RESUMO
HIC1 is a newly discovered tumor suppressor and transcriptional repressor that is frequently silenced in human tumors. HIC1 protein expression has been linked to better outcomes in breast cancers. The molecular mechanism underlying HIC1-mediated transcriptional and growth suppression, and the relevant targets of HIC1-mediated transcriptional modulation, is currently unclear. We have identified an HIC1 DNA-binding site in E2F-responsive gene promoters and demonstrate that HIC1 targets E2F-responsive genes for transcriptional regulation and growth suppression. We and others have recently discovered that Brg1, a central component of the SWI/SNF chromatin-remodeling family, is required for the transcriptional regulation of multiple cell cycle control-related genes, including E2F-responsive promoters. We studied HIC1 interactions with, and dependence upon, Brg1 activity, and found that HIC1 can recruit Brg1 to E2F-responsive promoters and that its transcriptional repression of these genes is dependent upon Brg1. These data indicate that HIC1 is a central molecule in a novel mechanism controlling cell growth and that the disruption of this HIC1-mediated pathway may lead to abnormal cell proliferation and, ultimately, cancer.
Assuntos
Proliferação de Células , Montagem e Desmontagem da Cromatina/fisiologia , Regulação para Baixo/genética , Fatores de Transcrição Kruppel-Like/fisiologia , Montagem e Desmontagem da Cromatina/genética , Proteínas Cromossômicas não Histona/metabolismo , DNA Helicases/metabolismo , DNA Helicases/fisiologia , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F1/fisiologia , Genes Supressores de Tumor/fisiologia , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/fisiologia , Ligação Proteica , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia , Transcrição Gênica/genética , Células Tumorais CultivadasRESUMO
The SWI/SNF complex participates as a co-activator in the transcriptional regulation of certain genes. Conversely, we and others have recently established that Brg1 and Brm, the central components of SWI/SNF, act instead as co-repressors for E2F-mediated transcriptional repression, and for the transcription of certain other promoters. We report here that Brg-1 and Brm can switch their mode of function at same promoter between activation and repression by ligand-directed differential coordination with BAF155, BAF170, HDAC1, p300 and prohibitin. This ligand and context-dependent reprogramming of the SWI/SNF complex allows it to differentially serve as either a co-repressor or a co-activator of transcription at the same promoter.
Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Regulação da Expressão Gênica/fisiologia , Receptores de Estrogênio/metabolismo , Proteínas Repressoras/fisiologia , Transativadores/fisiologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/fisiologia , Linhagem Celular Tumoral , Proteínas Cromossômicas não Histona/fisiologia , DNA Helicases/metabolismo , Proteínas de Ligação a DNA , Estrogênios/metabolismo , Humanos , Ligantes , Proteínas Nucleares/metabolismo , Proibitinas , Receptores de Estrogênio/genética , Fatores de Transcrição/fisiologiaRESUMO
We have identified and cloned a cDNA encoding a new member of the monooxygenase family of enzymes. This novel enzyme, which we call MOX (monooxygenase X; unknown substrate) is a clear sequence homologue of the enzyme dopamine beta-hydroxylase (DBH). MOX maintains many of the structural features of DBH, as evidenced by the retention of most of the disulfide linkages and all of the peptidyl ligands to the active site copper atoms. Unlike DBH, MOX lacks a signal peptide sequence and therefore is unlikely to be a secreted molecule. The steady-state mRNA levels of MOX are highest in the kidney, lung, and adrenal gland, indicating that the tissue distribution of MOX is broader than that of DBH. Antisera raised to a fusion protein of MOX identifies a single band of the expected mobility by Western blot analysis. MOX mRNA levels are elevated in some fibroblast cell strains at replicative senescence, through this regulation is not apparent in all primary cell strains. The gene for MOX resides on the q arm of chromosome 6 and the corresponding mouse homolog has been identified.
Assuntos
Dopamina beta-Hidroxilase/genética , Oxigenases de Função Mista/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Células Cultivadas , Mapeamento Cromossômico , Cromossomos Humanos Par 6 , Clonagem Molecular , DNA Complementar , Expressão Gênica , Humanos , Células Híbridas , Camundongos , Dados de Sequência Molecular , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologiaRESUMO
Hemoccult slides have been used in an attempt to determine their usefulness as a screening method for the detection of colorectal neoplasia. Two methods have been used. In the first, 300 unprepared patients had an immediate single-stool specimen tested with Hemoccult. Only nine patients were referred for investigation after this single test, and no case of colorectal neoplasia was discovered. In the second method over 2,500 three-stool test kits were distributed to the public, of which 1,160 (46%) have been returned and tested. Positive tests were obtained in 68 patients. Follow-up of 58 of these patients has led to the detection of three cases of carcinoma of the colon and nine cases of benign polyps greater than one centimetre in diameter. The cost of screening patients with a three-stool test has been calculated to be $2.50 per patient.
