{"title":"Cellular senescence in the cancer microenvironment.","authors":"Satoru Meguro, Makoto Nakanishi","doi":"10.1093/jb/mvaf001","DOIUrl":"10.1093/jb/mvaf001","url":null,"abstract":"<p><p>In this ageing society, the number of patients suffering from age-related diseases, including cancer, is increasing. Cellular senescence is a cell fate that involves permanent cell cycle arrest. Accumulated senescent cells in tissues over time present senescence-associated secretory phenotype (SASP) and make the inflammatory context, disturbing the tumour microenvironment. In particular, the effect of senescent cancer-associated fibroblasts on cancer progression has recently come under the spotlight. Although scientific evidence on the impact of cellular senescence on cancer is emerging, the association between cellular senescence and cancer is heterogeneous and the comprehensive mechanism is still not revealed. Recently, a therapy targeting senescent cells, senotherapeutics, has been reported to be effective against cancer in preclinical research and even clinical trials. With further research, the development of senotherapeutics as a novel cancer therapy is expected.</p>","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":"171-176"},"PeriodicalIF":2.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931762","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}
{"title":"Cellular senescence: mechanisms and relevance to cancer and aging.","authors":"Shota Yamauchi, Akiko Takahashi","doi":"10.1093/jb/mvae079","DOIUrl":"10.1093/jb/mvae079","url":null,"abstract":"<p><p>Cellular senescence is an irreversible cell cycle arrest induced by stresses such as telomere shortening and oncogene activation. It acts as a tumor suppressor mechanism that prevents the proliferation of potentially tumorigenic cells. Paradoxically, senescent stromal cells that arise in the tumor microenvironment have been shown to promote tumor progression. In addition, senescent cells that accumulate in vivo over time are thought to contribute to aging and age-related diseases. These deleterious effects of senescent cells involve the secretion of bioactive molecules such as inflammatory cytokines and chemokines, a phenomenon known as the senescence-associated secretory phenotype. While the role of cellular senescence in vivo is becoming increasingly clear, the intracellular signaling pathways that induce the expression of senescent phenotypes are not fully understood. In this review, we outline senescence-associated signaling pathways and their relevance to cancer and aging.</p>","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":"163-169"},"PeriodicalIF":2.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11879292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648319","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}
{"title":"Commentary on: γ-enolase (ENO2) is methylated at the Nτ position of His-190 among enolase isozymes.","authors":"Mitsuharu Hattori","doi":"10.1093/jb/mvae088","DOIUrl":"10.1093/jb/mvae088","url":null,"abstract":"","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":"197-198"},"PeriodicalIF":2.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828710","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}
{"title":"Identification and characterization of a novel hemolytic and hemagglutinating bifunctional lectin from the coral Acropora millepora.","authors":"Yuki Takahashi, Ryosuke Kamimura, Ryo Toyama, Shun Kita, Yuki Ushijima, Shigeto Taniyama, Hideaki Unno, Tomomitsu Hatakeyama, Shuichiro Goda","doi":"10.1093/jb/mvaf010","DOIUrl":"https://doi.org/10.1093/jb/mvaf010","url":null,"abstract":"<p><p>Two genes, AML-I and AML-II, have been reported to exhibit increased expression during the development of the coral Acropora millepora. They show amino acid sequence homology with CEL-III, a hemolytic lectin found in the sea cucumber Cucumaria echinata. CEL-III binds to carbohydrate chains on the surface of erythrocytes, forming heptameric pores in their membranes. To clarify the role of these proteins in coral, we identified and elucidated their functions. The carbohydrate binding domains of them showed similar carbohydrate-binding specificity as that of CEL-III. AML-I showed hemagglutinating activity in erythrocytes, whereas AML-II can only be prepared as an aggregate and its function could not yet be determined. AML-IΔC and AML-IIΔC mutants were generated through deletion of the C-terminal extended amino acid residues of them relative to CEL-III. AML-IΔC showed hemolytic activity toward erythrocytes, whereas AML-IIΔC showed no activity. A tobacco etch virus (TEV) protease recognition site was inserted into the C-terminus of AML-I to regulate these activities. The hemagglutinating activity of AML-I was converted into hemolytic activity after TEV protease treatment. As a result, TEV protease could control the hemolytic and hemagglutinating activity of the lectin, which could be useful as an anticancer or antiviral drug because of its cytotoxic activity.</p>","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449134","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}
{"title":"Photocontrol of the small GTPase Ras using its regulatory factor, GTPase-activating protein, modified with photochromic nanodevices.","authors":"Rajib Ahmed, Nobuyuki Nishibe, Ziyun Zhang, Shinsaku Maruta","doi":"10.1093/jb/mvaf009","DOIUrl":"https://doi.org/10.1093/jb/mvaf009","url":null,"abstract":"<p><p>Ras, a small GTPase, is central to the regulation of diverse cellular processes including transcription, cell cycle progression, growth, migration, cytoskeletal reorganization, apoptosis, cell survival, and senescence. Ras activation is mediated by GTP binding, whereas its inactivation occurs via GDP binding, which is tightly controlled by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). GAPs accelerate GTP hydrolysis, playing a crucial role in modulating Ras signaling to prevent excessive or prolonged activation. Here, we investigated monofunctional azobenzene derivatives as photochromic modulators to control the function of Ras in a light-dependent and reversible manner. Three thiol-reactive azobenzene derivatives with distinct electrostatic properties were synthesized and incorporated into GAP functional sites to modulate Ras activity. GAP mutants containing a single cysteine residue at the functional site were generated using an Escherichia coli expression system. Our results showed that modifications near the GAP \"arginine finger,\" a critical region for stabilizing the GTP hydrolysis transition state of Ras, induced significant light-dependent changes in GTPase activity. We achieved photoreversible control of the interaction between Ras and its effector Raf using these azobenzene derivatives. These findings suggest that Ras function can be precisely modulated using photochromic molecules, providing a novel light-based approach for controlling Ras activity.</p>","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390886","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}
{"title":"Mitochondria-targeting siRNA screening identifies mitochondrial calcium uniporter as a factor involved in nucleoid morphology.","authors":"Hirotaka Kanon, Takaya Ishihara, Reiko Ban-Ishihara, Azusa Ota, Tatsuki Yasuda, Aoi Ichikawa, Ruo Ueyama, Taiki Baba, Kohsuke Takeda, Emi Ogasawara, Naotada Ishihara","doi":"10.1093/jb/mvaf008","DOIUrl":"https://doi.org/10.1093/jb/mvaf008","url":null,"abstract":"<p><p>Mitochondria are believed to have originated from the endosymbiosis of bacteria and they still contain their own genome, which is called mitochondrial DNA (mtDNA). Under fluorescence microscopy of cultured mammalian cells, mtDNA is observed as numerous tiny dot-like structures called mitochondrial nucleoids. In live-imaging, the morphology and distribution of nucleoids are change dynamically, but the molecular details remain poorly understood. In this study, we constructed a custom siRNA library targeting 1,164 human mitochondria-related genes, and from live-imaging-based screening of HeLa cells, we identified that mitochondria calcium uniporter (MCU), a pore-forming subunit of the mitochondrial Ca2+ channel, is involved in nucleoid morphology. We found that suppression of MCU by RNAi induced the formation of highly enlarged nucleoids as well as respiratory dysfunction and that the re-introduction of MCU or treatment with Ca2+ ionophore recovered the enlarged nucleoid morphology. These results suggest that mitochondrial Ca2+ uptake via MCU is associated with nucleoid morphology. The constructed siRNA library might be widely applied to analyze the roles of mitochondrial proteins in various cellular events, making it useful to understand the multifaceted functions of mitochondria in human cells.</p>","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382595","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}
Peter W T Lee, Minoru Kobayashi, Takakuni Dohkai, Itsuki Takahashi, Takumi Yoshida, Hiroshi Harada
{"title":"2-Oxoglutarate-dependent dioxygenases as oxygen sensors: their importance in health and disease.","authors":"Peter W T Lee, Minoru Kobayashi, Takakuni Dohkai, Itsuki Takahashi, Takumi Yoshida, Hiroshi Harada","doi":"10.1093/jb/mvae087","DOIUrl":"10.1093/jb/mvae087","url":null,"abstract":"<p><p>Since low oxygen conditions below physiological levels, hypoxia, are associated with various diseases, it is crucial to understand the molecular basis behind cellular response to hypoxia. Hypoxia-inducible factors (HIFs) have been revealed to primarily orchestrate the hypoxic response at the transcription level and have continuously attracted great attention over the past three decades. In addition to these hypoxia-responsive effector proteins, 2-oxoglutarate-dependent dioxygenase (2-OGDD) superfamily including prolyl-4-hydroxylase domain-containing proteins (PHDs) and factor inhibiting HIF-1 (FIH-1) has attracted even greater attention in recent years as factors that act as direct oxygen sensors due to their necessity of oxygen for the regulation of the expression and activity of the regulatory subunit of HIFs. Herein, we present a detailed classification of 2-OGDD superfamily proteins, such as Jumonji C-domain-containing histone demethylases, ten-eleven translocation enzymes, AlkB family of DNA/RNA demethylases and lysyl hydroxylases, and discuss their specific functions and associations with various diseases. By introducing the multifaceted roles of 2-OGDD superfamily proteins in the hypoxic response, this review aims to summarize the accumulated knowledge about the complex mechanisms governing cellular adaptation to hypoxia in various physiological and pathophysiological contexts.</p>","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":"79-104"},"PeriodicalIF":2.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828707","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}
