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1.
Proc Natl Acad Sci U S A ; 119(4)2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35046037

RESUMO

SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and tumor suppressors, playing a critical role in innate immune defense against poxviruses and the development of myeloid tumors. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes. Predicted to be multidomain proteins with an architecture like that of the NOD-like receptors, SAMD9/9L molecular functions and domain structures are largely unknown. Here, we identified a SAMD9/9L effector domain that functions by binding to double-stranded nucleic acids (dsNA) and determined the crystal structure of the domain in complex with DNA. Aided with precise mutations that differentially perturb dsNA binding, we demonstrated that the antiviral and antiproliferative functions of the wild-type and GoF SAMD9/9L variants rely on dsNA binding by the effector domain. Furthermore, we showed that GoF variants inhibit global protein synthesis, reduce translation elongation, and induce proteotoxic stress response, which all require dsNA binding by the effector domain. The identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L-associated human diseases.

2.
J Asthma ; : 1-11, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-34962447

RESUMO

OBJECTIVES: We aimed to explore whether large airway remodeling and small airway structural changes exist in subjects with small airway asthma phenotype and to evaluate the relationships between quantitative high-resolution computed tomography (qHRCT) parameters and lung function. METHODS: We enrolled 15 subjects with small airway asthma phenotype and 18 healthy controls. The two groups were matched by age, sex and body square area (BSA) with propensity score matching (PSM). Pulmonary function and qHRCT parameters [wall thickness (WT), wall area (WA), lumen area (LA), wall area percentage (WA%) of the 4th-6th generations in the right upper lobe apical segmental bronchus (RB1), adjusted by BSA, WT/BSA, WA/BSA, and LA/BSA, relative volume change -860 HU to -950 HU (RVC-860 to -950) and the expiration to inspiration ratio of mean lung density (MLDE/I)) were compared between the groups. Correlation analysis was employed to assess the relationship between qHRCT parameters and pulmonary function. RESULTS: The small airway asthma phenotype had significantly higher WA%, RVC-860 to -950 and MLDE/I and lower LA/BSA than the healthy control. Additionally, we found moderate to strong correlations between impulse oscillation (IOS) indices and WA6% and WT6/BSA. No significant correlation was found between bronchial parameters and air trapping parameters (p > 0.05). CONCLUSIONS: Combining physiological tests with imaging approaches can lead to better evaluation of small airway disfunction (SAD) in asthmatic patients. Additionally, despite nonexistent airflow obstruction in patients with small airway asthma phenotype, large airway remodeling and small airway structural changes may appear simultaneously in the early stage of disease.

3.
Nat Chem Biol ; 2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34887587

RESUMO

In eukaryotic cells, many messenger RNAs (mRNAs) possess upstream open reading frames (uORFs) in addition to the main coding region. After uORF translation, the ribosome could either recycle at the stop codon or resume scanning for downstream start codons in a process known as reinitiation. Accumulating evidence suggests that some initiation factors, including eukaryotic initiation factor 3 (eIF3), linger on the early elongating ribosome, forming an eIF3-80S complex. Very little is known about how eIF3 is carried along with the 80S during elongation and whether the eIF3-80S association is subject to regulation. Here, we report that eIF3a undergoes dynamic O-linked N-acetylglucosamine (O-GlcNAc) modification in response to nutrient starvation. Stress-induced de-O-GlcNAcylation promotes eIF3 retention on the elongating ribosome and facilitates activating transcription factor 4 (ATF4) reinitiation. Eliminating the modification site from eIF3a via CRISPR genome editing induces ATF4 reinitiation even under the nutrient-rich condition. Our findings illustrate a mechanism in balancing ribosome recycling and reinitiation, thereby linking the nutrient stress response and translational reprogramming.

