title: Argyrin a reveals a critical role for the tumor suppressor protein p27(kip1) in mediating antitumor activities in response to proteasome inhibition.
abstract: A reduction in the cellular levels of the cyclin kinase inhibitor p27(kip1) is frequently found in many human cancers and correlates directly with patient prognosis. In this work, we identify argyrin A, a cyclical peptide derived from the myxobacterium Archangium gephyra, as a potent antitumoral drug. All antitumoral activities of argyrin A depend on the prevention of p27(kip1) destruction, as loss of p27(kip1) expression confers resistance to this compound. We find that argyrin A exerts its effects through a potent inhibition of the proteasome. By comparing the cellular responses exerted by argyrin A with siRNA-mediated knockdown of proteasomal subunits, we find that the biological effects of proteasome inhibition per se depend on the expression of p27(kip1).
authors.affiliation: Institute for Molecular Biology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Nickeleit
authors.forename: Steffen
authors.initials: S
authors.lastname: Zender
authors.forename: Florenz
authors.initials: F
authors.lastname: Sasse
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Gudrun
authors.initials: G
authors.lastname: Brandes
authors.forename: Inga
authors.initials: I
authors.lastname: Sörensen
authors.forename: Heinrich
authors.initials: H
authors.lastname: Steinmetz
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicka
authors.forename: Teresa
authors.initials: T
authors.lastname: Carlomagno
authors.forename: Dirk
authors.initials: D
authors.lastname: Menche
authors.forename: Ines
authors.initials: I
authors.lastname: Gütgemann
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.forename: Achim
authors.initials: A
authors.lastname: Gossler
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Markus
authors.initials: M
authors.lastname: Kalesse
authors.forename: Ronald
authors.initials: R
authors.lastname: Frank
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000517:prevention & control; D010456:Peptides, Cyclic / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D001897:Boronic Acids; C436291:CDKN1B protein, human; D015853:Cysteine Proteinase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; C530877:argyrin A; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex