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

---

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

Past research indicated that methylseleninic acid (MSA) is an excellent tool for investigating the cancer chemopreventive action of selenium in vitro. The present study was designed to examine the cellular and molecular effects of MSA in the MCF10AT1 and MCF10AT3B premalignant human breast cells. After exposure to MSA, both cell lines exhibited a dose- and time-dependent growth-inhibitory response as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay. Further characterization of cellular and molecular changes was carried out only with the MCF10AT1 cells. Flow cytometry analysis showed that MSA blocked cell cycle progression at the G(0)-G(1) phase. Induction of apoptosis was also observed with the use of either the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) or the annexin V binding method. cDNA microarray analyses with cell cycle- and apoptosis-targeted arrays were then applied to profile the gene expression changes mediating these two cellular events. The analyses were conducted at 6 and 12 h of MSA treatment using synchronized cells. The expression signals of 30 genes were found to be significantly altered by MSA. These genes fall into three categories: cell cycle checkpoint controllers (e.g., cyclins, cdcs, cdks, E2F family proteins, and serine/threonine kinases), apoptosis regulatory genes (e.g., Apo-3, c-jun, and cdk5/cyclin D1), and signaling molecules [e.g., mitogen-activated protein (MAP)/extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3'-kinase (PI3k) cascade genes]. The expression changes of 15 genes were selected for verification by Western or semiquantitative reverse transcription-PCR analyses. An agreement rate of 60% (9 of 15) was obtained from these confirmation experiments. On the basis of the above findings, tentative signaling pathways mediating the outcome of selenium-induced cell cycle arrest and apoptosis are proposed. The present study thus demonstrated the feasibility of applying cDNA microarray technology in delineating the mechanisms of the action of selenium and in pinpointing molecular targets as potential biomarkers for evaluating the efficacy of selenium intervention.
...
PMID:Identification of molecular targets associated with selenium-induced growth inhibition in human breast cells using cDNA microarrays. 1183 May 24

The essential role of selenium (Se) in nutrition is well established. The elucidation of the mechanisms by which selenium regulates the cell cycle can lead to a better understanding of the nature of selenium's essentiality and its role in disease prevention. In this study, the effects of selenium deficiency or adequacy (0.25 micromol/L selenite or selenomethionine) on HL-60 cell cycle progression were examined in serum-free media. Selenium was critical for promotion of HL-60 cell growth. Cell-cycle analysis revealed that selenium deficiency caused a decrease in G1 phase cells that corresponded to an increase in G2 and sub-G1 phase cells. Gene array analysis suggested that c-Myc, cyclin C, proliferating cell nuclear antigen, cyclin-dependent kinase (cdk)1, cdk2, cdk4, cyclin B and cyclin D2 mRNA levels were lower in selenium-deficient cells than in the cells supplemented with 0.25 micromol/L selenomethionine. The decrease in the c-Myc mRNA level in selenium-deficient cells was confirmed by reverse transcription-polymerase chain reaction analysis. Furthermore, the phosphorylation state of total cellular protein was higher (57%) in selenium-supplemented cells than in selenium-deficient cells. Collectively, these results suggest a novel role for selenium at 0.25 micromol/L in up-regulation of the expression of numerous cell cycle-related genes and total cellular phosphorylated proteins in HL-60 cells in serum-free culture media. This leads to the promotion of cell cycle progression, particularly G2/M transition and/or the reduction of apoptosis, primarily in G1 cells. These observations may have additional implications for understanding the nature of selenium's essentiality.
...
PMID:Selenite and selenomethionine promote HL-60 cell cycle progression. 1192 59

