title: The human trithorax protein hASH2 functions as an oncoprotein.
abstract: Regulation of chromatin is an important aspect of controlling promoter activity and gene expression. Posttranslational modifications of core histones allow proteins associated with gene transcription to access chromatin. Closely associated with promoters of actively transcribed genes, trimethylation of histone H3 at lysine 4 (H3K4me3) is a core histone mark set by several protein complexes. Some of these protein complexes contain the trithorax protein ASH2 combined with the MLL oncoproteins. We identified human ASH2 in a complex with the oncoprotein MYC. This finding, together with the observation that hASH2 interacts with MLL, led us to test whether hASH2 itself is involved in transformation. We observed that hASH2 cooperates with Ha-RAS to transform primary rat embryo fibroblasts (REF). Furthermore, transformation of REFs by MYC and Ha-RAS required the presence of rAsh2. In an animal model, the hASH2/Ha-RAS-transformed REFs formed rapidly growing tumors characteristic of fibrosarcomas that, compared with tumors derived from MYC/Ha-RAS transformed cells, were poorly differentiated. This finding suggests that ASH2 functions as an oncoprotein. Although hASH2 expression at the mRNA level was generally not deregulated, hASH2 protein expression was increased in most human tumors and tumor cell lines. In addition, knockdown of hASH2 inhibited tumor cell proliferation. Taken together, these observations define hASH2 as a novel oncoprotein.
authors.affiliation: Institut für Biochemie, Klinikum, RWTH Aachen University, Aachen, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Lüscher-Firzlaff
authors.forename: Isabella
authors.initials: I
authors.lastname: Gawlista
authors.forename: Jörg
authors.initials: J
authors.lastname: Vervoorts
authors.forename: Karsten
authors.initials: K
authors.lastname: Kapelle
authors.forename: Till
authors.initials: T
authors.lastname: Braunschweig
authors.forename: Gesa
authors.initials: G
authors.lastname: Walsemann
authors.forename: Chantal
authors.initials: C
authors.lastname: Rodgarkia-Schamberger
authors.forename: Henning
authors.initials: H
authors.lastname: Schuchlautz
authors.forename: Stephan
authors.initials: S
authors.lastname: Dreschers
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Richard
authors.initials: R
authors.lastname: Lilischkis
authors.forename: Christa
authors.initials: C
authors.lastname: Cerni
authors.forename: Axel
authors.initials: A
authors.lastname: Wellmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection
chemical_list: C485622:ASH2L protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors