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A specialised microenvironment, termed niche, provides extrinsic signals for the maintenance of residential stem cells. However, how residential stem cells maintain niche homeostasis and whether stromal niche cells could convert their fate into stem cells to replenish lost stem cells upon systemic stem cell loss remain largely unknown. Here, through systemic identification of JAK/STAT downstream targets in adult Drosophila testis, we show that Escargot (Esg), a member of the Snail family of transcriptional factors, is a putative JAK/STAT downstream target. esg is intrinsically required in cyst stem cells (CySCs) but not in germline stem cells (GSCs). esg depletion in CySCs results in CySC loss due to differentiation and non-cell autonomous GSC loss. Interestingly, hub cells are gradually lost by delaminating from the hub and converting into CySCs in esg-defective testes. Mechanistically, esg directly represses the expression of socs36E, the well-known downstream target and negative regulator of JAK/STAT signalling. Finally, further depletion of socs36E completely rescues the defects observed in esg-defective testes. Collectively, JAK/STAT target Esg suppresses SOCS36E to maintain CySC fate and repress niche cell conversion. Thus, our work uncovers a regulatory loop between JAK/STAT signalling and its downstream targets in controlling testicular niche homeostasis under physiological conditions.
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Crizotinib (CRZ), one of anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), has emerged as a frontline treatment for ALK-positive (ALK+) lung adenocarcinoma. However, the overexpression of P-glycoprotein (P-gp, a mitochondrial adenosine triphosphate (ATP)-dependent protein) in lung adenocarcinoma lesions causes multidrug resistance (MDR) and limits the efficacy of CRZ treatment. Herein, a mitochondria-targeting nanosystem, zeolitic imidazolate framework-90@indocyanine green (ZIF-90@ICG), was fabricated to intervene in mitochondria and overcome drug resistance. Due to the zinc ion (Zn2+) interference of ZIF-90 and the photodynamic therapy (PDT) of ICG, this nanosystem is well suited for damaging mitochondrial functions, thus downregulating the intracellular ATP level and inhibiting P-gp expression. In addition, systematic bioinformatics analysis revealed the upregulation of CD44 in CRZ-resistant cells. Therefore, hyaluronic acid (HA, a critical target ligand of CD44) was further modified on the surface of ZIF-90@ICG for active targeting. Overall, this ZIF-90@ICG nanosystem synergistically increased the intracellular accumulation of CRZ and reversed CRZ resistance to enhance its anticancer effect, which provides guidance for nanomedicine design to accurately target tumours and induce mitochondrial damage and represents a viable regimen for improving the prognosis of patients with ALK-TKIs resistance. STATEMENT OF SIGNIFICANCE: The original aim of our research was to combat multidrug resistance (MDR) in highly aggressive and lethal lymphoma kinase-positive (ALK+) lung adenocarcinoma. For this purpose, a cascade-targeted system was designed to overcome MDR, integrating lung adenocarcinoma-targeted hyaluronic acid (HA), mitochondrion-targeted zeolitic imidazolate framework-90 (ZIF-90), the clinically approved drug crizotinib (CRZ), and the fluorescence imaging agent/photosensitizer indocyanine green (ICG). Moreover, using a "two birds with one stone" strategy, ion interference and oxidative stress induced by ZIF-90 and photodynamic therapy (PDT), respectively, disrupt mitochondrial homeostasis, thus downregulating adenosine triphosphate (ATP) levels, inhibiting MDR-relevant P-glycoprotein (P-gp) expression and suppressing tumour metastasis. Overall, this research represents an attempt to implement the concept of MDR reversal and realize the trade-offs between MDR and therapeutic effectiveness.