4.
Nat Commun ; 12(1): 6604, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34782646

RESUMO

The fidelity of start codon recognition by ribosomes is paramount during protein synthesis. The current knowledge of eukaryotic translation initiation implies unidirectional 5'→3' migration of the pre-initiation complex (PIC) along the 5' UTR. In probing translation initiation from ultra-short 5' UTR, we report that an AUG triplet near the 5' end can be selected via PIC backsliding. Bi-directional ribosome scanning is supported by competitive selection of closely spaced AUG codons and recognition of two initiation sites flanking an internal ribosome entry site. Transcriptome-wide PIC profiling reveals footprints with an oscillation pattern near the 5' end and start codons. Depleting the RNA helicase eIF4A leads to reduced PIC oscillations and impaired selection of 5' end start codons. Enhancing the ATPase activity of eIF4A promotes nonlinear PIC scanning and stimulates upstream translation initiation. The helicase-mediated PIC conformational switch may provide an operational mechanism that unifies ribosome recruitment, scanning, and start codon selection.

5.
J Org Chem ; 86(23): 17063-17070, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34797073

RESUMO

A tandem rhodium(III)-catalyzed system was established to access 3,4-dihydroisoquinolin-1(2H)-one by coupling of N-methoxy-3-methylbenzamide with 2-methylidenetrimethylene carbonate. This one-pot synthesis protocol processed smoothly under mild reaction conditions. Moreover, a total of 28 examples, broad substrate scope, and high functional-group compatibility were observed. Preliminary mechanism studies were also conducted and demonstrated that the rhodium(III) catalyst played a vital role in the C-H-allylation and N-alkylation cyclization process.

6.
Acc Chem Res ; 54(23): 4272-4282, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34756012

RESUMO

ConspectusSynthetic messenger RNA (mRNA), once delivered into cells, can be readily translated into proteins by ribosomes, which do not distinguish exogenous mRNAs from endogenous transcripts. Until recently, the intrinsic instability and immunostimulatory property of exogenous RNAs largely hindered the therapeutic application of synthetic mRNAs. Thanks to major technological innovations, such as introduction of chemically modified nucleosides, synthetic mRNAs have become programmable therapeutic reagents. Compared to DNA or protein-based therapeutic reagents, synthetic mRNAs bear several advantages: flexible design, easy optimization, low-cost preparation, and scalable synthesis. Therapeutic mRNAs are commonly designed to encode specific antigens to elicit organismal immune response to pathogens like viruses, express functional proteins to replace defective ones inside cells, or introduce novel enzymes to achieve unique functions like genome editing. Recent years have witnessed stunning progress on the development of mRNA vaccines against SARS-Cov2. This success is built upon our fundamental understanding of mRNA metabolism and translational control, a knowledge accumulated during the past several decades. Given the astronomical number of sequence combinations of four nucleotides, sequence-dependent control of mRNA translation remains incompletely understood. Rational design of synthetic mRNAs with robust translation and optimal stability remains challenging. Massively paralleled reporter assay (MPRA) has been proven to be powerful in identifying sequence elements in controlling mRNA translatability and stability. Indeed, a completely randomized sequence in 5' untranslated region (5'UTR) drives a wide range of translational outputs. In this Account, we will discuss general principles of mRNA translation in eukaryotic cells and elucidate the role of coding and noncoding regions in the translational regulation. From the therapeutic perspective, we will highlight the unique features of 5' cap, 5'UTR, coding region (CDS), stop codon, 3'UTR, and poly(A) tail. By focusing on the design strategies in mRNA engineering, we hope this Account will contribute to the rational design of synthetic mRNAs with broad therapeutic potential.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34634827

