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)

Fumagillin analogue AGM-1470 potently inhibits angiogenesis with a minimal toxicity in vivo and is expected to be of therapeutic use as a powerful antitumor agent (Ingber et al., Nature, 348:555-557, 1990). In the present study, we have investigated the effects and the mechanism of action of AGM-1470 on cultured human umbilical vein endothelial cells. AGM-1470 acts directly on endothelial cells to inhibit growth factor-induced DNA synthesis, with half maximal and maximal effects obtained at approximately 2 x 10(-10) and 5 x 10(-9) M, respectively. AGM-1470 does not inhibit early G1 mitogenic events, such as cellular protein tyrosyl phosphorylation or the expression of immediate early genes c-fos and c-myc, but potently inhibits phosphorylation of RB protein, a tumor suppressor retinoblastoma gene product. The later addition of AGM-1470 up to 3 h after the growth factor stimulation still exerts full inhibitory effects on both DNA synthesis and RB phosphorylation, suggesting that the major site of action of AGM-1470 is located relatively late in the G1 phase. AGM-1470 inhibits growth factor-induced activation of candidate RB kinases cdc2 and cdk2 but fails to inhibit them directly in vitro. AGM-1470 completely abolishes the growth factor-induced mRNA expression of cdc2 and cyclin A and partially inhibits that of cyclin E but has little effect on the mRNA level of cdk2, cdk4, or cyclin D1. These results indicate that angioinhibitory action of AGM-1470 involves suppression of mRNA expression of specific members of cdks and cyclins and of activation of both cdc2 and cdk2 kinases in endothelial cells.
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PMID:A fumagillin derivative angiogenesis inhibitor, AGM-1470, inhibits activation of cyclin-dependent kinases and phosphorylation of retinoblastoma gene product but not protein tyrosyl phosphorylation or protooncogene expression in vascular endothelial cells. 801 59

Recent studies have revealed altered regulation of cyclins in breast cancer cells. To understand the role of aberrant cyclin B1 expression in the proliferation of breast cancer cells, we examined cyclin B1-associated proteins in estrogen-responsive MCF-7 cells in a cell cycle-dependent manner. Immunoprecipitation of cell lysate with a monoclonal anti-human cyclin B1 antibody, followed by Western blot probing with an anti-human cdc2 (PSTAIR) antibody revealed the presence of a 34 kDa protein in estradiol-treated cells at 16 h after initiation of cell cycle progression. Flow cytometry and [H-3]-thymidine (Thd) incorporation experiments showed a dramatic increase in the percentage of S phase cells at this time point. This protein was suppressed by an antiestrogen, 4-hydroxytamoxifen. It was not found in MCF-1OA, a normal breast epithelial cell line. The 34 kDa protein was not reactive with antibodies raised against other cyclin dependent kinases (CDKs), including p34(cdc2(Carboxy terminal)). This protein was functionally active as determined by histone H1 kinase activity. These data suggest that the induction of a cyclin B1-associated 34 kDa protein during the G1 --> S transition might be a positive regulator of cell cycle progression in estrogen-responsive breast cancer cells.
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PMID:Estrogenic regulation of a novel 34 kDa protein associated with cyclin B1 in MCF-7 breast cancer cells. 2159 4