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Background: Polyamine modification patterns in lung adenocarcinoma (LUAD) and their impact on prognosis, immune infiltration, and anti-tumor efficacy have not been systematically explored. Methods: Patients from The Cancer Genome Atlas (TCGA) were classified into subtypes according to polyamine metabolism-related genes using the consensus clustering method, and the survival outcomes and immune profile were compared. Meanwhile, the geneCluster was constructed according to the differentially expressed genes (DEGs) of the subtypes. Subsequently, the polyamine metabolism-related score (PMRS) system was established using the least absolute shrinkage and selection operator (LASSO) multivariate regression analysis in the TCGA training cohort (n = 245), which can be applied to characterize the prognosis. To verify the predictive performance of the PMRS, the internal cohort (n = 245) and the external cohort (n = 244) were recruited. The relationship between the PMRS and immune infiltration and antitumor responses was investigated. Results: Two distinct patterns (C1 and C2) were identified, in which the C1 subtype presented an adverse prognosis, high CD8+ T cell infiltration, tumor mutational burden (TMB), immune checkpoint, and low tumor immune dysfunction and exclusion (TIDE). Furthermore, two geneClusters were established, and similar findings were observed. The PMRS, including three genes (SMS, SMOX, and PSMC6), was then constructed to characterize the polyamine metabolic patterns, and the patients were divided into high- and low-PMRS groups. As confirmed by the validation cohort, the high-PMRS group possessed a poor prognosis. Moreover, external samples and immunohistochemistry confirmed that the three genes were highly expressed in tumor samples. Finally, immunotherapy and chemotherapy may be beneficial to the high-PMRS group based on the immunotherapy cohorts and low half-maximal inhibitory concentration (IC50) values. Conclusion: We identified distinct polyamine modification patterns and established a PMRS to provide new insights into the mechanism of polyamine action and improve the current anti-tumor strategy of LUAD.
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Background: Lymphangiogenesis (LYM) has an important role in tumor progression and is strongly associated with tumor metastasis. However, the clinical application of LYM has not progressed as expected. The potential value of LYM needs to be further developed in lung adenocarcinoma (LUAD) patients. Methods: The Sequencing data and clinical characteristics of LUAD patients were downloaded from The Cancer Genome Atlas and GEO databases. Multiple machine learning algorithms were used to screen feature genes and develop the LYM index. Immune cell infiltration, immune checkpoint expression, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and drug sensitivity analysis were used to explore the correlation of LYM index with immune profile and anti-tumor therapy. Results: We screened four lymphangiogenic feature genes (PECAM1, TIMP1, CXCL5 and PDGFB) to construct LYM index based on multiple machine learning algorithms. We divided LUAD patients into the high LYM index group and the low LYM index group based on the median LYM index. LYM index is a risk factor for the prognosis of LUAD patients. In addition, there was a significant difference in immune profile between high LYM index and low LYM index groups. LUAD patients in the low LYM index group seemed to benefit more from immunotherapy based on the results of TIDE algorithm. Conclusion: Overall, we confirmed that the LYM index is a prognostic risk factor and a valuable predictor of immunotherapy response in LUAD patients, which provides new evidence for the potential application of LYM.
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Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Linfangiogénesis , Adenocarcinoma del Pulmón/terapia , Genes Reguladores , Inmunoterapia , Neoplasias Pulmonares/terapiaRESUMEN
Balanced control of stem cell proliferation and differentiation underlines tissue homeostasis. Disruption of tissue homeostasis often results in many diseases. However, how endogenous factors influence the proliferation and differentiation of intestinal stem cells (ISCs) under physiological and pathological conditions remains poorly understood. Here, we find that the evolutionarily conserved endoplasmic reticulum membrane protein complex (EMC) negatively regulates ISC proliferation and intestinal homeostasis. Compromising EMC function in progenitors leads to excessive ISC proliferation and intestinal homeostasis disruption. Mechanistically, the EMC associates with and stabilizes Hippo (Hpo) protein, the key component of the Hpo signaling pathway. In the absence of EMC, Yorkie (Yki) is activated to promote ISC proliferation due to Hpo destruction. The EMC-Hpo-Yki axis also functions in enterocytes to maintain intestinal homeostasis. Importantly, the levels of the EMC are dramatically diminished in tunicamycin-treated animals, leading to Hpo destruction, thereby resulting in intestinal homeostasis disruption due to Yki activation. Thus, our study uncovers the molecular mechanism underlying the action of the EMC in intestinal homeostasis maintenance under physiological and pathological conditions and provides new insight into the pathogenesis of tunicamycin-induced tumorigenesis.
