Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.13.3 (histidine kinase)
 2,405 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

How bacteria regulate cell cycle progression at a molecular level is a fundamental but poorly understood problem. In Caulobacter crescentus, two-component signal transduction proteins are crucial for cell cycle regulation, but the connectivity of regulators involved has remained elusive and key factors are unidentified. Here we identify ChpT, an essential histidine phosphotransferase that controls the activity of CtrA, the master cell cycle regulator. We show that the essential histidine kinase CckA initiates two phosphorelays, each requiring ChpT, which lead to the phosphorylation and stabilization of CtrA. Downregulation of CckA activity therefore results in the dephosphorylation and degradation of CtrA, which in turn allow the initiation of DNA replication. Furthermore, we show that CtrA triggers its own destruction by promoting cell division and inducing synthesis of the essential regulator DivK, which feeds back to downregulate CckA immediately before S phase. Our results define a single integrated circuit whose components and connectivity can account for the cell cycle oscillations of CtrA in Caulobacter.
Nature 2006 Dec 14
PMID:Regulation of the bacterial cell cycle by an integrated genetic circuit. 1713

Epidermal growth factor receptor (EGFR) is usually overexpressed in nasopharyngeal carcinoma (NPC). Our recent in vitro study has demonstrated that cetuximab (an antibody drug against EGFR) inhibits the growth of NPC cell lines, HK1 and HONE-1. The present study investigates the effect of cetuximab on protein expressions of NPC cell lines. NPC cells were cultured in the absence or presence of cetuximab at the IC50 concentrations (3 nM for HK1 and 0.3 nM for HONE-1) for 48 h, and total cell lysates were extracted. The cell lysates were then subjected to two-dimensional polyacrylamide gel electrophoresis (2D PAGE), and the 2D gel images were compared to discover the protein changes caused by cetuximab treatment. The common differentially expressed proteins in NPC cell lines were identified by peptide mass fingerprinting. We found that heat shock protein gp96 was down-regulated, while alpha-enolase, tumor suppressor protein maspin, and p97 valosin containing protein were up-regulated after cetuximab treatment. Reverse-transcription polymerase chain reaction (RT-PCR) analysis confirmed that the changes in protein levels of gp96, maspin, and p97 coincided with mRNA levels, indicating that these proteins were regulated at transcriptional levels. Up-regulation of gp96 has been observed in various cancers and reported to have tumor protective effects. P97 is a multifunctional AAA (ATPase associated with a variety of activities) protein and is involved in numerous cellular activities including membrane transport, protein folding, protein degradation, and cell division. Maspin has been shown to increase apoptosis, and block the growth, invasion, and metastatic properties of many tumors. The comparative tumor suppression effects of cetuximab and maspin suggest that cetuximab might exert its antitumor effects partly by up-regulation of maspin expression. The study also indicates that proteomic analysis is a promising approach to elucidate the functional mechanisms of anticancer drugs. Pharmacoproteomic study may also help to identify clinical responders for drug treatment and provide insight for new drug development.
J Proteome Res 2006 Dec
PMID:Pharmacoproteomics study of cetuximab in nasopharyngeal carcinoma. 1713 27

When glucose-repressed, Saccharomyces cerevisiae cannot use acetic acid as a carbon source and is inhibited in growth by high levels of this compound, especially at low pH. Cultures exposed to a 100 mM acetate stress activate both the Hog1p and Slt2p stress-activated MAP kinases. Nevertheless, only active Hog1p, not Slt2p, is needed for the acquisition of acetate resistance. Hog1p undergoes more rapid activation by acetate in pH 4.5, than in pH 6.8 cultures, an indication that the acid may have to enter the cells in order to generate the Hog1p activatory signal. Acetate activation of Hog1p is absent in the ssk1Delta and pbs2Delta mutants, but is present in sho1Delta and ste11Delta, showing that it involves the Sln1p branch of the high-osmolarity glycerol (HOG) pathway signaling to Pbs2p. In low-pH (pH 4.5) cultures, the acetate-activated Hog1p, although conferring acetate resistance, does not generate the GPD1 gene or intracellular glycerol inductions that are hallmarks of activation of the HOG pathway by hyperosmotic stress.
FEMS Yeast Res 2006 Dec
PMID:Hog1p mitogen-activated protein kinase determines acetic acid resistance in Saccharomyces cerevisiae. 1715 24

The Ca2+ -activated K+ channel KCa3.1 is required for Ca2+ influx and the subsequent activation of B and T cells. Inhibitors of KCa3.1 are in development to treat autoimmune diseases and transplant rejection, underscoring the importance in understanding how these channels are regulated. We show that nucleoside diphosphate kinase B (NDPK-B), a mammalian histidine kinase, functions downstream of PI(3)P to activate KCa3.1. NDPK-B directly binds and activates KCa3.1 by phosphorylating histidine 358 in the carboxyl terminus of KCa3.1. Endogenous NDPK-B is also critical for KCa3.1 channel activity and the subsequent activation of CD4 T cells. These findings provide one of the best examples whereby histidine phosphorylation regulates a biological process in mammals, and provide an example whereby a channel is regulated by histidine phosphorylation. The critical role for NDPK-B in the reactivation of CD4 T cells indicates that understanding NDPK-B regulation should uncover novel pathways required for T cell activation.
Mol Cell 2006 Dec 08
PMID:Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. 1715 50

Two-component signal-transducing systems are ubiquitously distributed communication interfaces in bacteria. They consist of a histidine kinase that senses a specific environmental stimulus and a cognate response regulator that mediates the cellular response, mostly through differential expression of target genes. Histidine kinases are typically transmembrane proteins harboring at least two domains: an input (or sensor) domain and a cytoplasmic transmitter (or kinase) domain. They can be identified and classified by virtue of their conserved cytoplasmic kinase domains. In contrast, the sensor domains are highly variable, reflecting the plethora of different signals and modes of sensing. In order to gain insight into the mechanisms of stimulus perception by bacterial histidine kinases, we here survey sensor domain architecture and topology within the bacterial membrane, functional aspects related to this topology, and sequence and phylogenetic conservation. Based on these criteria, three groups of histidine kinases can be differentiated. (i) Periplasmic-sensing histidine kinases detect their stimuli (often small solutes) through an extracellular input domain. (ii) Histidine kinases with sensing mechanisms linked to the transmembrane regions detect stimuli (usually membrane-associated stimuli, such as ionic strength, osmolarity, turgor, or functional state of the cell envelope) via their membrane-spanning segments and sometimes via additional short extracellular loops. (iii) Cytoplasmic-sensing histidine kinases (either membrane anchored or soluble) detect cellular or diffusible signals reporting the metabolic or developmental state of the cell. This review provides an overview of mechanisms of stimulus perception for members of all three groups of bacterial signal-transducing histidine kinases.
Microbiol Mol Biol Rev 2006 Dec
PMID:Stimulus perception in bacterial signal-transducing histidine kinases. 1715 4

Nonmelanoma skin cancer (NMSC) is the most frequently diagnosed cancer in the United States. Deregulation of bcl-2 and ras family members is commonly observed in NMSC. It has been previously demonstrated that simultaneous bcl-2 and Ha-ras gene expression in keratinocytes results in disordered differentiation and resistance to cell death induced by ultraviolet (UV) radiation. It was, therefore, interest to assess the extent of cooperation between bcl-2 and Ha-ras during multistep skin carcinogenesis. The keratin 1 promoter was used to generate HK1.ras and HK1.bcl-2 transgenic mice, which were subsequently crossed to generate HK1.ras/bcl-2 double transgenic mice. The apoptotic index (AI) following UV-irradiation was significantly lower in HK1.bcl-2 and HKI.ras/bcl-2 epidermis compared to control littermates. Interestingly, the AI of HK1.ras/bcl-2 mice was significantly lower than even HK1.bcl-2 mice following UV-irradiation. To investigate the interaction of these oncogenes in skin tumorigenesis, a two-stage chemical carcinogenesis protocol was used to induce tumors. The individual contributions of Ha-ras and bcl-2 to papilloma latency, incidence, and growth rate in HK1.ras/bcl-2 double transgenic mice was marginally additive. Papillomas arising in HK1.ras transgenic mice exhibited the highest rate of apoptosis whereas papillomas arising in the HK1.ras/bcl-2 double transgenic mice exhibited rates of apoptosis that were significantly lower than papillomas arising in either control littermate or HK1.ras mice. Constitutive expression of either Ha-ras or bcl-2 exhibited similar rates of malignant tumor progression and they were not significantly different than control littermates. Importantly, when these two oncoproteins were coexpressed, a significant, and synergistic, increase in malignant transformation was observed.
Mol Carcinog 2007 Dec
PMID:Cooperation of Ha-ras and Bcl-2 during multistep skin carcinogenesis. 1753 44

