title: PU.1 is a major transcriptional activator of the tumour suppressor gene LIMD1.
abstract: LIMD1 is a tumour suppressor gene (TSG) down regulated in ∼80% of lung cancers with loss also demonstrated in breast and head and neck squamous cell carcinomas. LIMD1 is also a candidate TSG in childhood acute lymphoblastic leukaemia. Mechanistically, LIMD1 interacts with pRB, repressing E2F-driven transcription as well as being a critical component of microRNA-mediated gene silencing. In this study we show a CpG island within the LIMD1 promoter contains a conserved binding motif for the transcription factor PU.1. Mutation of the PU.1 consensus reduced promoter driven transcription by 90%. ChIP and EMSA analysis demonstrated that PU.1 specifically binds to the LIMD1 promoter. siRNA depletion of PU.1 significantly reduced endogenous LIMD1 expression, demonstrating that PU.1 is a major transcriptional activator of LIMD1.
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, UK.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Foxler
authors.forename: Victoria
authors.initials: V
authors.lastname: James
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Shelton
authors.forename: Thomas Q de A
authors.initials: TQ
authors.lastname: Vallim
authors.forename: Peter E
authors.initials: PE
authors.lastname: Shaw
authors.forename: Tyson V
authors.initials: TV
authors.lastname: Sharp
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016384:Consensus Sequence / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D060588:LIM Domain Proteins; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C403807:LIMD1 protein, human