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Proteínas de Drosophila , Proteínas Serina-Treonina Quinasas , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Transducción de Señal/fisiología , Proteínas de Drosophila/metabolismo , Tunicamicina/metabolismo , Transactivadores/metabolismo , Proliferación Celular , Proteínas Nucleares/metabolismo , Homeostasis , Drosophila melanogaster/metabolismoRESUMEN
The maintenance of germline stem cells (GSCs) is essential for tissue homeostasis. JAK/STAT signaling maintains GSC fate in Drosophila testis. However, how JAK/STAT signaling maintains male GSC fate through its downstream targets remains poorly understood. Here, we identify p115, a tER/cis-Golgi golgin protein, as a putative downstream target of JAK/STAT signaling. p115 maintains GSC fate independent of GM130 and GRASP65. p115 localizes in cytosol, the ER and Golgi apparatus in germline cells and is required for the morphology of the ER and Golgi apparatus. Furthermore, depletion of p115 in GSCs results in aberrant spindle orientation. Mechanistically, p115 associates with and stabilizes STAT. Finally, ectopic expression of STAT completely restores GSC loss caused by p115 depletion. Collectively, JAK/STAT signaling and p115 form a feedforward loop to maintain male GSC fate. Our work provides new insights into the regulatory mechanism of how stem cell maintenance is properly controlled by JAK/STAT signaling.
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Proteínas de Drosophila , Células Germinativas , Células Madre , Animales , Masculino , Drosophila melanogaster , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Factores de Transcripción STAT/metabolismo , Células Madre/metabolismo , Transducción de Señal , Quinasas Janus/metabolismoRESUMEN
Small cell lung cancer (SCLC) is one of a pathological type of lung cancer, and it is characterized by invasiveness, high malignancy and refractoriness. The mortality rate of SCLC is significantly higher than other types of lung cancer, and the treatment options for SCLC patients are limited. Delta-like ligand 3 (DLL3) is a Notch signaling ligand that plays a role in regulating the proliferation, development and metastasis of SCLC cells. Mnay studies have shown that DLL3 is overexpressed on the surface of SCLC cells, suggesting that DLL3 is a potential target for SCLC patients. A series of drug trials targeting DLL3 are underway. The Phase III clinical trials of Rova-T, a drug targeting DLL3, have not yielded the expected results. However, other drugs that target DLL3, such as AMG119, AMG757 and DLL3-targeted NIR-PIT, bring new ideas for SCLC treatment. Overall, DLL3 remains a valuable target for SCLC.
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Epithelial polarity is critical for proper functions of epithelial tissues, tumorigenesis, and metastasis. The evolutionarily conserved transmembrane protein Crumbs (Crb) is a key regulator of epithelial polarity. Both Crb protein and its transcripts are apically localized in epithelial cells. However, it remains not fully understood how they are targeted to the apical domain. Here, using Drosophila ovarian follicular epithelia as a model, we show that epithelial polarity is lost and Crb protein is absent in the apical domain in follicular cells (FCs) in the absence of Diamond (Dind). Interestingly, Dind is found to associate with different components of the dynactin-dynein complex through co-IP-MS analysis. Dind stabilizes dynactin and depletion of dynactin results in almost identical defects as those observed in dind-defective FCs. Finally, both Dind and dynactin are also required for the apical localization of crb transcripts in FCs. Thus our data illustrate that Dind functions through dynactin/dynein-mediated transport of both Crb protein and its transcripts to the apical domain to control epithelial apico-basal (A/B) polarity.
