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1.
Transl Oncol ; 33: 101676, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37086619

RESUMO

G0/G1 switch gene 2 (G0S2) is known to inhibit lipolysis by inhibiting adipose triglyceride lipase (ATGL). In this report, we dissect the role of G0S2 in ER+ versus ER- breast cancer. Overexpression of G0S2 in ER- cells increased cell proliferation, while G0S2 overexpression in ER+ cells decreased cell proliferation. Transcriptome analysis revealed that G0S2 mediated distinct but overlapping transcriptional responses in ER- and ER+ cells. G0S2 reduced genes associated with an epithelial phenotype, especially in ER- cells, including CDH1, ELF3, STEAP4 and TACSTD2, suggesting promotion of the epithelial-mesenchymal transition (EMT). G0S2 also repressed estrogen signaling and estrogen receptor target gene signatures, especially in ER+ cells, including TFF1 and TFF3. In addition, G0S2 overexpression increased cell migration in ER- cells and increased estrogen deprivation sensitivity in ER+ cells. Interestingly, two genes downstream of ATGL in fat utilization and very important in steroid hormone biosynthesis, HMGCS1 and HMGCS2, were downregulated in G0S2 overexpressing ER+ cells. In addition, HSD17B11, a gene that converts estradiol to its less estrogenic derivative, estrone, was highly upregulated in G0S2 overexpressing ER+ cells, suggesting G0S2 overexpression has a negative effect on estradiol production and maintenance. High expression of G0S2 and HSD17B11 was associated with improved relapse-free survival in breast cancer patients while high expression of HMGSC1 was associated with poor survival. Finally, we deleted G0S2 in breast cancer-prone MMTV-PyMT mice. Our data indicates a complex role for G0S2 in breast cancer, dependent on ER status, that may be partially mediated by suppression of the estrogen signaling pathway.

2.
JCI Insight ; 7(18)2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36134655

RESUMO

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell-derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.


Assuntos
Células-Tronco Pluripotentes Induzidas , Atrofia Óptica , Síndrome de Wolfram , Homozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas de Membrana/genética , Atrofia Óptica/genética , Atrofia Óptica/patologia , Síndrome de Wolfram/diagnóstico , Síndrome de Wolfram/genética , Síndrome de Wolfram/patologia
3.
JCI Insight ; 6(15)2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34185708

RESUMO

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic ß cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, ß cell functions were not significantly improved, but there was a significant correlation between baseline ß cell functions and change in ß cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1ß, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.


Assuntos
Dantroleno , Células Secretoras de Insulina , Interleucina-18/análise , Interleucina-1beta/análise , Qualidade de Vida , Acuidade Visual/efeitos dos fármacos , Síndrome de Wolfram , Adolescente , Adulto , Disponibilidade Biológica , Sinalização do Cálcio/efeitos dos fármacos , Criança , Dantroleno/administração & dosagem , Dantroleno/efeitos adversos , Dantroleno/farmacocinética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/estatística & dados numéricos , Relaxantes Musculares Centrais/administração & dosagem , Relaxantes Musculares Centrais/efeitos adversos , Relaxantes Musculares Centrais/farmacocinética , Exame Neurológico/efeitos dos fármacos , Resultado do Tratamento , Síndrome de Wolfram/diagnóstico , Síndrome de Wolfram/tratamento farmacológico , Síndrome de Wolfram/metabolismo , Síndrome de Wolfram/fisiopatologia
4.
Lab Invest ; 100(6): 849-862, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32060407

RESUMO

Wolfram Syndrome 1 (WFS1) protein is an endoplasmic reticulum (ER) factor whose deficiency results in juvenile-onset diabetes secondary to cellular dysfunction and apoptosis. The mechanisms guiding ß-cell outcomes secondary to WFS1 function, however, remain unclear. Here, we show that WFS1 preserves normal ß-cell physiology by promoting insulin biosynthesis and negatively regulating ER stress. Depletion of Wfs1 in vivo and in vitro causes functional defects in glucose-stimulated insulin secretion and insulin content, triggering Chop-mediated apoptotic pathways. Genetic proof of concept studies coupled with RNA-seq reveal that increasing WFS1 confers a functional and a survival advantage to ß-cells under ER stress by increasing insulin gene expression and downregulating the Chop-Trib3 axis, thereby activating Akt pathways. Remarkably, WFS1 and INS levels are reduced in type-2 diabetic (T2DM) islets, suggesting that WFS1 may contribute to T2DM ß-cell pathology. Taken together, this work reveals essential pathways regulated by WFS1 to control ß-cell survival and function primarily through preservation of ER homeostasis.


