Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylselenocysteine (MSC), an organic selenium compound is an effective chemopreventive agent against mammary cell growth both in vivo and in vitro but its mechanism of action is still not understood. We have previously demonstrated that MSC is able to inhibit growth in a synchronized TM6 mouse mammary epithelial tumor cell line at 16 h time point followed by apoptosis at 48 h. The decrease in cdk2 kinase activity was coincident with prolonged arrest of cells in S-phase. The present set of experiments showed that cdk2 phosphorylation was reduced by 72% in the MSC-treated cells at 16 h time point. Expression for gadd34, 45 and 153 was elevated 2.5 to 7 fold following MSC treatment only after 16 h time point. In order to investigate a possible upstream target for MSC, we analyzed protein kinase C (PKC) in this model. Total PKC activity was reduced in TM6 cells by MSC (50 microM) within 30 min of treatment, both in cytosolic (55.4 and 77.6%) and membrane (35.2 and 34.1%) fractions for calcium-dependent and independent PKCs, respectively. PMA significantly elevated the PKC activity in membrane fraction (P < 0.01) and MSC inhibited this activation by more than 57%. The effect of MSC was selenium specific as selenomethionine and sulfurmethyl-L-cysteine (SMC) did not alter PKC activity either in cytosolic or membrane fraction. Immunoblot analysis showed that PKC-alpha was translocated to the membrane by PMA and MSC did not alter this translocation. PKC-delta was faintly detectable in membrane fractions of control and MSC-treated cells. MSC treatment slightly reduced levels of PKC-e (in cytosolic and membrane fractions) and PKC-zeta (cytosolic fractions). The data presented herein suggest that PKC is a potential upstream target for MSC that may trigger one or all of the downstream effects; i.e. the decrease of cdk2 kinase activity, decreased DNA synthesis, elevation of gadd gene expression and finally apoptosis.
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PMID:Effects of methylselenocysteine on PKC activity, cdk2 phosphorylation and gadd gene expression in synchronized mouse mammary epithelial tumor cells. 1065 18

Methylseleninic acid (MSeA) is a synthetic organoselenium form known to be effective against mammary carcinogenesis in vivo. Using the synchronized mouse mammary epithelial tumor cell (TM6) model, we have previously shown that 5 microM MSeA significantly inhibits cell growth and induces a reversible growth arrest in the G1 phase. In the present study, we examined the effects of MSeA on Rb, cyclin dependent kinase 2 (cdk2), cdk4, cyclin E and cyclin D1. Growth arrest of cells was accompanied by a reduction in total cdk2 kinase and cyclin E-associated cdk2 kinase activities. The p27 levels associated with cdk2 were elevated during the cell cycle. In addition, growth inhibition correlated with a relative increase in the hypophosphorylated form of Rb in MSeA-treated cells and Egr1 was elevated in MSeA-treated cells. The Kinetworks Protein Kinase Screen (KPKS 1.0) was used to examine 75 protein kinases. MSeA treatment resulted in differential expression of several protein-serine/threonine kinases, protein-tyrosine kinases and protein-threonine/tyrosine kinases. Some of these kinases are being reported for the first time as being altered by MSeA. The outcome of these experiments will be of significance since these kinases are known to be involved in survival and/or apoptotic pathways of tumor cells.
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PMID:In vitro growth inhibition of mouse mammary epithelial tumor cells by methylseleninic acid: involvement of protein kinases. 1868 92