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Proteínas de Drosophila , Animales , Polaridad Celular , Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Complejo Dinactina/metabolismo , Dineínas/metabolismo , Células Epiteliales/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismoRESUMEN
Background: Nowadays, the characteristics and treatment of advanced pulmonary large cell neuroendocrine carcinoma (LCNEC) remain controversial. This study aimed to analyze the similarity of clinical characteristics, survival outcomes and treatment modalities between advanced LCNEC and advanced small cell lung cancer (SCLC) to provide more evidence for the study of advanced LCNEC. Methods: All SCLC and LCNEC patient data were obtained from the SEER database (2010-2019). Pearson's χ2 test was used to compare the differences in clinical characteristics. Propensity score matching (PSM) was utilized to balance the bias of the variables between patients. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify prognostic factors. KM analysis was used to calculate survival. Results: A total of 1094 patients with IV LCNEC and 20939 patients with IV SCLC were included in this study. The demographic characteristics and tumor characteristics of IV LCNEC and IV SCLC were different (p < 0.05). After PSM, the overall survival (OS) for IV LCNEC and IV SCLC was 6.0 months, the cancer-specific survival (CSS) was 7.0 months, and there was no significant difference in OS or CSS between the two groups. Risk/protective factors for OS and CSS were similar for IV LCNEC and IV SCLC patients. Survival outcomes were similar in patients with IV LCNEC and IV SCLC with different treatment modalities; chemoradiotherapy significantly improved OS and CSS in patients with IV LCNEC (9.0 months) and SCLC (10.0 months), however, radiotherapy alone did not improve survival in patients with IV LCNEC. Conclusions: These results confirmed that the prognosis and treatment modalities are similar and that advanced LCNEC could be treated as advanced SCLC, which provide new evidence for the treatment of advanced LCNEC patients.
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Background: Lung cancer has a high incidence and mortality rate worldwide. Vasculogenic mimicry (VM) is a specific modality of tumor angiogenesis that could potentially be a new target for tumor therapy. The purpose of this study was to explore the role of VM-related genes in assessing the prognosis and immune landscape of lung cancer. Methods: VM-related genes were obtained from previous studies, and the expression data and clinical data of lung adenocarcinoma (LUAD) patients were obtained from the TCGA database and GEO database. We performed enrichment analysis of 24 VM-related genes and screened hub genes by constructing a protein-protein interaction network and using Cytoscape software. Subsequently, we developed the VM score based on univariate Cox regression analysis and Lasso analysis and validated the VM score on the GSE72094 dataset. In addition, we constructed a nomogram based on the VM score in the TCGA cohort. Finally, we explored the correlation between the VM score and the tumor microenvironment, immune cell infiltration, immune checkpoints, and drug sensitivity. Results: Enrichment analysis revealed that VM-related genes were associated with the HIF signaling pathway and angiogenic pathway. We developed a VM score based on 3 genes (EPHA2, LAMC2 and LOXL2) in LUAD patients. Kaplan-Meier analysis showed that the VM score was associated with poor prognosis in LUAD patients. The receiver operating characteristic curve suggested that the VM score and nomogram are valid predictors for the overall survival of LUAD patients. The VM score was significantly correlated with immune cell infiltration, such as naïve B cells, neutrophils, and eosinophils, and there was a difference in the TME between the high VM score group and the low VM score group. LUAD patients in the high VM score group were more sensitive to antitumor drugs. Conclusion: In summary, the VM score developed in this study is a valuable indicator for evaluating the prognosis and immune landscape of LUAD patients. VM may be a potential target for antitumor therapy in lung cancer.
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Previous studies have shown that asthma is a risk factor for lung cancer, while the mechanisms involved remain unclear. We attempted to further explore the association between asthma and non-small cell lung cancer (NSCLC) via bioinformatics analysis. We obtained GSE143303 and GSE18842 from the GEO database. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) groups were downloaded from the TCGA database. Based on the results of differentially expressed genes (DEGs) between asthma and NSCLC, we determined common DEGs by constructing a Venn diagram. Enrichment analysis was used to explore the common pathways of asthma and NSCLC. A protein-protein interaction (PPI) network was constructed to screen hub genes. KM survival analysis was performed to screen prognostic genes in the LUAD and LUSC groups. A Cox model was constructed based on hub genes and validated internally and externally. Tumor Immune Estimation Resource (TIMER) was used to evaluate the association of prognostic gene models with the tumor microenvironment (TME) and immune cell infiltration. Nomogram model was constructed by combining prognostic genes and clinical features. 114 common DEGs were obtained based on asthma and NSCLC data, and enrichment analysis showed that significant enrichment pathways mainly focused on inflammatory pathways. Screening of 5 hub genes as a key prognostic gene model for asthma progression to LUAD, and internal and external validation led to consistent conclusions. In addition, the risk score of the 5 hub genes could be used as a tool to assess the TME and immune cell infiltration. The nomogram model constructed by combining the 5 hub genes with clinical features was accurate for LUAD. Five-hub genes enrich our understanding of the potential mechanisms by which asthma contributes to the increased risk of lung cancer.
