RESUMO
Multiple myeloma (MM) represents the malignant proliferation of terminally differentiated B cells, which, in many cases, is associated with the maintenance of high levels of the oncoprotein c-MYC. Overexpression of the histone methyltransferase MMSET (WHSC1/NSD2), due to t(4;14) chromosomal translocation, promotes the proliferation of MM cells along with global changes in chromatin; nevertheless, the precise mechanisms by which MMSET stimulates neoplasia remain incompletely understood. We found that MMSET enhances the proliferation of MM cells by stimulating the expression of c-MYC at the post-transcriptional level. A microRNA (miRNA) profiling experiment in t(4;14) MM cells identified miR-126* as an MMSET-regulated miRNA predicted to target c-MYC mRNA. We show that miR-126* specifically targets the 3'-untranslated region (3'-UTR) of c-MYC, inhibiting its translation and leading to decreased c-MYC protein levels. Moreover, the expression of this miRNA was sufficient to decrease the proliferation rate of t(4;14) MM cells. Chromatin immunoprecipitation analysis showed that MMSET binds to the miR-126* promoter along with the KAP1 corepressor and histone deacetylases, and is associated with heterochromatic modifications, characterized by increased trimethylation of H3K9 and decreased H3 acetylation, leading to miR-126* repression. Collectively, this study shows a novel mechanism that leads to increased c-MYC levels and enhanced proliferation of t(4;14) MM, and potentially other cancers with high MMSET expression.
Assuntos
Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , MicroRNAs/genética , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Repressoras/metabolismo , Apoptose , Western Blotting , Imunoprecipitação da Cromatina , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/genética , Humanos , Imunoprecipitação , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
The status of experimental tests of general relativity is reviewed on the occasion of its 75th anniversary. Einstein's equivalence principle is well supported by experiments such as the Eötvös experiment, tests of special relativity, and the gravitational redshift experiment. Tests of general relativity have reached high precision, including the light deflection and the perihelion advance of Mercury, proposed by Einstein 75 years ago, and new tests such as the Shapiro time delay and the Nordtvedt effect in lunar motion. Gravitational wave damping has been detected to an accuracy of 1 percent on the basis of measurements of the binary pulsar. The status of the "fifth force" is discussed, along with the frontiers of experimental relativity, including proposals for testing relativistic gravity with advanced technology and spacecraft.