title: Interference with the expression of a novel human polycomb protein, hPc2, results in cellular transformation and apoptosis.
abstract: Polycomb (Pc) is involved in the stable and heritable repression of homeotic gene activity during Drosophila development. Here, we report the identification of a novel human Pc homolog, hPc2. This gene is more closely related to a Xenopus Pc homolog, XPc, than to a previously described human Pc homolog, CBX2 (hPc1). However, the hPc2 and CBX2/hPc1 proteins colocalize in interphase nuclei of human U-2 OS osteosarcoma cells, suggesting that the proteins are part of a common protein complex. To study the functions of the novel human Pc homolog, we generated a mutant protein, delta hPc2, which lacks an evolutionarily conserved C-terminal domain. This C-terminal domain is important for hPc2 function, since the delta hPc2 mutant protein which lacks the C-terminal domain is unable to repress gene activity. Expression of the delta hPc2 protein, but not of the wild-type hPc2 protein, results in cellular transformation of mammalian cell lines as judged by phenotypic changes, altered marker gene expression, and anchorage-independent growth. Specifically in delta hPc2-transformed cells, the expression of the c-myc proto-oncogene is strongly enhanced and serum deprivation results in apoptosis. In contrast, overexpression of the wild-type hPc2 protein results in decreased c-myc expression. Our data suggest that hPc2 is a repressor of proto-oncogene activity and that interference with hPc2 function can lead to derepression of proto-oncogene transcription and subsequently to cellular transformation.
authors.affiliation: E. C. Slater Instituut, University of Amsterdam, The Netherlands.
authors.forename: D P
authors.initials: DP
authors.lastname: Satijn
authors.forename: D J
authors.initials: DJ
authors.lastname: Olson
authors.forename: J
authors.initials: J
authors.lastname: van der Vlag
authors.forename: K M
authors.initials: KM
authors.lastname: Hamer
authors.forename: C
authors.initials: C
authors.lastname: Lambrechts
authors.forename: H
authors.initials: H
authors.lastname: Masselink
authors.forename: M J
authors.initials: MJ
authors.lastname: Gunster
authors.forename: R G
authors.initials: RG
authors.lastname: Sewalt
authors.forename: R
authors.initials: R
authors.lastname: van Driel
authors.forename: A P
authors.initials: AP
authors.lastname: Otte
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002467:Cell Nucleus / Q000737:chemistry; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003001:Cloning, Molecular; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D008025:Ligases; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D012516:Osteosarcoma / Q000737:chemistry; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D051381:Rats; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
chemical_list: C570426:Cbx2 protein, mouse; C000715470:MAS1 protein, human; D063146:Polycomb-Group Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C570427:CBX4 protein, human