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Adenocarcinoma del Pulmón , Asma , Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Asma/genética , Microambiente TumoralRESUMEN
Zinc (Zn), extolled as "the flower of life" in modern medicine, has been extensively highlighted with its physiological functions to maintain growth, development, and metabolism homeostasis. Driven by the substantial advancement of nanotechnology and oncology, Zn-involved nanomedicines integrating the intrinsic bioactivity of Zn species and the physiochemical attributes of Zn-composed nanosystems have blazed a highly efficient and relatively biosafe antineoplastic path. In this review, we aim to highlight and discuss the recent representative modalities of emerging Zn-involved oncology nanomedicine, mainly emphasizing the rational design, biological effect and biosafety, and therapeutic strategies. In addition, we provide the underlying critical obstacles and future perspectives of Zn-involved oncology nanomedicines, primarily focusing on the chances and challenges of clinical translation. Furthermore, we hope the review can give rise to opportunities within oncology nanomedicine and other biomedical fields, promoting the prosperity and progress of the "Zincic Age".
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Nanopartículas , Neoplasias , Humanos , Nanomedicina , Zinc , Nanopartículas/uso terapéutico , Nanotecnología , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológicoRESUMEN
Tissue phenotypic plasticity facilitates rapid adaptation of organisms to biotic and/or abiotic pressure. The reproductive capacity of honey bee workers (Apis mellifera) is plastic and responsive to pheromones produced by broods and the queen. Egg laying workers (ELWs), which could reactivate their ovaries and lay haploid eggs upon queen lost, have been commonly discussed from many aspects. However, it remains unclear whether midgut homeostasis in ELWs is affected during plastic changes. Here, we found that the expression of nutrition- and autophagy-related genes was up-regulated in the midguts of ELWs, compared with that in nurse workers (NWs) by RNA-sequencing. Furthermore, the area and number of autophagosomes were increased, along with significantly increased cell death in the midguts of ELWs. Moreover, cell cycle progression in the midguts of ELWs was increased compared with that in NWs. Consistent with the up-regulation of nutrition-related genes, the body and midgut sizes, and the number of intestinal proliferation cells of larvae reared with royal jelly (RJ) obviously increased more than those reared without RJ in vitro. Finally, cell proliferation was dramatically suppressed in the midguts of ELWs when autophagy was inhibited. Altogether, our data suggested that autophagy was induced and required to sustain cell proliferation in ELWs' midguts, thereby revealing the critical role of autophagy played in the intestines during phenotypic plasticity changes.
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Autofagia , Intestinos , Abejas/genética , Animales , Larva/fisiología , Autofagia/genética , Adaptación Fisiológica , Proliferación CelularRESUMEN
PURPOSE: We aimed to explore the prognostic value of integrin-ß superfamily members (ITGBs) and their role in immune cell infiltration in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Study cases were acquired from The Cancer Genome Atlas database and The Human Protein Atlas. We then used R package and several online tools to analyze and visualize the roles of ITGBs in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). RESULTS: We found that ITGBs were differentially expressed in NSCLC. In LUAD, high expression of ITGB1 and ITGB4 was an independent risk factor for poor prognosis, and ITGB7 was an independent protective factor for overall survival; in LUSC, high expression of ITGB1, 3, 5, and 6 was associated with poor prognosis, and ITGB8 was an independent protective factor for disease-specific survival. Protein-protein interaction networks for the most associated co-expressed genes revealed the following target genes of ITGBs: PTPRC, ITGAM, and ITGB2 in LUAD and FN1, PTPRC, and ITGB2 in LUSC. Gene ontology analysis revealed that functions related to adhesion, junction, and binding were highly enriched in LUAD and LUSC. ITGBs were significantly associated with immune cell infiltration and the expression of immunomodulation-related genes in LUAD and LUSC. CONCLUSION: ITGBs were differentially expressed in NSCLC. ITGB1, 4, and 7 and ITGB1, 3, 5, 6, and 8 were found as prognostic markers in LUAD and LUSC, respectively. ITGBs were significantly associated with immune cell infiltration and the expression of immunomodulation-related genes.
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Background: Lung adenocarcinoma (LUAD) is one of the most frequent causes of tumor-related mortality worldwide. Recently, the role of N7-methylguanosine (m7G) in tumors has begun to receive attention, but no investigation on the impact of m7G on LUAD. This study aims to elucidate the significance of m7G on the prognosis and immunotherapy in LUAD. Methods: Consensus clustering was employed to determine the molecular subtype according to m7G-related regulators extracted from The Cancer Genome Atlas (TCGA) database. Survival, clinicopathological features and tumor mutational burden (TMB) analysis were applied to research molecular characteristics of each subtype. Subsequently, "limma" package was used to screen differentially expressed genes (DEGs) between subtypes. In the TCGA train cohort (n = 245), a prognostic signature was established by univariate Cox regression, lasso regression and multivariate Cox regression analysis according to DEGs and survival analysis was employed to assess the prognosis. Then the prognostic value of the signature was verified by TCGA test cohort (n = 245), TCGA entire cohort (n = 490) and GSE31210 cohort (n = 226). Moreover, the association among immune infiltration, clinical features and the signature was investigated. The immune checkpoints, TMB and tumor immune dysfunction and exclusion (TIDE) were applied to predict the immunotherapy response. Results: Two novel molecular subtypes (C1 and C2) of LUAD were identified. Compared to C2 subtype, C1 subtype had poorer prognosis and higher TMB. Subsequently, the signature (called the "m7G score") was constructed according to four key genes (E2F7, FAM83A, PITX3, and HOXA13). The distribution of m7G score were significantly different between two molecular subtypes. The patients with lower m7G score had better prognosis in TCGA train cohort and three verification cohort. The m7G score was intensively related to immune infiltration. Compared with the lower score, the higher m7G score was related to remarkable upregulation of the PD-1 and PD-L1, the higher TMB and the lower TIDE score. Conclusion: This study established a m7G-related signature for predicting prognosis and immunotherapy in LUAD, which may contribute to the development of new therapeutic strategies for LUAD.
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Germline stem cells (GSCs) are critical for the reproduction of an organism. The self-renewal and differentiation of GSCs must be tightly controlled to avoid uncontrolled stem cell proliferation or premature stem cell differentiation. However, how the self-renewal and differentiation of GSCs are properly controlled is not fully understood. Here, we find that the novel intrinsic factor Yun is required for female GSC maintenance in Drosophila. GSCs undergo precocious differentiation due to de-repression of differentiation factor Bam by defective BMP/Dpp signaling in the absence of yun. Mechanistically, Yun associates with and stabilizes Thickveins (Tkv), the type I receptor of Dpp/BMP signaling. Finally, ectopic expression of a constitutively active Tkv (TkvQD) completely suppresses GSC loss caused by yun depletion. Collectively, these data demonstrate that Yun functions through Tkv to maintain GSC fate. Our results provide new insight into the regulatory mechanisms of how stem cell maintenance is properly controlled.
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Proteínas de Drosophila , Células Madre Oogoniales , Animales , Diferenciación Celular/fisiología , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Femenino , Células Germinativas , Factor Intrinseco/metabolismo , Células Madre Oogoniales/metabolismo , Ovario/metabolismo , Proteínas Serina-Treonina Quinasas , Receptores de Superficie Celular/metabolismoRESUMEN
Stem cells maintain adult tissue homeostasis under physiological conditions. Uncontrolled stem cell proliferation will lead to tumorigenesis. How stem cell proliferation is precisely controlled is still not fully understood. Phosphorylation of Yun is essential for ISC proliferation. Yun is essential for the proliferation of normal and transformed intestinal stem cells. Our mass spectrometry and biochemical data suggest that Yun can be phosphorylated at multiple residues in vivo. Interestingly, we show that the phosphorylation among these residues is likely interdependent. Furthermore, phosphorylation of each residue in Yun is important for its function in ISC proliferation regulation. Thus, our study unveils the important role of post-translational modification of Yun in stem cell proliferation.
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Proteínas de Drosophila , Adulto , Proliferación Celular , Transformación Celular Neoplásica , Proteínas de Drosophila/metabolismo , Humanos , Intestinos , FosforilaciónRESUMEN
Adult tissue homeostasis is maintained by residential stem cells. The proliferation and differentiation of adult stem cells must be tightly balanced to avoid excessive proliferation or premature differentiation. However, how stem cell proliferation is properly controlled remains elusive. Here, we find that auxilin (Aux) restricts intestinal stem cell (ISC) proliferation mainly through EGFR signaling. aux depletion leads to excessive ISC proliferation and midgut homeostasis disruption, which is unlikely caused by defective Notch signaling. Aux is expressed in multiple types of intestinal cells. Interestingly, aux depletion causes a dramatic increase in EGFR signaling, with a strong accumulation of EGFR at the plasma membrane and an increased expression of EGFR ligands in response to tissue stress. Furthermore, Aux co-localizes and associates with EGFR. Finally, blocking EGFR signaling completely suppresses the defects caused by aux depletion. Together, these data demonstrate that Aux mainly safeguards EGFR activation to keep a proper ISC proliferation rate to maintain midgut homeostasis.
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Proteínas de Drosophila , Animales , Auxilinas/metabolismo , Proliferación Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Receptores ErbB/metabolismo , Intestinos , Receptores de Péptidos de Invertebrados/genética , Receptores de Péptidos de Invertebrados/metabolismoRESUMEN
Stem cells constantly divide and differentiate to maintain adult tissue homeostasis, and uncontrolled stem cell proliferation leads to severe diseases such as cancer. How stem cell proliferation is precisely controlled remains poorly understood. Here, from an RNA interference (RNAi) screen in adult Drosophila intestinal stem cells (ISCs), we identify a factor, Yun, required for proliferation of normal and transformed ISCs. Yun is mainly expressed in progenitors; our genetic and biochemical evidence suggest that it acts as a scaffold to stabilize the Prohibitin (PHB) complex previously implicated in various cellular and developmental processes and diseases. We demonstrate that the Yun/PHB complex is regulated by and acts downstream of EGFR/MAPK signaling. Importantly, the Yun/PHB complex interacts with and positively affects the levels of the transcription factor E2F1 to regulate ISC proliferation. In addition, we find that the role of the PHB complex in cell proliferation is evolutionarily conserved. Thus, our study uncovers a Yun/PHB-E2F1 regulatory axis in stem cell proliferation.
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Células Madre Adultas/metabolismo , Proliferación Celular/fisiología , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Factor de Transcripción E2F1/metabolismo , Intestinos/metabolismo , Prohibitinas/metabolismo , Animales , Animales Modificados Genéticamente , Diferenciación Celular/fisiología , Homeostasis/fisiología , Interferencia de ARN/fisiología , Transducción de Señal/fisiologíaRESUMEN
Adult stem cells are critical for the maintenance of residential tissue homeostasis and functions. However, the roles of cellular protein homeostasis maintenance in stem cell proliferation and tissue homeostasis are not fully understood. Here, we find that Derlin-1 and TER94/VCP/p97, components of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, restrain intestinal stem cell proliferation to maintain intestinal homeostasis in adult Drosophila. Depleting any of them results in increased stem cell proliferation and midgut homeostasis disruption. Derlin-1 is specifically localized in the ER of progenitors, and its C-terminus is required for its function. Interestingly, we find that increased stem cell proliferation is resulted from elevated ROS levels and activated JNK signaling in Derlin-1- or TER94-deficient progenitors. Further removal of reactive oxygen species (ROS) or inhibition of JNK signaling almost completely suppresses increased stem cell proliferation. Together, these data demonstrate that the ERAD pathway is critical for stem cell proliferation and tissue homeostasis. Thus, we provide insights into our understanding of the mechanisms underlying cellular protein homeostasis maintenance (ER protein quality control) in tissue homeostasis and tumor development.