Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Mol Cell ; 65(5): 900-916.e7, 2017 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-28238654

RESUMO

Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization.


Assuntos
Proteínas de Transporte/metabolismo , Quebras de DNA de Cadeia Dupla , DNA Helicases/metabolismo , Histona Acetiltransferases/metabolismo , Processamento de Proteína Pós-Traducional , Proteína-Arginina N-Metiltransferases/metabolismo , Reparo de DNA por Recombinação , ATPases Associadas a Diversas Atividades Celulares , Acetilação , Animais , Arginina , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Transporte/genética , DNA Helicases/genética , Instabilidade Genômica , Células HEK293 , Células HeLa , Histona Acetiltransferases/genética , Histonas/metabolismo , Humanos , Lisina Acetiltransferase 5 , Metilação , Camundongos , Camundongos Transgênicos , Proteína-Arginina N-Metiltransferases/genética , Interferência de RNA , Fatores de Tempo , Transfecção , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
2.
Clin Cancer Res ; 29(9): 1651-1657, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36469000

RESUMO

On March 23, 2022, the FDA approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The recommended 177Lu-PSMA-617 dose is 7.4 gigabecquerels (GBq; 200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity. The FDA granted traditional approval based on VISION (NCT03511664), which was a randomized (2:1), multicenter, open-label trial that assessed the efficacy and safety of 177Lu-PSMA-617 plus best standard of care (BSoC; n = 551) or BSoC alone (n = 280) in men with progressive, PSMA-positive mCRPC. Patients were required to have received ≥1 androgen receptor pathway inhibitor, and one or two prior taxane-based chemotherapy regimens. There was a statistically significant and clinically meaningful improvement in overall survival (OS), with a median OS of 15.3 months in the 177Lu-PSMA-617 plus BSoC arm and 11.3 months in the BSoC arm, respectively (HR: 0.62; 95% confidence interval: 0.52-0.74; P < 0.001). The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving 177Lu-PSMA-617 were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. This article summarizes the FDA review of data supporting traditional approval of 177Lu-PSMA-617 for this indication.


Assuntos
Lutécio , Neoplasias de Próstata Resistentes à Castração , Masculino , Adulto , Humanos , Lutécio/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos , Resultado do Tratamento , Compostos Radiofarmacêuticos , Dipeptídeos/efeitos adversos , Antígeno Prostático Específico , Taxoides/uso terapêutico
3.
Clin Cancer Res ; 28(8): 1487-1492, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-34916216

RESUMO

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.


Assuntos
Neoplasias da Mama , Adulto , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Aprovação de Drogas , Feminino , Humanos , Receptor ErbB-2/uso terapêutico , Trastuzumab/efeitos adversos
4.
Nat Commun ; 12(1): 6313, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34728620

RESUMO

Cross-talk between distinct protein post-translational modifications is critical for an effective DNA damage response. Arginine methylation plays an important role in maintaining genome stability, but how this modification integrates with other enzymatic activities is largely unknown. Here, we identify the deubiquitylating enzyme USP11 as a previously uncharacterised PRMT1 substrate, and demonstrate that the methylation of USP11 promotes DNA end-resection and the repair of DNA double strand breaks (DSB) by homologous recombination (HR), an event that is independent from another USP11-HR activity, the deubiquitylation of PALB2. We also show that PRMT1 is a ubiquitylated protein that it is targeted for deubiquitylation by USP11, which regulates the ability of PRMT1 to bind to and methylate MRE11. Taken together, our findings reveal a specific role for USP11 during the early stages of DSB repair, which is mediated through its ability to regulate the activity of the PRMT1-MRE11 pathway.


Assuntos
Arginina/metabolismo , Proteína Homóloga a MRE11/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Rad51 Recombinase/metabolismo , Reparo de DNA por Recombinação , Proteínas Repressoras/metabolismo , Tioléster Hidrolases/metabolismo , Ubiquitinação , Arginina/química , Linhagem Celular , Dano ao DNA , Instabilidade Genômica , Humanos , Metilação
5.
Mol Cell Oncol ; 5(3): e1441628, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29876520

RESUMO

The arginine methyltransferase PRMT5 has been increasingly associated with cancer development. Here we describe our recent findings that PRMT5 is a critical regulator of breast cancer stem cell survival via the epigenetic regulation of FOXP1. Consequently, PRMT5 inhibitors could potentially eradicate cancer stem cells thereby preventing tumour relapse.

6.
Cell Rep ; 21(12): 3498-3513, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29262329

RESUMO

Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.


Assuntos
Neoplasias da Mama/genética , Fatores de Transcrição Forkhead/genética , Código das Histonas , Células-Tronco Neoplásicas/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteínas Repressoras/genética , Animais , Neoplasias da Mama/metabolismo , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Epigênese Genética , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/fisiologia , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo
7.
FEBS Lett ; 554(3): 342-6, 2003 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-14623091

RESUMO

Metabolomic characteristics in boar spermatozoa were studied using [1,2-(13)C(2)]glucose and mass isotopomer analysis. In boar spermatozoa, glycolysis was the main pathway of glucose utilization producing lactate/pyruvate, whereas no gluconeogenesis was seen. Slight glycogen synthesis through the direct pathway and some incorporation of pyruvate into the Krebs cycle also took place. Neither RNA ribose-5-phosphate nor fatty acid synthesis from glucose occurred despite the detection of pyruvate dehydrogenase activity. In contrast to the known metabolic activities in dog sperm, boar spermatozoa have low levels of energy production and biosynthetic activities suggesting two different metabolic profiles for the two different phenotypes.


Assuntos
Glucose/metabolismo , Espermatozoides/metabolismo , Suínos/metabolismo , Animais , Isótopos de Carbono , Ciclo do Ácido Cítrico/fisiologia , Ácidos Graxos/biossíntese , Glucose/análogos & derivados , Glicogênio/biossíntese , Glicólise , Lactatos/metabolismo , Masculino , Espectrometria de Massas/métodos , Via de Pentose Fosfato/fisiologia , Motilidade dos Espermatozoides
8.
PLoS One ; 5(2): e9059, 2010 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-20140202

RESUMO

The SCL (TAL1) transcription factor is a critical regulator of haematopoiesis and its expression is tightly controlled by multiple cis-acting regulatory elements. To elaborate further the DNA elements which control its regulation, we used genomic tiling microarrays covering 256 kb of the human SCL locus to perform a concerted analysis of chromatin structure and binding of regulatory proteins in human haematopoietic cell lines. This approach allowed us to characterise further or redefine known human SCL regulatory elements and led to the identification of six novel elements with putative regulatory function both up and downstream of the SCL gene. They bind a number of haematopoietic transcription factors (GATA1, E2A LMO2, SCL, LDB1), CTCF or components of the transcriptional machinery and are associated with relevant histone modifications, accessible chromatin and low nucleosomal density. Functional characterisation shows that these novel elements are able to enhance or repress SCL promoter activity, have endogenous promoter function or enhancer-blocking insulator function. Our analysis opens up several areas for further investigation and adds new layers of complexity to our understanding of the regulation of SCL expression.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação da Expressão Gênica , Proteínas Proto-Oncogênicas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/metabolismo , Acetilação , Sítios de Ligação/genética , Fator de Ligação a CCCTC , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Análise por Conglomerados , Células HL-60 , Histonas/metabolismo , Humanos , Células K562 , Lisina/metabolismo , Metilação , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Repressoras/metabolismo , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Células U937
9.
PLoS One ; 5(8): e12339, 2010 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-20808788

RESUMO

It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons ("exon-intron marking"), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing.


Assuntos
Éxons/genética , Histonas/metabolismo , Íntrons/genética , Nucleossomos/genética , Nucleossomos/metabolismo , Regulação da Expressão Gênica , Humanos , Células K562 , RNA Polimerase II/metabolismo , Transcrição Gênica
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa