. Cultures of arrested cells, via contact inhibition or DNA damage, exhibited decreased Rb phosphorylation and increased Rb acetylation. Overexpression of SIRT1 in either confluent or etoposide-treated cells resulted in a significant reduction in Rb acetylation, which was restored with nicotinamide. Gene knockdown of SIRT1 by siRNA (short interfering RNA) produced an accumulation of acetylated Rb. This increase was augmented further when siRNA against SIRT1 was used in conjunction with nicotinamide. In conclusion, our results demonstrate that SIRT1 is an in vitro and in vivo deacetylase for the Rb tumour suppressor protein.
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PMID:Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1. 1762 57

In the human adrenal cortex, the peptide hormone adrenocorticotropin (ACTH) directs cortisol and adrenal androgen biosynthesis by activating a cAMP/cAMP-dependent protein kinase (PKA) pathway. Carboxyl-terminal binding protein 1 (CtBP1) is a corepressor that regulates transcription of the CYP17 gene by periodically interacting with steroidogenic factor-1 in response to ACTH signaling. Given that CtBP1 function is regulated by NADH binding, we hypothesized that ACTH-stimulated changes in cellular pyridine nucleotide concentrations modulate the ability of CtBP1 to repress CYP17 transcription. Further, we postulated that PKA evokes changes in the phosphorylation status of CtBP1 that control the ability of the protein to bind to steroidogenic factor-1 and the coactivator GCN5 (general control nonderepressed 5) and repress CYP17 gene expression. We show that ACTH alters pyridine nucleotide redox state and identify amino acid residues in CtBP1 that are targeted by PKA and PAK6. Both ACTH/cAMP signaling and NADH/NAD+ ratio stimulate nuclear-cytoplasmic oscillation of both CtBP proteins. We provide evidence that PKA 1) induces metabolic changes in the adrenal cortex and 2) phosphorylates CtBP proteins, particularly CtBP1 at T144, resulting in CtBP protein partnering and ACTH-dependent CYP17 transcription.
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PMID:Phosphorylation of CtBP1 by cAMP-dependent protein kinase modulates induction of CYP17 by stimulating partnering of CtBP1 and 2. 1818 56

A variety of pharmacological effectors of signal transduction pathways were used to investigate the elicitor-activated sequence of cellular responses by which yeast extract (YE) or methyljasmonate (MeJA) enhanced production of silymarin in cell cultures of Silybum marianum. As we recently showed that inhibition of external and internal calcium fluxes significantly increased flavonolignan production in S. marianum cultures, we examined whether calcium mediates signaling events leading to enhancement of silymarin production upon YE or MeJA elicitation. Pre-treatment of cultures with calcium chelators, calcium blockers or intracellular antagonists enhanced the elicitor effect of YE or MeJA. The increase of intracellular-free Ca(2+) level also promoted the elicitor effect, suggesting that an external source of calcium or alterations in internal calcium fluxes were not required for the elicitation to occur. Activation of phosphorylation/dephosphorylation cascades did not appear to mediate the elicitation mechanism; the increase in silymarin induced by elicitation was not suppressed by inhibitors of protein phosphatases or by protein kinase inhibitors. No H(2)O(2) generation was detected at any time after elicitation. Also, diphenyleneiodonium, a potent inhibitor of NAD(P)H-oxidase, did not block silymarin production in elicited cultures. From these results, we conclude that S. marianum cell cultures do not appear to employ conserved signaling components in the transduction of the elicitor signal to downstream responses such as silymarin production.
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PMID:Some common signal transduction events are not necessary for the elicitor-induced accumulation of silymarin in cell cultures of Silybum marianum. 1831 69

Nicotinamide adenine dinucleotide (NAD), generally considered a key component involved in redox reactions, has been found to participate in an increasingly diverse range of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. In recent years, medicinal chemists have become interested in the therapeutic potential of molecules affecting interactions of NAD with NAD-dependent enzymes. Also, enzymes involved in de novo biosynthesis, salvage pathways, and down-stream utilization of NAD have been extensively investigated and implicated in a wide variety of diseases. These studies have bolstered NAD-based therapeutics as a new avenue for the discovery and development of novel treatments for medical conditions ranging from cancer to aging. Industrial and academic groups have produced structurally diverse molecules which target NAD metabolic pathways, with some candidates advancing into clinical trials. However, further intensive structural, biological, and medical studies are needed to facilitate the design and evaluation of new generations of NAD-based therapeutics. At this time, the field of NAD-therapeutics is most likely at a stage similar to that of the early successful development of protein kinase inhibitors, where analogs of ATP (a more widely utilized metabolite than NAD) began to show selectivity against target enzymes. This review focuses on key representative opportunities for research in this area, which extends beyond the scope of this article.
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PMID:Nicotinamide adenine dinucleotide based therapeutics. 1833 80

The purpose of this study was to investigate the role of the oestrogen receptor subtypes ERalpha and ERbeta in mediating the non-genomic effects of 17-beta-estradiol (E(2)) in two human endometrial cancer cell lines (RL95-2 and HEC-1A) expressing different levels of these receptor subtypes. Western blotting analysis using phosphorylation site-specific antibodies showed that physiological concentrations of E(2) rapidly (<20 min) activated PKCalpha, but not PKCdelta in the RL95-2 cell line. E(2) had no effect on PKCalpha or PKCdelta activity in the HEC-1A cell line and suppressed basal levels of PKA activity in both cell lines. PKCalpha activation coincided with its membrane translocation. ERalpha was detected in the RL95-2 cell line by Western blotting and RT-PCR but not in the HEC-1A cells, which did express ERbeta. A selective ERalpha agonist PPT had the same effect as E(2) on PKCalpha activation in the RL95-2 cells, but the selective ERbeta agonist DPN had no such effect. A 46kDa variant of ERalpha increased in abundance in the cell membrane within 20 min of E(2) treatment suggesting that ERalpha mediated the E(2) non-genomic effects on PKCalpha through the formation of a membrane associated signalling complex.
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PMID:Membrane ERalpha-dependent activation of PKCalpha in endometrial cancer cells by estradiol. 1853 51