Prostate cancer (PCA) is the most common histological malignancy and the second leading cause of cancer deaths among North American men. There has been considerable interest in the chemopreventative properties of selenium. In this study, we assessed whether selenium inhibits cell growth and associated cell cycle regulatory proteins. Human PCA cells (LNCaP, PC3, PC3-AR2, and PC3-M) were incubated with and without selenium (Seleno-DL-methionine, 150 microM) for 24, 48, and 72 h. Cells were fixed and stained with propidium iodide for flow cytometry analysis. In parallel experiments, total protein was extracted, immunoprecipitated with cyclin E antibody, and analyzed by Western blot for the expression of cell cycle markers. Treatment with selenium caused G1 arrest and an 80% reduction in the S phase of LNCaP with no effect on PC3. However, PC3 cells transfected with the androgen receptor (PC3-AR2) exhibited a G2/M arrest and a marked reduction (57%) in the S phase during cell cycle progression. In the analysis of cell cycle regulatory molecules, selenium-treated cells demonstrated a significant induction of cyclin-dependent kinase inhibitors Cip1/p21 and Kip1/p27. These data suggest that selenium possesses strong antiproliferative properties in regard to human PCA. This effect appears to be dependent on the presence of a functioning androgen receptor. This provides a theoretical basis for Phase III studies of selenium in PCA prevention.
...
PMID:Selenium modulation of cell proliferation and cell cycle biomarkers in human prostate carcinoma cell lines. 1198 Jun 47

Previous work based on mono-methyl selenium compounds that are putative precursors of methylselenol has strongly implicated this metabolite in the induction of caspase-mediated apoptosis of human prostate carcinoma and leukemia cells and G1 arrest in human vascular endothelial and cancer epithelial cells. To test the hypothesis that methylselenol itself is responsible for exerting these cellular effects, we examined the apoptotic action on DU145 human prostate cancer cells and the G1 arrest effect on the human umbilical vein endothelial cells (HUVECs) of methylselenol generated with seleno-L-methionine as a substrate for L-methionine-alpha-deamino-gamma-mercaptomethane lyase (EC4.4.1.11, also known as methioninase). Exposure of DU145 cells to methylselenol so generated in the sub-micromolar range led to caspase-mediated cleavage of poly(ADP-ribose) polymerase, nucleosomal DNA fragmentation, and morphologic apoptosis and resulted in a profile of biochemical effects similar to that of methylseleninic acid (MSeA) exposure as exemplified by the inhibition of phosphorylation of protein kinase AKT and extracellularly regulated kinases 1/2. In HUVEC, methylselenol exposure recapitulated the G1 arrest action of MSeA in mitogen-stimulated G1 progression during mid-G1 to late G1. This stage specificity was mimicked by inhibitors of phosphatidylinositol 3-kinase. The results support methylselenol as an active selenium metabolite for inducing caspase-mediated apoptosis and cell-cycle G1 arrest. This cell-free methylselenol-generation system is expected to have significant usefulness for studying the biochemical and molecular targeting mechanisms of this critical metabolite and may constitute the basis of a novel therapeutic approach for cancer, using seleno-L-methionine as a prodrug.
...
PMID:Induction of caspase-mediated apoptosis and cell-cycle G1 arrest by selenium metabolite methylselenol. 1211 5

Selenium has been implicated as a promising chemopreventive agent for prostate cancer. Whereas the anticancer mechanisms have not been clearly defined, one hypothesis relates to selenium metabolites, especially the monomethyl selenium pool, generated under supranutritional selenium supplementation. To explore potential molecular targets for mediating the chemopreventive activity, we contrasted the effects of methylseleninic acid (MSeA), a novel precursor of methylselenol, versus sodium selenite, a representative of the hydrogen selenide metabolite pool, on apoptosis execution, cell cycle distribution, and selected protein kinases in DU145 human prostate cancer cells. Exposure of DU145 cells to 3 microM MSeA led to a profound G1 arrest at 24 h, and exposure to greater concentrations led to not only G1 arrest, but also to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose) polymerase (PARP), two biochemical hallmarks of apoptosis. Immunobiot analyses indicated that G1 arrest induced by the subapoptogenic doses of MSeA was associated with increased expression of p27kip1 and p21cip1, but apoptosis was accompanied by dose-dependent decreases of phosphorylation of protein kinase AKT and extracellular signal-regulated kinase (ERK1/2) in the absence of any phosphorylation change in p38 mitogen-activated protein kinase (p38MAPK) and c-Jun NH2-terminal kinase (JNK1/2). In contrast, selenite exposure caused S-phase arrest and caspase-independent apoptotic DNA fragmentation, which were associated with decreased expression of p27kip1 and p21cip1 and increased phosphorylation of AKT, JNK1/2, and p38MAPK. Although apoptosis induction by MSeA exposure was not sensitive to superoxide dismutase added into the cell culture medium, cell detachment and DNA nucleosomal fragmentation induced by selenite exposure were greatly attenuated by this enzyme, supporting a chemical mediator role of superoxide for these processes. Despite a temporal relationship of AKT and ERK1/2 de-phosphorylation changes before the onset of PARP cleavage in MSeA-exposed cells, experiments with phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 did not show an enhancing effect of specific blocking of AKT on MSeA-induction of PARP cleavage. Taken together, exposure of DU145 cells to MSeA versus selenite induced differential patterns of cell cycle arrest and apoptosis execution as well as distinct patterns of effects on AKT, ERK1/2, JNK1/2, and p38MAPK phosphorylation and p27kip1 and p21cip1 expression. Multiple molecular pathways are likely differentially targeted by selenium metabolite pools to mediate cancer chemoprevention.
...
PMID:Distinct effects of methylseleninic acid versus selenite on apoptosis, cell cycle, and protein kinase pathways in DU145 human prostate cancer cells. 1248 29

