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.
Gadd45a transcriptional induction elicited by the Aurora kinase inhibitor MK-0457 in Bcr-Abl-expressing cells is driven by Oct-1 transcription factor
MANCINI, MANUELA;LEO, ELISA;ALUIGI, MICHELA;BORSI, ENRICA;BARBIERI, ENZA;SANTUCCI, MARIA ALESSANDRA
2012
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