RESUMO

BACKGROUND AND STUDY AIMS: Although laminectomy with lateral mass screw fixation (LCSF) is an effective surgical treatment for cervical spondylotic myelopathy (CSM), loss of cervical curvature may result. This study aimed to investigate the effect of cervical curvature on spinal cord drift distance and clinical efficacy. PATIENTS AND METHODS: We retrospectively analyzed 78 consecutive CSM patients with normal cervical curvature who underwent LCSF. Cervical curvature was measured according to Borden's method 6 months after surgery. Study patients were divided into two groups: group A, reduced cervical curvature (cervical lordosis depth 0-7mm; n = 42); and group B, normal cervical curvature (cervical lordosis depth 7-17mm; n = 36). Spinal cord drift distance, laminectomy width, neurologic functional recovery, axial symptom (AS) severity, and incidence of C5 palsy were measured and compared. RESULTS: Cervical lordosis depth was 5.1 ± 1.2 mm in group A and 12.3 ± 2.4 mm in group B (p < 0.05). Laminectomy width was 21.5 ± 2.6 mm in group A and 21.9 ± 2.8 mm in group B (p > 0.05). Spinal cord drift distance was significantly shorter in group A (1.9 ± 0.4 vs. 2.6 ± 0.7 mm; p < 0.05). The Japanese Orthopaedic Association (JOA) score significantly increased after surgery in both groups (p < 0.05). Neurologic recovery rate did not differ between the two groups (61.5 vs. 62.7%; p > 0.05). AS severity was significantly higher in group A (p < 0.05). C5 palsy occurred in three group A patients (7.1%) and four group B patients (11.1%), but the difference was not significant (p > 0.05). CONCLUSION: After LCSF, 53.8% of the patients developed loss of cervical curvature. A smaller cervical curvature resulted in a shorter spinal cord drift distance. Loss of cervical curvature was related to AS severity but not improvement of neurologic function or incidence of C5 palsy.

8.
Int Immunopharmacol ; 101(Pt B): 108233, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34653730

RESUMO

The diversity of immune responses in allergic diseases is critically mediated by dendritic cells (DCs), including myeloid and plasmacytoid DCs. Allergen inhalation increased the release of IL-33 from patients with allergic rhinitis (AR), which affecting the downstream cells by binding to its receptor (ST2). However, the effects of inhaled allergens on the expression of ST2 by DCs and IL-33 on the function of mDCs are unknown. The levels of ST2+mDCs and ST2+pDCs in the blood from patients with AR and healthy subjects were examined using flow cytometry. Moreover, the patients were challenged using the allergens and the levels of ST2+mDCs and ST2+pDCs were investigated at different time points. We found that there were higher levels of ST2+ mDCs and ST2+ pDCs in patients with AR, and these levels were further increased 0.5 h after allergen inhalation. Additionally, the type 2 immune response was upregulated after challenge. IL-33 treatment increased the expression of ST2 on mDCs. Our study demonstrated that ST2 was upregulated on DCs after allergen inhalation and that mDCs responded directly to IL-33 through ST2, suggesting that the IL-33/ST2 axis might play an important role in the pathogenesis of allergic rhinitis by DCs.

9.
Mol Cell ; 81(20): 4191-4208.e8, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34686314

RESUMO

To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions.

10.
Front Cell Dev Biol ; 9: 695007, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497805

RESUMO

A group of circulating microRNAs (miRNAs) have been implicated in the pathogenesis of Parkinson's disease. However, a comprehensive study of the interactions between pathogenic miRNAs and their downstream Parkinson's disease (PD)-related target genes has not been performed. Here, we identified the miRNA expression profiles in the plasma and circulating exosomes of Parkinson's disease patients using next-generation RNA sequencing. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses showed that the miRNA target genes were enriched in axon guidance, neurotrophin signaling, cellular senescence, and the Transforming growth factor-ß (TGF-ß), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) and mechanistic target of rapamycin (mTOR) signaling pathways. Furthermore, a group of aberrantly expressed miRNAs were selected and further validated in individual patient plasma, human neural stem cells (NSCs) and a rat model of PD. More importantly, the full scope of the regulatory network between these miRNAs and their PD-related gene targets in human neural stem cells was examined, and the findings revealed a similar but still varied downstream regulatory cascade involving many known PD-associated genes. Additionally, miR-23b-3p was identified as a novel direct regulator of alpha-synuclein, which is possibly the key component in PD. Our current study, for the first time, provides a glimpse into the regulatory network of pathogenic miRNAs and their PD-related gene targets in PD. Moreover, these PD-associated miRNAs may serve as biomarkers and novel therapeutic targets for PD.

11.
Org Biomol Chem ; 19(39): 8487-8491, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34545904

RESUMO

An efficient and practical approach for the synthesis of medicinally important acridones was developed from anthranils and commercially available arylboronic acids by a tandem copper(I)-catalyzed electrophilic amination/Ag(I)-mediated oxidative annulation strategy. This new and straightforward protocol displayed a broad substrate scope (25 examples) and high functional group tolerance. What's more, a possible mechanistic proposal was also presented.

12.
Exp Neurol ; 345: 113831, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34363807

RESUMO

In strong contrast to limited repair within the mammalian central nervous system, the spinal cord of adult zebrafish is capable of almost complete recovery following injury. Understanding the mechanism underlying neural repair and functional recovery in zebrafish may lead to innovative therapies for human spinal cord injury (SCI). Since neuropeptide Y (NPY) plays a protective role in the pathogenesis of several neurological diseases, in the present study, we evaluated the effects of NPY on neuronal repair and subsequent recovery of motor function in adult zebrafish following SCI. Real-time quantitative PCR (qRT-PCR), in situ hybridization and immunostaining for NPY revealed decreased NPY expression at 12 hours (h), 6 and 21 days (d) after SCI. Double-immunostaining for NPY and islet-1, a motoneuron marker, showed that NPY was expressed in spinal cord motoneurons. Morpholino (MO) treatment for suppressing the expression of NPY inhibited supraspinal axon regrowth and locomotor recovery, in which double-staining for proliferating cell nuclear antigen (PCNA) and islet-1 showed a reduction in motoneuron proliferation. Similarly, a downregulated mRNA level of Y1 receptor of NPY (NPY1R) was also detected at 12 h, 6 and 21 d after injury. Immunostaining for NPY and in situ hybridization for NPY1R revealed that NPY1R was co-localized with NPY. Collectively, the results suggest that NPY expression in motoneurons promotes descending axon regeneration and locomotor recovery in adult zebrafish after SCI, possibly by regulating motoneuron proliferation through activation of NPY1R.

13.
Org Lett ; 23(15): 5719-5723, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34286981

RESUMO

A rhodium(III)-catalyzed C-H allylation of (hetero)arenes by using 2-methylidenetrimethylene carbonate as an efficient allylic source has been developed for the first time. Five different directing groups including oxime, N-nitroso, purine, pyridine, and pyrimidine were compatible, delivering various branched allylarenes bearing an allylic hydroxyl group in moderate to excellent yields.

14.
Methods Mol Biol ; 2298: 399-414, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34085257

RESUMO

N6-methyladenosine (m6A) is a major epitranscriptomic mark exerting crucial diverse roles in RNA metabolisms, including RNA stability, mRNA translation, and RNA structural rearrangement. m6A modifications at different RNA regions may have distinct molecular effects. Here, we describe a CRISPR-Cas9-based approach that enables targeted m6A addition or removal on endogenous RNA molecules without altering the nucleotide sequence. By fusing a catalytically inactive Cas9 with engineered m6A modification enzymes, the programmable m6A editors are capable of achieving RNA methylation and demethylation at desired sites, facilitating dissection of regional effects of m6A and diversifying the toolkits for RNA manipulation.


Assuntos
Adenosina/análogos & derivados , Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , RNA/genética , Adenosina/genética , Sequência de Bases/genética , Linhagem Celular Tumoral , Edição de Genes/métodos , Células HeLa , Humanos , Metilação , RNA Mensageiro/genética
16.
Proc Natl Acad Sci U S A ; 118(25)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34131081

RESUMO

Long noncoding RNAs (lncRNAs) are key regulators of gene expression in diverse cellular contexts and biological processes. Given the surprising range of shapes and sizes, how distinct lncRNAs achieve functional specificity remains incompletely understood. Here, we identified a heat shock-inducible lncRNA, Heat, in mouse cells that acts as a transcriptional brake to restrain stress gene expression. Functional characterization reveals that Heat directly binds to heat shock transcription factor 1 (HSF1), thereby targeting stress genes in a trans-acting manner. Intriguingly, Heat is heavily methylated in the form of m6A. Although dispensable for HSF1 binding, Heat methylation is required for silencing stress genes to attenuate heat shock response. Consistently, m6A depletion results in prolonged activation of stress genes. Furthermore, Heat mediates these effects via the nuclear m6A reader YTHDC1, forming a transcriptional silencing complex for stress genes. Our study reveals a crucial role of nuclear epitranscriptome in the transcriptional regulation of heat shock response.

17.
BMC Musculoskelet Disord ; 22(1): 494, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34049522

RESUMO

BACKGROUND: Macrophages and inflammatory cytokines play important roles in bone fracture healing. However, the expression patterns of macrophages and inflammatory cytokines during fracture healing under the condition of postmenopausal osteoporosis have not been fully revealed. METHODS: Tibia transverse fracture was established 12 weeks after ovariectomy or sham operation in 16-week old female mice. Tibias were harvested before fracture or 1, 3, 5, 7, 14, 21, 28 days after fracture for radiological and histological examinations. M1/M2 inflammatory macrophages, osteal macrophages and gene expressions of tumor necrosis factor-α, interleukin-6, interleukin-1ß and macrophage conversion related molecules in the fracture haematoma or callus were also detected. RESULTS: The processes of fracture healing, especially the phases of endochondral ossification and callus remodeling, were delayed in ovariectomized mice. The expressions of tumor necrosis factor-α and interleukin-6, but not interleukin-1ß, in the fracture haematoma or callus were disturbed. Expressions of tumor necrosis factor-α were decreased at 1, 14 and 21 days post-fracture (DPF), and were increased at 3, 5 and 7 DPF. Interleukin-6 expressions at 1, 3 and 21 DPF were significantly increased. We found the decreases in M1 and M2 macrophages at 1 DPF of the initial inflammatory stage. M2 macrophages at 14 DPF of the middle stage and osteal macrophages at 14, 21 and 28 DPF of the middle and late stages of fracture healing were also reduced in ovariectomized mice. CONCLUSIONS: The expressions of macrophages and inflammatory cytokines were impaired in ovariectomized mice, which might contribute partially to poor fracture healing.


Assuntos
Consolidação da Fratura , Fraturas da Tíbia , Animais , Calo Ósseo/diagnóstico por imagem , Citocinas , Feminino , Humanos , Macrófagos , Camundongos , Fraturas da Tíbia/diagnóstico por imagem
18.
Biochem Biophys Res Commun ; 556: 16-22, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33836343

RESUMO

Evidence suggests constipation precedes motor dysfunction and is the most common gastrointestinal symptom in Parkinson's disease (PD). 5-HT4 receptor (5-HT4R) agonist prucalopride has been approved to treat chronic constipation. Here, we reported intraperitoneal injection of prucalopride for 7 days increased dopamine and decreased dopamine turnover. Prucalopride administration improved motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mouse models. Prucalopride treatment also ameliorated intestinal barrier impairment and increased IL-6 release in PD model mice. However, prucalopride treatment exerted no impact on JAK2/STAT3 pathway, suggesting that prucalopride may stimulate IL-6 via JAK2/STAT3-independent pathway. In conclusion, prucalopride exerted beneficial effects in MPTP-induced Parkinson's disease mice by attenuating the loss of dopamine, improving motor dysfunction and intestinal barrier.


Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Doença de Parkinson/prevenção & controle , Doença de Parkinson/fisiopatologia , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Janus Quinase 2/metabolismo , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/fisiopatologia , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson Secundária/fisiopatologia , Doença de Parkinson Secundária/prevenção & controle , Fator de Transcrição STAT3/metabolismo
19.
Methods Mol Biol ; 2252: 221-237, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33765278

RESUMO

Ribosome profiling is a powerful technique that enables researchers to monitor translational events across the transcriptome. It provides a snapshot of ribosome positions and density across the transcriptome at a sub-codon resolution. Here we describe the whole procedure of profiling ribosome footprints in mammalian cells. Two methods for Ribo-seq library construction are introduced, and their advantages and disadvantages are compared. There is a room for further improvement of Ribo-seq in terms of the amount of starting material, the duration of library construction, and the resolution of sequencing results.


Assuntos
Biblioteca Gênica , Poli A/metabolismo , RNA Mensageiro/genética , Ribossomos/metabolismo , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biossíntese de Proteínas , RNA Mensageiro/química , Análise de Sequência de RNA/métodos , Software
20.
Nat Commun ; 12(1): 1589, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707434

RESUMO

Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.


Assuntos
Cisteína/metabolismo , Cistina/metabolismo , Ferroptose/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Glutationa/metabolismo , Células HEK293 , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Neoplasias/patologia
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