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1.
Nucleic Acids Res ; 52(11): 6472-6489, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38752489

RESUMO

Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2 and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how telomere association of orphan NRs is involved in ALT activation remains unclear. Here, we demonstrate that telomeric tethering of orphan NRs in human fibroblasts initiates formation of ALT-associated PML bodies (APBs) and features of ALT activity, including ALT telomere DNA synthesis, telomere sister chromatid exchange, and telomeric C-circle generation, suggesting de novo ALT induction. Overexpression of orphan NRs exacerbates ALT phenotypes in ALT cells, while their depletion limits ALT. Orphan NRs initiate ALT via the zinc finger protein 827, suggesting the involvement of chromatin structure alterations for ALT activation. Furthermore, we found that orphan NRs and deficiency of the ALT suppressor ATRX-DAXX complex operate in concert to promote ALT activation. Moreover, PML depletion by gene knockout or arsenic trioxide treatment inhibited ALT induction in fibroblasts and ALT cancer cells, suggesting that APB formation underlies the orphan NR-induced ALT activation. Importantly, arsenic trioxide administration abolished APB formation and features of ALT activity in ALT cancer cell line-derived mouse xenografts, suggesting its potential for further therapeutic development to treat ALT cancers.


Assuntos
Fibroblastos , Proteína da Leucemia Promielocítica , Homeostase do Telômero , Humanos , Animais , Proteína da Leucemia Promielocítica/metabolismo , Proteína da Leucemia Promielocítica/genética , Camundongos , Fibroblastos/metabolismo , Telômero/metabolismo , Telômero/genética , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Troca de Cromátide Irmã , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Trióxido de Arsênio/farmacologia , Chaperonas Moleculares
2.
Structure ; 30(12): 1563-1564, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36459974

RESUMO

Emerging models of telomere and associated proteins in Tetrahymena have broadened our understanding of telomeric processes. In this issue of Structure, Ma et al. pinpoint a region in p50 that associates with the CST complex. The interaction mediated by p50 is crucial for the optimal positioning of TERT to maintain homeostasis at the chromosome ends.


Assuntos
Telomerase , Tetrahymena , Domínio Catalítico , Telômero , Homeostase
3.
Int J Mol Sci ; 23(23)2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36499545

RESUMO

Most cases of acquired aplastic anemia (AA) arise from autoimmune destruction of hematopoietic stem and progenitor cells. Human leukocyte antigen (HLA)-haploidentical nonmyeloablative hematopoietic stem cell transplantation (HSCT) plus post-transplantation cyclophosphamide (PTCy) is increasingly applied to salvage AA using bone marrow as graft and anti-thymocyte globulin (ATG) in conditioning. Herein, we characterize a cohort of twelve AA patients clinically and molecularly, six who possessed other immunological disorders (including two also carrying germline SAMD9L mutations). Each patient with SAMD9L mutation also carried an AA-related rare BCORL1 variant or CTLA4 p.T17A GG genotype, respectively, and both presented short telomere lengths. Six of the ten patients analyzed harbored AA-risky HLA polymorphisms. All patients recovered upon non-HSCT (n = 4) or HSCT (n = 8) treatments. Six of the eight HSCT-treated patients were subjected to a modified PTCy-based regimen involving freshly prepared peripheral blood stem cells (PBSC) as graft and exclusion of ATG. All patients were engrafted between post-transplantation days +13 and +18 and quickly reverted to normal life, displaying a sustained complete hematologic response and an absence of graft-versus-host disease. These outcomes indicate most AA cases, including of the SAMD9L-inherited subtype, are immune-mediated and the modified PTCy-based regimen we present is efficient and safe for salvage.


Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Soro Antilinfocitário/uso terapêutico , Anemia Aplástica/genética , Anemia Aplástica/terapia , Condicionamento Pré-Transplante , Doença Enxerto-Hospedeiro/etiologia , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Antígenos HLA , Estudos Retrospectivos
4.
Methods Mol Biol ; 2450: 467-478, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35359323

RESUMO

Telomere shortening is a hallmark of aging and eventually constrains the proliferative capacity of cells. The protocols discussed here are used for monitoring telomeres comprehensively in Aeolosoma viride, a model system for regeneration studies. We present methods for analyzing the activity of telomerase enzyme in regenerating tissue by telomeric repeat amplification protocol (TRAP) assay, for comparing telomere length between existing tissue and newly regenerated tissue by telomere restriction fragment (TRF) assay, as well as for visualizing telomeres by fluorescence in situ hybridization (FISH).


Assuntos
Anelídeos , Telomerase , Animais , Hibridização in Situ Fluorescente , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo , Homeostase do Telômero
5.
J Hematol Oncol ; 11(1): 74, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855336

RESUMO

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) has, in recent years, emerged as an important tumor cell behavior associated with high metastatic potential and drug resistance. Interestingly, protein SUMOylation and hepatocyte growth factor could respectively reduce the effect of small molecule inhibitors on tyrosine kinase activity of mutated epidermal growth factor receptor of lung adenocarcinomas (LADC). The actual mechanism is yet to be resolved. METHODS: Immunohistochemistry was used to stain proteins in LADC specimens. Protein expression was confirmed by Western blotting. In vitro, expression of proteins was determined by Western blotting and immunocytochemistry. Levels of circular RNA were determined by reverse transcription-polymerase chain reaction. RESULTS: SAE2 and cirRNA CCDC66 were highly expressed in LADC. Expression of SAE2 was mainly regulated by EGFR; however, expression of cirRNA CCDC66 was positively regulated by FAK and c-Met but negatively modulated by nAchR7α. EGFR-resistant H1975 also highly expressed cirRNA CCDC66. Immediate response of hypoxia increased phosphorylated c-Met, SAE2, and epithelial-to-mesenchymal transition. Either activation of FAK or silencing of nAchR7α increased cirRNA CCDC66. CONCLUSIONS: HGF/c-Met regulates expression of SAE2 and cirRNA CCDC66 to increase EMT and drug resistance of LADC cells. Multimodality drugs concurrently aiming at these targets would probably provide more benefits for cancer patients.


Assuntos
Proteínas do Olho/genética , Fator de Crescimento de Hepatócito/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Adenocarcinoma/patologia , Linhagem Celular , Ácidos Nucleicos Livres/análise , Resistência a Medicamentos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas , Enzimas Ativadoras de Ubiquitina/metabolismo
6.
Mol Carcinog ; 56(11): 2424-2433, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28577326

RESUMO

In this study, we examined the role of autophagy in the initiation of lipid increases in renal epithelial HK2 cells. We found that trivalent chromium [Cr(III)] induced autophagy by activating sphingomyelin phosphodiesterase 2 (SMPD2). SMPD2 increases levels of ceramide and other lipids. Confocal immunofluorescence microscopy showed that signals of ceramide overlapped with LC3, suggesting that ceramide might play an important role in the formation of autophagosome. In conclusion, our data indicate that Cr(III) induces autophagy via structural aberration of organelle membrane, in particular by the increase of lipid compositions in addition to autophagy-associated proteins.


Assuntos
Autofagia/efeitos dos fármacos , Ceramidas/metabolismo , Cromo/farmacologia , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Rim/efeitos dos fármacos , Esfingomielina Fosfodiesterase/metabolismo , Linhagem Celular , Células Epiteliais/metabolismo , Humanos , Rim/citologia , Rim/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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