TGF-beta induced G(1) cell cycle arrest requires the activity of the proteasome pathway. Transforming growth factor.
Transforming growth factor-beta (TGF-beta) induces a potent G(1)/S-phase cell cycle arrest of epithelial cells by inhibiting the activities of cyclin D- and cyclin E-associated kinase complexes. Downregulation of the kinase activities is mediated by induction of cyclin dependent kinase (CDK) inhibitor p15(Ink4b) which blocks CDK4 and CDK6 kinases and leads to binding of p27(Kip1) to CDK2-cyclin E complex. Levels of several of these factors are controlled by the ubiquitin-proteasome pathway. We demonstrate here that proteasomal inhibitors release the cells from TGF-beta imposed G(1)-phase arrest and instigate the entry of the cells into S-phase. Proteasomal inhibitors are shown to specifically increase the activity of the cyclin D-kinase complex by increasing the levels of p27(Kip1) and cyclin D and by maintaining CDK4/6 protein levels leading to phosphorylation of the retinoblastoma protein without increasing cyclin E-associated kinase activity. The results indicate caution in the potential therapeutic use of the proteasome inhibitors due to unscheduled initiation of DNA replication in the presence of a physiological growth inhibitor.
Zhang
Fan
F
Haartman Institute, Department of Virology and Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Central Hospital Laboratory Diagnostics, Finland.
Mönkkönen
Mia
M
Roth
Stina
S
Laiho
Marikki
M
D000818:Animals; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D007976:Leupeptins / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism
D018797:Cell Cycle Proteins; D016213:Cyclins; D004791:Enzyme Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde