Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human cytomegalovirus UL97 is an unusual protein kinase that can phosphorylate nucleoside analogs such as ganciclovir but whose specificity for exogenous protein substrates has remained unknown. We found that purified, recombinant glutathione S-transferase-UL97 fusion protein can phosphorylate histone H2B. Phosphorylation was abrogated by substitution of glutamine for a conserved lysine in subdomain II and inhibited by a new antiviral drug, maribavir. Sequencing and mass spectrometric analyses of purified (32)P-labeled tryptic peptides of H2B revealed that the sites of phosphorylation were, in order of extent, Ser-38, Ser-87, Ser-6, Ser-112, and Ser-124. Phosphorylation of synthetic peptides containing these sites, analyzed using a new, chimeric gel system, correlated with their phosphorylation in H2B. Phosphorylation of the Ser-38 peptide by UL97 occurred on Ser-38 and was specifically sensitive to maribavir, whereas phosphorylation of this peptide by cAMP-dependent protein kinase occurred on Ser-36. The extent of phosphorylation was greatest with peptides containing an Arg or Lys residue 5 positions downstream (P+5) from the Ser. Substitution with Ala at this position essentially eliminated activity. These results identify exogenous protein and peptide substrates of UL97, reveal an unusual dependence on the P+5 position, and may abet discovery of new inhibitors of UL97 and human cytomegalovirus replication.
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PMID:Specific phosphorylation of exogenous protein and peptide substrates by the human cytomegalovirus UL97 protein kinase. Importance of the P+5 position. 1204 83

The physiological significance of the casein kinase 2 (CK2)-mediated phosphorylation of type II cAMP-dependent protein kinase (PKAIIalpha) and free type II regulatory (R) subunit (RIIalpha) on their activities was mainly investigated in vitro. In these experiments, [gamma-32P]GTP was used as a phosphate donor for the CK2-mediated phosphorylation of free RIIalpha and PKAIIalpha (bovine heart) in vitro. It was found that: (i). CK2 phosphorylated only threonine (Thr)-residues of free RIIalpha and phosphorylated preferentially Thr-residues of the R subunit (RIIalpha) of PKAIIalpha (PKA RIIalpha) in vitro; (ii). this phosphorylation was selectively inhibited by quercetin (an CK2 inhibitor); and (iii). the phosphorylation of free RIIalpha by CK2 resulted in the reduction of its suppressive effect on the activity (phosphorylation of histone H2B) of the catalytic (C) subunit and in the reduction of its ability to form a complex with the C subunit in vitro. As expected, the activity of PKAIIalpha was approx. 3.5-fold enhanced after its R subunit was fully phosphorylated by CK2 in vitro. cAMP synergistically stimulated the activity of PKAIIalpha phosphorylated by CK2 in vitro. These results strongly suggest that CK2 may be a protein kinase responsible for the activation of PKAIIalpha through specific phosphorylation of its R subunit at the cellular level.
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PMID:A novel CK2-mediated activation of type II cAMP-dependent protein kinase through specific phosphorylation of its regulatory subunit (RIIalpha) in vitro. 1451 65

LKB1/STK11 is a tumor suppressor gene responsible for Peutz-Jeghers syndrome, an inherited cancer disorder associated with genome instability. The LKB1 protein functions in the regulation of cell proliferation, polarization and differentiation. Here, we suggest a role of LKB1 in non-homologous end joining (NHEJ), a major DNA double-strand break (DSB) repair pathway. LKB1 localized to DNA ends upon the generation of micro-irradiation and I-SceI endonuclease-induced DSBs. LKB1 inactivation either by RNA interference or by kinase-dead mutation compromised NHEJ-mediated DNA repair by suppressing the accumulation of BRM, a catalytic subunit of the SWI/SNF complex, at DSB sites, which promotes the recruitment of an essential NHEJ factor, KU70. AMPK2, a major substrate of LKB1 and a histone H2B kinase, was recruited to DSBs in an LKB1-dependent manner. AMPK2 depletion and a mutation of H2B that disrupted the AMPK2 phoshorylation site impaired KU70 and BRM recruitment to DSB sites. LKB1 depletion induced the formation of chromosome breaks and radials. These results suggest that LKB1-AMPK signaling controls NHEJ and contributes to genome stability.
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PMID:Possible involvement of LKB1-AMPK signaling in non-homologous end joining. 2358 81

Metformin, one of the most widely prescribed antihyperglycemic drugs, has recently received increasing attention for its potential effects with regard to cancer prevention and treatment. However, the mechanisms behind the suppression of cancer cell growth by metformin remain far from completely understood. The aim of the present study was to investigate whether metformin could regulate histone modification and its downstream gene transcription, and its potential function in inhibiting breast cancer cell proliferation. A T47D cell proliferation curve was determined by cell counting following metformin treatment with differing doses or time courses. The cell cycle was analyzed by flow cytometry with propidium iodide staining. Histone H2B monoubiquitination was evaluated by western blotting subsequent to histone extraction. The histone H2B monoubiquitination downstream gene expression level was determined by quantitative PCR. The results showed that metformin changed the cell-cycle check-point and inhibited breast cancer cell proliferation in a dose-dependent manner. AMPK was activated and histone H2B monoubiquitination and downstream gene transcription were inhibited following metformin treatment in the T47D cells. The effect of metformin on T47D cell proliferation was dependent on AMPK activity. It was concluded that metformin can suppress breast cancer cell growth by the activation of AMPK and the inhibition of histone H2B monoubiquitination and downstream gene transcription. This study reveals a novel potential mechanism of cancer cell growth suppression by metformin.
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PMID:Metformin inhibits histone H2B monoubiquitination and downstream gene transcription in human breast cancer cells. 2500 58


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