Selenium (Se) is an essential trace element for animals. Selenocysteine (Sec), the 21st aminoacid, is a component of selenoproteins and has been founded in the active center of selenoenzymes. The functions of Se within the body have been primarily shown in the forms of selenoproteins, especially selenoenzymes. Incorporation of selenocysteine occurs on the basis of genetic expression and Se is the only trace element under direct genetic control. Recently, findings have shown that Se and selenocompounds conducted many other potential functions such as protection against inflammatory factors, inhibition of protein kinase C (PKC), stimulation of MAP kinase (mitogen activated protein kinase/myelin basic protein kinase) and S6 kinase (ribosomal S6 protein kinase), regulation of the immune system and interaction with other elements and vitamins etc, suggesting that the roles of Se in human health may be more diverse than previously suspected.
...
PMID:[Research progress in physiological functions of selenoenzyme and other selenocompounds]. 1254 53

Ebselen, a selenium-containing heterocyclic compound, prevents ischemia-induced cell death. However, the molecular mechanism through which ebselen exerts its cytoprotective effect remains to be elucidated. Using sodium nitroprusside (SNP) as a nitric oxide (NO) donor, we show here that ebselen potently inhibits NO-induced apoptosis of differentiated PC12 cells. This was associated with inhibition of NO-induced phosphatidyl Serine exposure, cytochrome c release, and caspase-3 activation by ebselen. Analysis of key apoptotic regulators during NO-induced apoptosis of differentiated PC12 cells showed that ebselen blocks the activation of the apoptosis signaling-regulating kinase 1 (ASK1), and inhibits phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal protein kinase (JNK). Moreover, ebselen inhibits NO-induced p53 phosphorylation at Ser15 and c-Jun phosphorylation at Ser63 and Ser73. It appears that inhibition of p38 MAPK and p53 phosphorylation by ebselen occurs via a thiol-redox-dependent mechanism. Interestingly, ebselen also activates p44/42 MAPK, and inhibits the downregulation of the antiapoptotic protein Bcl-2 in SNP-treated PC12 cells. Together, these findings suggest that ebselen protects neuronal cells from NO cytotoxicity by reciprocally regulating the apoptotic and antiapoptotic signaling cascades.
...
PMID:Ebselen inhibits NO-induced apoptosis of differentiated PC12 cells via inhibition of ASK1-p38 MAPK-p53 and JNK signaling and activation of p44/42 MAPK and Bcl-2. 1471 91

