Genes to Cells最新文献

The HAT Inhibitor ISOX-DUAL Diminishes Ischemic Areas in a Mouse Model of Oxygen-Induced Retinopathy

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-02-07 DOI: 10.1111/gtc.13196

Kengo Nakanishi, Yoshihiro Takamura, Yusei Nakano, Masaru Inatani, Masaya Oki

{"title":"The HAT Inhibitor ISOX-DUAL Diminishes Ischemic Areas in a Mouse Model of Oxygen-Induced Retinopathy","authors":"Kengo Nakanishi, Yoshihiro Takamura, Yusei Nakano, Masaru Inatani, Masaya Oki","doi":"10.1111/gtc.13196","DOIUrl":"https://doi.org/10.1111/gtc.13196","url":null,"abstract":"Retinal ischemic disease results in significant visual impairment due to the development of fragile and disorganized, pathologically running blood vessels in the eye. Currently, the mainstay treatment for this disease is the intravitreal administration of anti-VEGF drugs targeting vascular endothelial growth factor (VEGF), which induces angiogenesis. However, current anti-VEGF drugs do not diminish the ischemic areas that lead to angiogenesis, making fundamental treatment challenging. Since retinopathy is an acquired disease caused by hypoxic stimulation from ischemia, we paid particular attention to histone acetylases. We conducted a drug screening experiment using a mouse model of oxygen-induced retinopathy (OIR), which replicates retinal ischemic disease, through the intraperitoneal administration of 17 distinct inhibitors targeting histone acetyltransferases (HAT). The results indicated that, among the 17 inhibitors, only ISOX-DUAL decreased neovascularization and ischemic regions. Furthermore, microarray analysis was conducted on the drug-treated samples to refine genes altered by the administration of ISOX-DUAL. There were 21 genes associated with angiogenesis, including Angpt2, Hmox1, Edn1, and Serpine1, exhibited upregulation in OIR mice and downregulation following treatment with ISOX-DUAL. Furthermore, STRING analysis confirmed that the aforementioned four genes are downstream factors of hypoxia-inducible factors and are assumed to be important factors in retinal ischemic diseases.","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 2","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13196","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Protein Kinase aPKC as Well as the Small GTPases RhoA and Cdc42 Regulates Neutrophil Chemotaxis Partly by Recruiting the ROCK Kinase to the Leading Edge

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-02-05 DOI: 10.1111/gtc.70002

Atsushi Naito, Sachiko Kamakura, Junya Hayase, Akira Kohda, Hiroaki Niiro, Koichi Akashi, Hideki Sumimoto

{"title":"The Protein Kinase aPKC as Well as the Small GTPases RhoA and Cdc42 Regulates Neutrophil Chemotaxis Partly by Recruiting the ROCK Kinase to the Leading Edge","authors":"Atsushi Naito, Sachiko Kamakura, Junya Hayase, Akira Kohda, Hiroaki Niiro, Koichi Akashi, Hideki Sumimoto","doi":"10.1111/gtc.70002","DOIUrl":"https://doi.org/10.1111/gtc.70002","url":null,"abstract":"The small GTPases RhoA and Cdc42 and their effector proteins play crucial roles in neutrophil chemotaxis. However, endogenous localization and regulation of these proteins have remained largely unknown. Here, we show, using a trichloroacetic acid fixation method, that endogenous RhoA and Cdc42 are preferentially accumulated at the F-actin-rich leading edge (pseudopod) during chemotaxis of human neutrophil-like PLB-985 cells in response to the chemoattractant C5a. Interestingly, the enrichment of RhoA is impaired by knockdown of Cdc42, indicating a positive regulation by Cdc42. Depletion of Cdc42 or RhoA each induces the formation of multiple pseudopods, confirming their significance in cell polarization with an organized actin network at the front. The Rho-associated kinase ROCK is also recruited to the leading edge during chemotaxis in a manner dependent on not only RhoA and Cdc42 but also aPKC, a Cdc42-interacting kinase that can also bind to ROCK. ROCK promotes phosphorylation of the myosin light chain at the front, possibly regulating pseudopod contractility. Knockdown of aPKC suppresses neutrophil chemotaxis by disturbing pseudopod orientation without forming multiple protrusions. An incorrectly oriented pseudopod is also observed in ROCK-depleted cells. Thus, aPKC, as well as RhoA and Cdc42, likely regulates neutrophil chemotaxis partly by recruiting ROCK to the leading edge for correct directionality.","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 2","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143112146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Vacuolar Sts1 Degradation-Induced Cytoplasmic Proteasome Translocation Restores Cell Proliferation

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-02-04 DOI: 10.1111/gtc.70004

Noritaka Ohigashi, Shoshiro Hirayama, Hideki Yashiroda, Shigeo Murata

{"title":"Vacuolar Sts1 Degradation-Induced Cytoplasmic Proteasome Translocation Restores Cell Proliferation","authors":"Noritaka Ohigashi, Shoshiro Hirayama, Hideki Yashiroda, Shigeo Murata","doi":"10.1111/gtc.70004","DOIUrl":"https://doi.org/10.1111/gtc.70004","url":null,"abstract":"<div>\u0000 \u0000 The proteasome is a large multicatalytic complex conserved across eukaryotes that regulates multiple cellular processes through the degradation of ubiquitinated proteins. The proteasome is predominantly localized to the nucleus in proliferating cells and translocates to the cytoplasm in the stationary phase. Sts1 reportedly plays a vital role in the nuclear import of the proteasome during proliferation in yeast Saccharomyces cerevisiae. However, the mechanisms underlying cytoplasmic translocation of the proteasome in the stationary phase remain unknown. Here, we showed that the ubiquitin ligase Hul5 promotes vacuolar sequestration of Sts1 in a catalytic activity-dependent manner and thus suppresses the nuclear import of the proteasome during the stationary phase. We further demonstrated that cytoplasmic translocation of the proteasome plays a vital role in the clearance of ubiquitinated protein aggregates, mitochondrial quality control, and resuming proliferation from cellular quiescence. Our results provide insights into the mechanisms and significance of the cytoplasmic localization of proteasomes in cellular quiescence.\u0000 </div>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 2","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulation of Gut Starvation Responses Through Drosophila NP3253 Neurons

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-02-04 DOI: 10.1111/gtc.70005

Quang-Dat Nguyen, Kiho Fujii, Kentaro Ishibashi, Haruka Hashiba, Wakako Ohtsubo, Haruki Kitazawa, Hiromu Tanimoto, Naoyuki Fuse, Shoichiro Kurata

{"title":"Regulation of Gut Starvation Responses Through Drosophila NP3253 Neurons","authors":"Quang-Dat Nguyen, Kiho Fujii, Kentaro Ishibashi, Haruka Hashiba, Wakako Ohtsubo, Haruki Kitazawa, Hiromu Tanimoto, Naoyuki Fuse, Shoichiro Kurata","doi":"10.1111/gtc.70005","DOIUrl":"https://doi.org/10.1111/gtc.70005","url":null,"abstract":"<div>\u0000 \u0000 The “gut–brain axis,” a bidirectional communication system between the gastrointestinal tract and the central nervous system, plays a crucial role in regulating complex physiological functions in response to nutrients, pathogens, and microbiota. However, the cellular and molecular mechanisms governing this regulation remain poorly understood. Using Drosophila melanogaster as a model organism, we previously identified NP3253 neurons, located in both the brain and gut, as key contributors to gut homeostasis during oral bacterial infection. Here, we found a novel role of NP3253 neurons in regulating starvation resistance. We observed that a subset of NP3253 neurons in the gut were activated during starvation. To investigate downstream effect, we conducted RNA-Seq analysis on the gut of adult flies with genetically silenced NP3253 neurons, comparing gene expression under starved and fed conditions. This analysis identified 26 genes differentially expressed in response to both starvation and NP3253 neuronal activity. Among these, CG12643, encoding an uncharacterized short peptide, was found to be essential for starvation resistance in the gut. Our findings demonstrate that NP3253 neurons modulate the gut gene expression in response to starvation, thereby supporting physiological adaptation to environmental stressors.\u0000 </div>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 2","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An Attention-Based Deep Neural Network Model to Detect Cis-Regulatory Elements at the Single-Cell Level From Multi-Omics Data

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-02-04 DOI: 10.1111/gtc.70000

Ken Murakami, Keita Iida, Mariko Okada

{"title":"An Attention-Based Deep Neural Network Model to Detect Cis-Regulatory Elements at the Single-Cell Level From Multi-Omics Data","authors":"Ken Murakami, Keita Iida, Mariko Okada","doi":"10.1111/gtc.70000","DOIUrl":"https://doi.org/10.1111/gtc.70000","url":null,"abstract":"Cis-regulatory elements (cREs) play a crucial role in regulating gene expression and determining cell differentiation and state transitions. To capture the heterogeneous transitions of cell states associated with these processes, detecting cRE activity at the single-cell level is essential. However, current analytical methods can only capture the average behavior of cREs in cell populations, thereby obscuring cell-specific variations. To address this limitation, we proposed an attention-based deep neural network framework that integrates DNA sequences, genomic distances, and single-cell multi-omics data to detect cREs and their activities in individual cells. Our model shows higher accuracy in identifying cREs within single-cell multi-omics data from healthy human peripheral blood mononuclear cells than other existing methods. Furthermore, it clusters cells more precisely based on predicted cRE activities, enabling a finer differentiation of cell states. When applied to publicly available single-cell data from patients with glioma, the model successfully identified tumor-specific SOX2 activity. Additionally, it revealed the heterogeneous activation of the ZEB1 transcription factor, a regulator of epithelial-to-mesenchymal transition-related genes, which conventional methods struggle to detect. Overall, our model is a powerful tool for detecting cRE regulation at the single-cell level, which may contribute to revealing drug resistance mechanisms in cell sub-populations.","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 2","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcriptomic Regulation by Astrocytic m6A Methylation in the mPFC

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-02-04 DOI: 10.1111/gtc.70003

You-Lu Wen, Fang Guo, Ting-ting Gu, Yan-ping Zeng, Xiong Cao

{"title":"Transcriptomic Regulation by Astrocytic m6A Methylation in the mPFC","authors":"You-Lu Wen, Fang Guo, Ting-ting Gu, Yan-ping Zeng, Xiong Cao","doi":"10.1111/gtc.70003","DOIUrl":"https://doi.org/10.1111/gtc.70003","url":null,"abstract":"Astrocytes, the most prevalent type of glial cells, have been found to play a crucial part in numerous physiological functions. By offering metabolic and structural support, astrocytes are vital for the proper functioning of the brain and regulating information processing and synaptic transmission. Astrocytes located in the medial prefrontal cortex (mPFC) are highly responsive to environmental changes and have been associated with the development of brain disorders. One of the primary mechanisms through which the brain responds to environmental factors is epitranscriptome modification. M6-methyladenosine methylation is the most prevalent internal modification of eukaryotic messenger RNA (mRNA), and it significantly impacts transcript processing and protein synthesis. However, the effects of m6A on astrocyte transcription and function are still not well understood. Our research demonstrates that ALKBH5, an RNA demethylase of m6A found in astrocytes, affects gene expression in the mPFC. These findings suggest that further investigation into the potential role of astrocyte-mediated m6A methylation in the mPFC is warranted.","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 2","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.70003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

WDR74-Mediated Ribosome Biogenesis and Proteome Dynamics During Mouse Preimplantation Development 小鼠着床前发育过程中wdr74介导的核糖体生物发生和蛋白质组动力学。

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-01-22 DOI: 10.1111/gtc.70001

Ayaka Kakihara, Marino Maemura, Atsushi Hatano, Masaki Matsumoto, Yu-ichi Tsukada

{"title":"WDR74-Mediated Ribosome Biogenesis and Proteome Dynamics During Mouse Preimplantation Development","authors":"Ayaka Kakihara, Marino Maemura, Atsushi Hatano, Masaki Matsumoto, Yu-ichi Tsukada","doi":"10.1111/gtc.70001","DOIUrl":"10.1111/gtc.70001","url":null,"abstract":"<div>\u0000 \u0000 Preimplantation embryonic development is orchestrated by dynamic changes in the proteome and transcriptome, regulated by mechanisms such as maternal-to-zygotic transition. Here, we employed label-free quantitative proteomics to comprehensively analyze proteome dynamics from germinal vesicle oocytes to blastocysts in mouse embryos. We identified 3490 proteins, including 715 consistently detected across all stages, revealing stage-specific changes in proteins associated with translation, protein modification, and mitochondrial metabolism. Comparison with transcriptomic data highlighted a low correlation between mRNA and protein levels, underscoring the significance of non-transcriptional regulatory mechanisms during early development. Additionally, we analyzed WD repeat-containing protein 74 (WDR74)-deficient embryos generated using CRISPR-Cas9 genome editing. WDR74, a pre-60S ribosome maturation factor, was found to be critical for ribosome biogenesis and cell division. Furthermore, WDR74 deficiency led to a significant reduction in ribosomal protein large subunit and impaired progression beyond the morula stage. Key ribosomal proteins such as ribosomal protein L24 (RPL24) and ribosomal protein L26 (RPL26), which influence cell division timing, were notably affected, while small subunit proteins remained largely unchanged. Taken together, our study demonstrates the utility of integrating genome editing with proteomic analysis to elucidate molecular mechanisms underlying early embryogenesis, and provides new insights into protein-level regulation of preimplantation development.\u0000 </div>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activation of Evolutionarily Young Endogenous Retroviruses Is Implicated in COVID-19 Immunopathology 进化年轻内源性逆转录病毒的激活与COVID-19免疫病理有关

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-01-19 DOI: 10.1111/gtc.13194

Reia Yoshida, Hitoshi Ohtani

{"title":"Activation of Evolutionarily Young Endogenous Retroviruses Is Implicated in COVID-19 Immunopathology","authors":"Reia Yoshida, Hitoshi Ohtani","doi":"10.1111/gtc.13194","DOIUrl":"10.1111/gtc.13194","url":null,"abstract":"The dysfunction of the innate immune system is well-described as a clinical characteristic of COVID-19. While several groups have reported human endogenous retroviruses (ERVs) as enhancing factors of immune reactivity, characterization of the COVID-19-specific ERVs has not yet been sufficiently conducted. Here, we revealed the transcriptome profile of more than 500 ERV subfamilies and innate immune response genes in eight different cohorts of platelet, peripheral blood mononuclear cells (PBMCs), lung, frontal cortex of brain, ventral midbrain, pooled human umbilical vein endothelial cells (pHUVECs), placenta, and cardiac microvascular endothelial cells (HCMEC) from COVID-19 patients (total; n = 124) and normal samples (total; n = 53) using publicly available datasets. While upregulation of ERV subfamilies was found in platelets, PBMCs, and placenta, the immune reactivity was confined to only platelets and PBMCs. It is noteworthy that the evolutionary ages of the upregulated ERV subfamilies detected in platelets and PBMCs were younger than other ERV subfamilies, but the tendency was not seen in the upregulated ERV subfamilies in placenta. The results suggest that only evolutionarily young ERVs can function as enhancing factors of the immune reactivity in COVID-19 patients. The finding should be instrumental in understanding the COVID-19 immunopathology.","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

“Chance and Necessity” on the Molecular Evolution of REV3 (a Catalytic Subunit of DNA Polymerase ζ)—The Dual Roles of Translesion and Neuronal Extension REV3 （DNA聚合酶ζ的催化亚基）分子进化的“偶然与必然”——翻译和神经元延伸的双重作用。

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-01-17 DOI: 10.1111/gtc.13189

Kagemasa Kajiwara, Kouichi Yamada

{"title":"“Chance and Necessity” on the Molecular Evolution of REV3 (a Catalytic Subunit of DNA Polymerase ζ)—The Dual Roles of Translesion and Neuronal Extension","authors":"Kagemasa Kajiwara, Kouichi Yamada","doi":"10.1111/gtc.13189","DOIUrl":"10.1111/gtc.13189","url":null,"abstract":"<div>\u0000 \u0000 Catalytic subunit of DNA polymerase ζ (REV3), involved in translesion-replication is evolutionarily conserved from yeast and plants to higher eukaryotes. However, a large intermediate domain is inserted in REV3 of humans and mice. The domain has “DUF4683” region, which is significantly similar to human neurite extension and migration factor (NEXMIF). This region was also found in REV3 of invertebrates such as Ciona intestinalis (sea squirt) … and Lingula anatina (Brachiopoda). We hypothesize foreign sequences were introduced into the Rev3 genes in the ancestral species of L. anatina, which would have gradually evolved into the DUF4683 region through overly complicated processes. Besides DUF4683, various exogenous sequences would have been inserted during the REV3 evolution. Therefore, insertion events of foreign sequences are all products of “necessity”. tBLASTn analysis of the Callorhinchus milii (elephant shark) genome with the C. milii REV3 sequence identified three neural factors (NEXMIF, NEXMIF-like and AHDC1) in distinct positions of the genome. These factors may have differentiated from the Rev3 gene in Chondrichthyes, which had experienced two rounds of whole-genome duplication, and may have evolved into neurite-forming proteins in vertebrates. L. anatina has the DUF4683 C-terminal proximal consensus (SPPRA/CWSP) in REV3. However, the consensus was not necessarily maintained in Mollusca, the closely related animal phylum of L. anatina. Just as written by Jacques Monod, we assume “chance” (mutation in DNA) and “necessity” (selection at the “organism” population level) were frequently repeated on the Rev3 in Cambrian ancestors. As a result, certain species developed the DUF4683 consensus of a neurite extension activity.\u0000 </div>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HIF1α Plays a Crucial Role in the Development of TFE3–Rearranged Renal Cell Carcinoma by Orchestrating a Metabolic Shift Toward Fatty Acid Synthesis

IF 1.3 4区生物学

Genes to Cells Pub Date : 2025-01-14 DOI: 10.1111/gtc.13195

Hidekazu Nishizawa, Shintaro Funasaki, Wenjuan Ma, Yoshiaki Kubota, Kazuhide Watanabe, Yuichiro Arima, Shoichiro Kuroda, Takaaki Ito, Mitsuko Furuya, Takanobu Motoshima, Akira Nishiyama, Sally Mehanna, Yorifumi Satou, Hisashi Hasumi, Ryosuke Jikuya, Kazuhide Makiyama, Tomohiko Tamura, Yuichi Oike, Yasuhito Tanaka, Toshio Suda, Laura S. Schmidt, W. Marston Linehan, Masaya Baba, Tomomi Kamba

{"title":"HIF1α Plays a Crucial Role in the Development of TFE3–Rearranged Renal Cell Carcinoma by Orchestrating a Metabolic Shift Toward Fatty Acid Synthesis","authors":"Hidekazu Nishizawa, Shintaro Funasaki, Wenjuan Ma, Yoshiaki Kubota, Kazuhide Watanabe, Yuichiro Arima, Shoichiro Kuroda, Takaaki Ito, Mitsuko Furuya, Takanobu Motoshima, Akira Nishiyama, Sally Mehanna, Yorifumi Satou, Hisashi Hasumi, Ryosuke Jikuya, Kazuhide Makiyama, Tomohiko Tamura, Yuichi Oike, Yasuhito Tanaka, Toshio Suda, Laura S. Schmidt, W. Marston Linehan, Masaya Baba, Tomomi Kamba","doi":"10.1111/gtc.13195","DOIUrl":"10.1111/gtc.13195","url":null,"abstract":"Tumor development often requires cellular adaptation to a unique, high metabolic state; however, the molecular mechanisms that drive such metabolic changes in TFE3–rearranged renal cell carcinoma (TFE3-RCC) remain poorly understood. TFE3-RCC, a rare subtype of RCC, is defined by the formation of chimeric proteins involving the transcription factor TFE3. In this study, we analyzed cell lines and genetically engineered mice, demonstrating that the expression of the chimeric protein PRCC-TFE3 induced a hypoxia-related signature by transcriptionally upregulating HIF1α and HIF2α. The upregulation of HIF1α by PRCC-TFE3 led to increased cellular ATP production by enhancing glycolysis, which also supplied substrates for the TCA cycle while maintaining mitochondrial oxidative phosphorylation. We crossed TFE3-RCC mouse models with Hif1α and/or Hif2α knockout mice and found that Hif1α, rather than Hif2α, is essential for tumor development in vivo. RNA-seq and metabolomic analyses of the kidney tissues from these mice revealed that ketone body production is inversely correlated with tumor development, whereas de novo lipid synthesis is upregulated through the HIF1α/SREBP1-dependent mechanism in TFE3-RCC. Our data suggest that the coordinated metabolic shift via the PRCC-TFE3/HIF1α/SREBP1 axis is a key mechanism by which PRCC-TFE3 enhances cancer cell metabolism, promoting tumor development in TFE3-RCC.","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"30 1","pages":""},"PeriodicalIF":1.3,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0