Chronic alcohol consumption affects the gene expression of a NAD-dependent deacetylase Sirtuis 1 (SIRT1) and the peroxisome proliferator-activated receptor-gamma coactivator1alpha (PGC-1alpha). Our aim was to verify that it also alters the forkhead (FoxO1) and p53 transcription factor proteins, critical in the hepatic response to oxidative stress and regulated by SIRT1 through its deacetylating capacity. Accordingly, rats were pair-fed the Lieber-DeCarli alcohol-containing liquid diets for 28 days. Alcohol increased hepatic mRNA expression of FoxO1 (p=0.003) and p53 (p=0.001) while corresponding protein levels remained unchanged. However phospho-FoxO1 and phospho-Akt (protein kinase) were both decreased by alcohol consumption (p=0.04 and p=0.02, respectively) while hepatic p53 was found hyperacetylated (p=0.017). Furthermore, mitochondrial SIRT5 was reduced (p=0.0025), and PGC-1alpha hyperacetylated (p=0.027), establishing their role in protein modification. Thus, alcohol consumption disrupts nuclear-mitochondrial interactions by post-translation protein modifications, which contribute to alteration of mitochondrial biogenesis through the newly discovered reduction of SIRT5.
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PMID:Alcohol alters hepatic FoxO1, p53, and mitochondrial SIRT5 deacetylation function. 1855 8

It is important to understand the mechanisms that control muscle precursor cell (MPC) proliferation for the development of countermeasures to offset the deleterious effects of the aging-related loss of skeletal muscle mass (and myonuclei) and the impaired ability of old muscle to regrow and regenerate. Over-expression of the NAD+-dependent histone deacetylase Sirt1 increased MPC proliferation and cell cycle progression as evidenced by increased 5-bromo-2'-deoxyuridine (BrdU) incorporation, an increase in cell number, proliferating cell nuclear antigen expression, and the phosphorylation of retinoblastoma protein. Associated with the Sirt1-mediated increase in MPC cycle progression were the bidirectional decreases and increases in the expression of the cyclin-dependent kinase inhibitors p21(Waf/Cip1) and p27(Kip1), respectively. Based upon our recent observation that lowering oxygen (O2) in culture from ambient (20%) to estimated physiological levels (5%) increased MPC proliferation, we next measured Sirt1 protein at 5% and 20% O2. Interestingly, in addition to increased proliferation in MPCs cultured at 5% O2, Sirt1 expression increased, compared to 20% O2. Using O2 levels as a platform to modulate basal Sirt1 protein, activation of Sirt1 activity with resveratrol in 20% O2 increased MPC proliferation while inhibition of Sirt1 with nicotinamide in 5% O2 lowered proliferation. For the first time, Sirt1 has been shown to increase MPC proliferation. These findings could have clinical significance since MPC proliferation has important implications in regulating skeletal muscle growth, maintenance, and repair, and the aging-related loss of skeletal muscle mass.
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PMID:Sirt1 increases skeletal muscle precursor cell proliferation. 1892 99

An efficient DNA strand break repair contributes to the radioresistance of Deinococcus radiodurans, which harbors the DNA repair pathways nearly identical to Escherichia coli. The molecular mechanisms of these proteins functioning in 2 diverse classes of bacteria seem to be different. The macromolecular interactions and formation of multiprotein complexes in vivo have gained significant importance in explaining the mechanism of the complex cellular processes. Here, we report the identification of a novel DNA metabolic protein complex from D. radiodurans. A similar complex has, however, not been found in E. coli. Mass spectrometric analysis showed the presence of a few known DNA repair proteins, molecular chaperones, and a large number of uncharacterized proteins from D. radiodurans R1. Biochemical and immunoblotting results indicated the presence of the protein promoting DNA repair A, DNA polymerase, Mg2+, and (or) Mn2+ -dependent 5'-->3' exonuclease activity along with protein kinase activity and phosphoproteins. DNA ligase activity was completely dependent upon the ATP requirement, as no ligase activity was seen in the presence of NAD as a cofactor. These results suggest the molecular interactions of the known DNA repair proteins with uncharacterized proteins in the macromolecular complex and the regulation of DNA degradation with the involvement of ATP and protein kinase functions.
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PMID:Identification of a DNA processing complex from Deinococcus radiodurans. 1892 46

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key metabolic regulator implicated in a variety of cellular processes. It functions as a glycolytic enzyme, a protein kinase, and a metabolic switch under oxidative stress. Its enzymatic inactivation causes a major shift in the primary carbohydrate flux. Furthermore, the protein is implicated in regulating transcription, ER-to-Golgi transport, and apoptosis. We found that Saccharomyces cerevisiae cells null for all GAPDH paralogues (Tdh1, Tdh2, and Tdh3) survived the counter-selection of a GAPDH-encoding plasmid when the NAD(+) metabolizing deacetylase Sir2 was overexpressed. This phenotype required a fully functional copy of SIR2 and resulted from hyper-recombination between S. cerevisiae plasmids. In the wild-type background, GAPDH overexpression increased the plasmid recombination rate in a growth-condition dependent manner. We conclude that GAPDH influences yeast episome stability via Sir2 and propose a model for the interplay of Sir2, GAPDH, and the glycolytic flux.
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PMID:Interfering with glycolysis causes Sir2-dependent hyper-recombination of Saccharomyces cerevisiae plasmids. 1939 Jun 37


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