title: Sumoylation of MEL1S at lysine 568 and its interaction with CtBP facilitates its repressor activity and the blockade of G-CSF-induced myeloid differentiation.
abstract: MEL1 (MDS1/EVI1-like gene 1/PRDM16), which was identified as a gene near the chromosomal breakpoint in t(1;3)(p36;q21)-positive human acute myeloid leukemia cells, belongs to the PRDI-BF1-RIZ1 homologous (PR) domain (PRDM) family of transcription repressors. The short form of MEL1 (MEL1S), which lacks the PR-domain at the N-terminus, is the main form expressed in t(1;3)(p36;q21)-positive acute myeloid leukemia cells. The overexpression of MEL1S blocks granulocyte colony-stimulating factor (G-CSF)-induced myeloid differentiation in interleukin-3-dependent murine myeloid L-G3 cells. In this study, we show that treatment with the histone deacetylase inhibitor trichostatin A abolished the blockade of myeloid differentiation in L-G3 cells overexpressing MEL1S. The expression of MEL1S containing mutated CtBP-interacting motif (CIM) in L-G3 cells still blocked the myeloid differentiation induced by G-CSF. We found that the small ubiquitin-related modifier (SUMO) motif (SM) at lysine 568 (VKAE) adjacent to the CIM was necessary to obtain the maximum transcriptional repressor activity of MEL1S. L-G3 cells expressing MEL1S, and bearing mutated CIM and SM differentiated into granulocytes in response to G-CSF; this indicated that both the SUMO modification at lysine 568 and CtBP binding were required for MEL1S-mediated transcriptional repression and blockade of differentiation, which might be relevant for the process of leukemogenesis.
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Nishikata
authors.forename: S
authors.initials: S
authors.lastname: Nakahata
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Kaneda
authors.forename: E
authors.initials: E
authors.lastname: Ichihara
authors.forename: N
authors.initials: N
authors.lastname: Yamakawa
authors.forename: K
authors.initials: K
authors.lastname: Morishita
mesh_terms: D001853:Bone Marrow / Q000187:drug effects*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism*; D058207:Sumoylation; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C416371:PRDM16 protein, human; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor; C012589:trichostatin A; D008239:Lysine