Mimosine arrests cells in G1 by enhancing the levels of p27(Kip1).
The plant amino acid mimosine, an effective inhibitor of DNA replication, has been demonstrated to arrest cell cycle progression in late G1. To understand further the molecular mechanism by which mimosine affects the cell cycle, we treated quiescent cells with serum in the presence of 800 microM mimosine. The cells did not enter S phase and were completely arrested in G1 phase. Although neither the mitogenic induction of the G1 cyclins nor the protein levels of cdk2 or cdk4 were affected, serum-dependent activation of cdk2 was blocked. This corresponded to elevated levels of the cdk inhibitor p27(Kip1). This was not mediated through inhibition of degradation but rather involved increased synthesis of both p27(Kip1) mRNA and protein. Mimosine did not appear to affect mitogen-dependent signals that normally lead to p27(Kip1) downregulation since the inhibitor was induced to even greater levels in quiescent, unstimulated cells. In the presence of mimosine, actinomycin D treatment for 2 h prevented the increase of p27(Kip1) mRNA, but p27(Kip1) protein levels were still enhanced under these conditions. We propose that mimosine blocks the cell cycle in late G1 phase by upregulation of p27(Kip1) protein levels through transcriptional and posttranscriptional regulatory mechanisms.
Wang
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Division of Basic Biomedical Sciences, School of Medicine, Vermillion, South Dakota, 57069, USA.
Miskimins
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Miskimins
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D016475:3T3 Cells; D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D056741:Cyclin D; D019927:Cyclin E / Q000096:biosynthesis; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008898:Mimosine / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012710:Serum Albumin, Bovine; D008898:Mimosine; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases