title: Gadd45a transcriptional induction elicited by the Aurora kinase inhibitor MK-0457 in Bcr-Abl-expressing cells is driven by Oct-1 transcription factor.
abstract: The advantage of Aurora kinase (AK) inhibitors in chronic myeloid leukemia (CML) therapy mostly arises from "off-target" effects on tyrosine kinase (TK) activity of wild type (wt) or mutated Bcr-Abl proteins which drive the disease resistance to imatinib (IM). We proved that the AK inhibitor MK-0457 induces the growth arrest DNA damage-inducible (Gadd) 45a through recruitment of octamer-binding (Oct)-1 transcription factor at a critical promoter region for gene transcription and covalent modifications of histone H3 (lysine 14 acetylation, lysine 9 de-methylation). Such epigenetic chromatin modifications may depict a general mechanism promoting the re-activation of tumor suppressor genes silenced by Bcr-Abl.
authors.affiliation: Dipartimento di Ematologia e Scienze Oncologiche Lorenzo e Ariosto Seràgnoli, University of Bologna - Medical School, Bologna, Italy. mancini manu@yahoo.com
authors.forename: Manuela
authors.initials: M
authors.lastname: Mancini
authors.forename: Elisa
authors.initials: E
authors.lastname: Leo
authors.forename: Michela
authors.initials: M
authors.lastname: Aluigi
authors.forename: Chiara
authors.initials: C
authors.lastname: Marcozzi
authors.forename: Enrica
authors.initials: E
authors.lastname: Borsi
authors.forename: Enza
authors.initials: E
authors.lastname: Barbieri
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Santucci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D050811:Octamer Transcription Factor-1 / Q000378:metabolism / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000097642:GADD45 Proteins; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D016044:Fusion Proteins, bcr-abl; D006657:Histones; D009687:Nuclear Proteins; D050811:Octamer Transcription Factor-1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines