title: The estrogen-responsive B box protein is a novel regulator of the retinoid signal.
abstract: Retinoic acid (RA) induces growth arrest, cell death, and differentiation in many human cancer cells in vitro and has entered routine clinical use for the treatment of several human cancer types. One mechanism by which cancer cells evade retinoid-induced effects is through repression of retinoic acid receptor beta (RARbeta) gene transcription. The RA response element beta (betaRARE) is the essential DNA sequence required for retinoid-induced RARbeta transcription. Here we show that the estrogen-responsive B box protein (EBBP), a member of the RING-B box-coiled-coil protein family, is a betaRARE-binding protein. EBBP undergoes serine threonine phosphorylation and enhanced protein stability after RA treatment. Following RA treatment, we also observed increased nuclear EBBP levels in aggregates with the promyelocytic leukemia protein at promyelocytic leukemia nuclear bodies. EBBP enhanced RA-responsive RARbeta transcription in RA-sensitive and -resistant cancer cells, which were resistant to both a histone deacetylase inhibitor and a demethylating agent. EBBP-specific small interfering RNA reduced basal and RA-induced RARbeta expression. EBBP increased betaRARE-transactivating function through its coiled-coil domain. Taken together, our work suggests that EBBP may have a pivotal role in the retinoid anti-cancer signal.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, New South Wales 2031, Australia.
authors.forename: Belamy B
authors.initials: BB
authors.lastname: Cheung
authors.forename: Jessica
authors.initials: J
authors.lastname: Bell
authors.forename: Anna
authors.initials: A
authors.lastname: Raif
authors.forename: Andrew
authors.initials: A
authors.lastname: Bohlken
authors.forename: Joanne
authors.initials: J
authors.lastname: Yan
authors.forename: Ben
authors.initials: B
authors.lastname: Roediger
authors.forename: Anne
authors.initials: A
authors.lastname: Poljak
authors.forename: Stewart
authors.initials: S
authors.lastname: Smith
authors.forename: Michelle
authors.initials: M
authors.lastname: Lee
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Thomas
authors.forename: Maria
authors.initials: M
authors.lastname: Kavallaris
authors.forename: Murray
authors.initials: M
authors.lastname: Norris
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.forename: Hsiao-Lai
authors.initials: HL
authors.lastname: Liu
authors.forename: Deborah
authors.initials: D
authors.lastname: Zajchowski
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001943:Breast Neoplasms; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma; D009687:Nuclear Proteins / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; C070576:PML protein, human; D014212:Tretinoin; C117731:TRIM16 protein, human; D044767:Ubiquitin-Protein Ligases