RESUMO
Hormone replacement therapy (HRT) has been shown to increase bone density, reduce the risk of fracture and can successfully relieve menopausal symptoms. From a time when HRT was the major therapeutic option for the management of osteoporosis, women and their clinicians now have a range of treatments available. Following the publication of the Women's Health Initiative (WHI) and the Million Women Study highlighting potential side-effects, such as breast cancer, heart disease and stroke, many doctors and women are now reluctant to use HRT. The National Osteoporosis Society felt that the role of HRT in the management of osteoporosis needed to be clarified. Using the Charity's expert clinical and scientific advisers, and through public consultation with members and key stakeholders, a Position Statement has been published. We conclude that HRT has a role to play in the management of osteoporosis in postmenopausal women below the age of 60 years. The key recommendations of the Position Statement are presented in this paper.
Assuntos
Terapia de Reposição Hormonal/estatística & dados numéricos , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/prevenção & controle , Fatores Etários , Neoplasias da Mama/epidemiologia , Doenças Cardiovasculares/epidemiologia , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Reino UnidoRESUMO
Perturbation of normal endoplasmic reticulum (ER) function induces a stress response found throughout eukaryotes, sometimes termed the unfolded protein response (UPR). In yeast, auxotrophic mutants have identified two genes, IRE1 and HAC1, whose products are key components. Normally HAC1 mRNA is not translated owing to a 252-nt "intron." Disruption of ER function activates Ire1p to remove this intron through endogenous endoribonuclease activity. Together with tRNA ligase, cleavage and splicing produces a translatable HAC1 mRNA to give Hac1p, a transcription factor that upregulates the expression of genes responsive to ER stress. No Hac1p homologue has been identified in mammalian cells, but Ire1p homologues exist with endoribonuclease activity required for a fully functional UPR, raising the possibility that the key features of the yeast UPR might be conserved in higher eukaryotic cells. To address this, we expressed yeast HAC1 in HeLa and HEK 293T human cell lines, both on its own and as fusions with yellow fluorescent protein (YFP) to investigate its processing and translation. HAC1 mRNA was not processed, but efficiently translated irrespective of whether the cells were subjected to ER stress. Expression of exogenous HAC1 mRNA constructs in yeast showed UPR-induced splicing required the presence of its 3' UTR. These results suggest that the mammalian ER stress response has diverged from the yeast UPR.
Assuntos
Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição , Regiões 3' não Traduzidas , Proteínas de Bactérias/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica , Linhagem Celular , Retículo Endoplasmático/metabolismo , Células HeLa , Humanos , Íntrons , Proteínas Luminescentes/metabolismo , Microscopia Confocal , Microscopia de Fluorescência , Plasmídeos/metabolismo , Reação em Cadeia da Polimerase , RNA de Transferência/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Regulação para CimaRESUMO
Gene silencing associated with aberrant methylation of promoter region CpG islands is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor and other genes in human cancers. The hypothesis that aberrant methylation plays a direct causal role in carcinogenesis hinges on the question of whether aberrant methylation is sufficient to drive gene silencing. To identify downstream targets of methylation-induced gene silencing, we used a human cell model in which aberrant CpG island methylation is induced by ectopic expression of DNA methyltransferase. Here we report the isolation and characterization of TMS1 (target of methylation-induced silencing), a novel CpG island-associated gene that becomes hypermethylated and silenced in cells overexpressing DNA cytosine-5-methyltransferase-1. We also show that TMS1 is aberrantly methylated and silenced in human breast cancer cells. Forty percent (11 of 27) of primary breast tumors exhibited aberrant methylation of TMS1. TMS1 is localized to chromosome 16p11.2-12.1 and encodes a 22-kDa predicted protein containing a COOH-terminal caspase recruitment domain, a recently described protein interaction motif found in apoptotic signaling molecules. Ectopic expression of TMS1 induced apoptosis in 293 cells and inhibited the survival of human breast cancer cells. The data suggest that methylation-mediated silencing of TMS1 confers a survival advantage by allowing cells to escape from apoptosis, supporting a new role for aberrant methylation in breast tumorigenesis.