The aberrant behavior of cancer reflects upregulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Theoretically, it should be feasible to decrease the activity of these pathways-or increase the activity of pathways that oppose them-with noncytotoxic agents. Since multiple pathways are dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, the greatest and most durable therapeutic benefit will likely be achieved with combination regimens that address several targets. Thus, a multifocal signal modulation therapy (MSMT) of cancer is proposed. This concept has already been documented by researchers who have shown that certain combinations of signal modulators-of limited utility when administered individually-can achieve dramatic suppression of tumor growth in rodent xenograft models. The present essay attempts to guide development of MSMTs for prostate cancer. Androgen ablation is a signal-modulating measure already in standard use in the management of delocalized prostate cancer. The additional molecular targets considered here include the type 1 insulin-like growth factor receptor, the epidermal growth factor receptor, mammalian target of rapamycin, NF-kappaB, hypoxia-inducible factor-1alpha, hsp90, cyclooxygenase-2, protein kinase A type I, vascular endothelial growth factor, 5-lipoxygenase, 12-lipoxygenase, angiotensin II receptor type 1, bradykinin receptor type 1, c-Src, interleukin-6, ras, MDM2, bcl-2/bclxL, vitamin D receptor, estrogen receptor-beta, and PPAR-. Various nutrients and phytochemicals suspected to have potential utility in prostate cancer prevention and therapy, but whose key molecular targets are still unknown, might reasonably be incorporated into MSMTs for prostate cancer; these include lycopene, selenium, green tea polyphenols, genistein, and silibinin. MSMTs can be developed systematically by testing various combinations of signal-modulating agents, in concentrations that can feasibly be achieved and maintained clinically, on human prostate cancer cell lines; combinations that appear promising can then be tested in xenograft models and, ultimately, in the clinic. Some signal modulators can increase response to cytotoxic drugs by upregulating effectors of apoptosis. When MSMTs fail to raise the spontaneous apoptosis rate sufficiently to achieve tumor stasis or regression, incorporation of appropriate cytotoxic agents into the regimen may improve the clinical outcome.
...
PMID:Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy. 1552 6

The coiled-coil domain of dystrophia myotonica protein kinase (DMPK) has been cloned, overexpressed, purified and crystallized. Two crystal forms have been obtained that belong to space groups P3 and P2(1)2(1)2(1) and diffract to 2.4 and 1.6 A resolution, respectively. Experimental phases were obtained by MAD from an SeMet derivative. The location of selenium sites used molecular-replacement phases obtained from search models lacking sequence similarity with the coiled-coil under study. Both crystal forms contain three polypeptide chains in the asymmetric unit.
...
PMID:Crystallization and preliminary X-ray analysis of the coiled-coil domain of dystrophia myotonica kinase. 1558 83

Methylselenol has been implicated as an active metabolite for the anticancer effect of selenium in part through the induction of cancer cell apoptosis. Since inactivation of the AKT/protein kinase B negative regulator gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) is common in prostate cancer (PCa), we compared PTEN wild-type DU145 PCa cells (low basal AKT activity) with PTEN-mutant LNCaP PCa cells (high basal AKT activity) for their apoptosis responses to the methylselenol precursor methylseleninic acid (MSeA) and sodium selenite, an inorganic salt. Our results show that LNCaP cells withstood approximately 4 times higher doses of MSeA than DU145 cells, although they were slightly more sensitive than the latter to selenite-induced apoptosis. Treatment by MSeA modestly attenuated AKT phosphorylation and increased phospho-ERK1/2 in LNCaP cells. Selenite treatment increased the phosphorylation of p53 Ser15 and both kinases, but the selenite-induced apoptosis was not influenced by chemical inhibitors of either kinase. In contrast, PI3K/AKT inhibitors greatly sensitized LNCaP cells to apoptosis induced by MSeA, accompanied by increased mitochondrial release of cytochrome c and multiple caspase activation without changing p53 Ser15 phosphorylation. The apoptosis was further accentuated by extracellular signal regulated kinases 1 and 2 (ERK1/2) inhibition without further increase in cytochrome c release. The general caspase inhibitor z-VAD-fmk completely blocked MSeA-induced apoptosis when both kinases were inhibited, whereas a caspase-8 inhibitor exerted a greater protection than did a caspase-9 inhibitor. Transfection of DU145 cells with a constitutively active AKT increased their resistance to MSeA-induced apoptosis. In summary, AKT played an important role in regulating apoptosis sensitivity of LNCaP and DU145 cells to MSeA. An MSeA-induced activation of ERK1/2 in LNCaP cells also contributed to resistance to apoptosis. However, these kinases did not significantly regulate caspase-mediated apoptosis induced by selenite in LNCaP cells. These findings support the differential involvement of these protein kinase pathways in regulating apoptosis induction by different forms of selenium.
...
PMID:PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. 1584 51


<< Previous 1 2 3 4 5 6 Next >>

---