Assuntos
Células Secretoras de Insulina , Proteínas de Membrana , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Células Cultivadas , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Insulina/análise , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Camundongos Knockout , Transdução de Sinais/fisiologia , Síndrome de Wolfram
5.
Sci Rep ; 9(1): 5199, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914711

RESUMO

Endoplasmic reticulum (ER) stress in beta cells is an important pathogenic component of both type 1 and type 2 diabetes mellitus, as well as genetic forms of diabetes, especially Wolfram syndrome. However, there are currently no convenient ways to assess ER stress in beta cells, raising the need for circulating ER stress markers indicative of beta cell health. Here we show that pancreatic stone protein/regenerating protein (PSP/reg) is a potential biomarker for ER stressed beta cells. PSP/reg levels are elevated in cell culture and mouse models of Wolfram syndrome, a prototype of ER stress-induced diabetes. Moreover, PSP/reg expression is induced by the canonical chemical inducers of ER stress, tunicamycin and thapsigargin. Circulating PSP/reg levels are also increased in some patients with Wolfram syndrome. Our results therefore reveal PSP/reg as a potential biomarker for beta cells under chronic ER stress, as is the case in Wolfram syndrome.


Assuntos
Estresse do Retículo Endoplasmático , Células Secretoras de Insulina/metabolismo , Litostatina/metabolismo , Adulto , Animais , Biomarcadores/sangue , Criança , Humanos , Litostatina/sangue , Masculino , Proteínas de Membrana/metabolismo , Camundongos Knockout , Modelos Biológicos , Ratos , Síndrome de Wolfram/sangue , Adulto Jovem
6.
Mol Ecol ; 27(18): 3627-3640, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30059176

RESUMO

Bats are a diverse radiation of mammals of enduring interest for understanding the evolution of sensory specialization. Colour vision variation among species has previously been linked to roosting preferences and echolocation form in the suborder Yinpterochiroptera, yet questions remain about the roles of diet and habitat in shaping bat visual ecology. We sequenced OPN1SW and OPN1LW opsin genes for 20 species of leaf-nosed bats (family Phyllostomidae; suborder Yangochiroptera) with diverse roosting and dietary ecologies, along with one vespertilionid species (Myotis lavali). OPN1LW genes appear intact for all species, and predicted spectral tuning of long-wavelength opsins varied among lineages. OPN1SW genes appear intact and under purifying selection for Myotis lavali and most phyllostomid bats, with two exceptions: (a) We found evidence of ancient OPN1SW pseudogenization in the vampire bat lineage, and loss-of-function mutations in all three species of extant vampire bats; (b) we additionally found a recent, independently derived OPN1SW pseudogene in Lonchophylla mordax, a cave-roosting species. These mutations in leaf-nosed bats are independent of the OPN1SW pseudogenization events previously reported in Yinpterochiropterans. Therefore, the evolution of monochromacy (complete colour blindness) has occurred in both suborders of bats and under various evolutionary drivers; we find independent support for the hypothesis that obligate cave roosting drives colour vision loss. We additionally suggest that haematophagous dietary specialization and corresponding selection on nonvisual senses led to loss of colour vision through evolutionary sensory trade-off. Our results underscore the evolutionary plasticity of opsins among nocturnal mammals.


Assuntos
Cavernas , Quirópteros/fisiologia , Visão de Cores , Dieta/veterinária , Evolução Molecular , Animais , Brasil , Quirópteros/genética , Opsinas/genética , Filogenia
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