The Bacillus subtilis BceAB ABC transporter involved in a defense mechanism against bacitracin is composed of a membrane-spanning domain and a nucleotide-binding domain. Induction of the structural bceAB genes requires the BceR response regulator and the BceS histidine kinase of a signal transduction system. However, despite the presence of such a transduction system and of bacitracin, no transcription from an unaltered bceA promoter is observed in cells lacking the BceAB transporter. Expression in trans of the BceAB transporter in these bceAB cells restores the transcription from the bceA promoter. Cells possessing a mutated nucleotide-binding domain of the transporter are also no longer able to trigger transcription from the bceA promoter in the presence of bacitracin, although the mutated ABC transporter is still bound to the membrane. In these cells, expression of the bceA promoter can no longer be detected, indicating that the ABC transporter not only must be present in the cell membrane, but also must be expressed in a native form for the induction of the bceAB genes. Several hypotheses are discussed to explain the simultaneous need for bacitracin, a native signal transduction system, and an active BceAB ABC transporter to trigger transcription from the bceA promoter.
J Bacteriol 2007 Dec
PMID:Resistance to bacitracin in Bacillus subtilis: unexpected requirement of the BceAB ABC transporter in the control of expression of its own structural genes. 1790 82

Two-component signal transduction systems consisting of a sensor histidine kinase and a response regulator/transcription factor interpret a multitude of environmental and cellular signals and coordinate the expression of a wide array of genes in bacteria. Signal recognition by sensor histidine kinases is the province of a sensor complex consisting of several protein domains that together serve to augment or attenuate the activity of the histidine kinase and thereby of gene expression. Recent investigations have shown the diverse strategies bacteria use to assemble protein domains into the sensor complexes to accomplish signaling. Structural studies of such domains are leading to an understanding of the mechanisms by which sensor complexes recognize signals and regulate kinase activity.
Curr Opin Struct Biol 2007 Dec
PMID:Sensor complexes regulating two-component signal transduction. 1791 92

Among the sigma70 family bacterial sigma factors, group 2 sigma factors have similar promoter recognition specificity to group 1 (principal) sigma factors and express and function under specific environmental and physiological conditions. In general, the cyanobacterial genome encodes more than four group 2 sigma factors, and the unicellular Synechococcus elongatus PCC 7942 (Synechococcus) has five group 2 sigma factors (RpoD2-6). In this study, we analyzed expression of group 2 sigma factors of Synechococcus at both mRNA and protein levels, and we showed that the rpoD3 expression was activated only by high light (1,500 micromol photons m(-2) s(-1)) among the various stress conditions examined. After high light shift, rpoD3 mRNA accumulated transiently within the first 5 min and diminished subsequently, whereas RpoD3 protein increased gradually during the first several hours. We also found that the rpoD3 deletion mutant rapidly lost viability under the same conditions. Analysis of the rpoD3 promoter structure revealed the presence of an HLR1 (high light-responsive element 1) sequence, which was suggested to be responsible for the high light-induced transcription under the control of the NblS (histidine kinase)-RpaB (response regulator) two-component system (Kappell, A. D., and van Waasbergen, L. G. (2007) Arch. Microbiol. 187, 337-342), at +6 to +23 with respect to the transcriptional start site. Here we demonstrated that recombinant RpaB protein specifically bound to HLR1 of the rpoD3 and hliA genes in vitro, and overexpression of a truncated RpaB variant harboring only the phosphoreceiver domain derepressed the transcription in vivo. Thus, we have concluded that phosphorylated RpaB are repressing the rpoD3 and hliA transcription under normal growth conditions, and the RpaB dephosphorylation induced by high light stress results in transcriptional derepression.
J Biol Chem 2007 Dec 21
PMID:Induction of a group 2 sigma factor, RPOD3, by high light and the underlying mechanism in Synechococcus elongatus PCC 7942. 1797 31

Integral membrane proteins have become the focus of interest of many laboratories and structural genomics consortia, but their study is hampered by bottlenecks in production, solubilization, purification and crystallization. In our laboratory we have addressed the problem of high-level protein expression in the membrane of Escherichia coli by use of Mistic, a novel Bacillus subtilis protein, as a fusion partner. In this study we examine the effect of Mistic on protein expression and membrane integration levels of members of the E. coli histidine kinase receptor family. We find that Mistic fusion invariably increases the overall yield by targeting the cargo proteins more efficiently to the membrane and may even replace the signal sequence. Mistic fusion methods will likely be instrumental for high-level expression of other integral membrane proteins.
J Struct Funct Genomics 2007 Dec
PMID:Application of Mistic to improving the expression and membrane integration of histidine kinase receptors from Escherichia coli. 1798 11


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