title: A new, unexpected action of olomoucine, a CDK inhibitor, on normal human cells: up-regulation of CLIMP-63, a cytoskeleton-linking membrane protein.
abstract: Inhibition of cyclin-dependent kinases (CDKs) is a novel strategy in the therapy of human malignancies. The pharmacological CDK inhibitors representing a few distinct classes of compounds exert different target specificity. Considering the fact that dividing and quiescent cells differ in their CDK activity and in the pattern of their expression, one might expect that anti-proliferative efficiency of the pharmacological CDK inhibitors would depend on the mitotic index of treated cells. The present article shows that olomoucine (OLO), a weak CDK2 inhibitor has new, unexpected activity. At concentrations up to 100 microM OLO did not inhibit proliferation of normal human cells, but arrested growth of human HL-60 leukemia cells. The anti-proliferative effect of OLO was clearly weaker than that of roscovitine (ROSC). Surprisingly, OLO at low doses strongly up-regulated a cellular protein with approximately 65 kDa in normal, but not in immortalized and cancer cells. By mass spectrometric analysis CLIMP-63, a cytoskeleton-linking membrane protein was identified as the major component of the up-regulated protein band. These results were subsequently confirmed by immunoblotting. Further experiments revealed that OLO, but not ROSC, strongly up-regulates CLIMP-63 in a dose- and time-dependent manner solely in senescent cells.
authors.affiliation: Cell Cycle Regulation Group, Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria. jozefa.gadek-wesierski@meduniwien.ac.at
authors.forename: Józefa
authors.initials: J
authors.lastname: Wesierska-Gadek
authors.forename: Marieta
authors.initials: M
authors.lastname: Gueorguieva
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Kramer
authors.forename: Carmen
authors.initials: C
authors.lastname: Ranftler
authors.forename: Bettina
authors.initials: B
authors.lastname: Sarg
authors.forename: Herbert
authors.initials: H
authors.lastname: Lindner
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004247:DNA / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D018922:HL-60 Cells; D006801:Humans; D007701:Kinetin / Q000494:pharmacology* / Q000633:toxicity; D008168:Lung / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D012867:Skin / Q000166:cytology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C081876:CKAP4 protein, human; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011687:Purines; D000077546:Roscovitine; C090046:olomoucine; D004247:DNA; D018844:Cyclin-Dependent Kinases; D007701:Kinetin