{"title":"Characterization of UGT8 as a monogalactosyl diacylglycerol synthase in mammals.","authors":"Yohsuke Ohba, Mizuki Motohashi, Makoto Arita","doi":"10.1093/jb/mvae084","DOIUrl":"10.1093/jb/mvae084","url":null,"abstract":"<p><p>Monogalactosyl diacylglycerol (MGDG) is a major membrane lipid component in plants and is crucial for proper thylakoid functioning. However, MGDG in mammals has not received much attention, partly because of its relative scarcity in mammalian tissues. In addition, the biosynthetic pathway of MGDG in mammals has not been thoroughly analysed, although some reports have suggested that UGT8, a ceramide galactosyltransferase, has the potential to catalyse MGDG biosynthesis. Here, we successfully captured the endogenous levels of MGDG in HeLa cells using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS)-based lipidomics. Cellular MGDG was completely depleted in CRISPR/Cas9-mediated UGT8 knockout (KO) HeLa cells. Transient overexpression of UGT8 enhanced MGDG production in HeLa cells, and the corresponding cell lysates displayed MGDG biosynthetic activity in vitro. Site-directed mutagenesis revealed that His358 within the UGT signature sequence was important for its activity. UGT8 was localized in the endoplasmic reticulum and activation of the unfolded protein response by membrane lipid saturation was impaired in UGT8 KO cells. These results demonstrate that UGT8 is an MGDG synthase in mammals and that UGT8 regulates membrane lipid saturation signals in cells.</p>","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":"141-152"},"PeriodicalIF":2.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11795506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806835","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}
{"title":"Commentary for: a lipid scramblase TMEM41B is involved in the processing and transport of GPI-anchored proteins.","authors":"Hiroto Hirayama","doi":"10.1093/jb/mvae085","DOIUrl":"10.1093/jb/mvae085","url":null,"abstract":"<p><p>Glycosylphosphatidylinositol (GPI) anchoring is a conserved post-translational modification in eukaryotes. This modification allows acceptor proteins to be expressed at the cell surface as GPI-anchored proteins (GPI-APs), which play critical roles in various biological processes. It has been proposed that remodelling of GPI after transferring acceptor proteins, including the PGAP1-dependent deacylation of GPI-inositol, functions as a checkpoint for transporting mature GPI-APs from the endoplasmic reticulum (ER) to the Golgi. A previous study identified several factors involved in regulating PGAP1-dependent GPI-inositol deacylation, including proteins associated with the calnexin cycles, SELT and CLPTM1. A recent report by Cao et al., revealed that the loss of TMEM41B, an ER-resident lipid scramblase, rescues the defect in GPI-inositol deacylation in SELT-KO cells. Further investigation demonstrated that TMEM41B is essential for the efficient transport of both GPI-APs and transmembrane proteins from the ER to the Golgi. The study also found that PGAP1 proteins accumulate in the ER of TMEM41B-KO cells, suggesting that perturbations in the ER-membrane lipid integrity stabilize PGAP1 proteins, thereby enhancing the PGAP1 activity within the ER. These findings highlight that defects in TMEM41B impact two distinct processes: (i) the transport of GPI-APs from the ER to the Golgi, and (ii) the deacylation of GPI-APs.</p>","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":"69-71"},"PeriodicalIF":2.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807016","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}
{"title":"Species-specific differences in acetaminophen hepatotoxicity depend on HSP70 expression level.","authors":"Daisuke Tsuji, Reiko Akagi","doi":"10.1093/jb/mvae086","DOIUrl":"10.1093/jb/mvae086","url":null,"abstract":"<p><p>Acetaminophen (N-Acetyl-p-aminophenol: APAP) is one of the most commonly used analgesic/antipyretic drugs with proven safety at therapeutic doses, however, over-dosage causes dose-dependent liver damage, leading to acute liver failure in severe cases. The level of APAP-induced liver injury has been known to vary amongst animal species, and APAP concentrations that induce cell death have been investigated using primary cultured cells. We constructed in vitro model of APAP-induced hepatotoxicity using mouse, rat and human hepatoma cell lines to investigate species differences in the APAP-induced cytotoxicity by monitoring cell death as a marker. The EC50 for each cell line was Hepa1-6 (mouse) < H-4-II-E (rat) < Hep3B (human), whilst the expression of heat shock protein 70 (HSP70), which was a typical molecular chaperone, positively correlated with the EC50 of each cell. Heat shock treatment, which caused activation of heat shock factor 1 (HSF1) followed by significant induction of HSP70, partially suppressed APAP-induced cell death in Hepa1-6 and H-4-II-E. Moreover, HSP70 or HSF1 siRNA treatment in Hep3B enhanced APAP-induced cell death. These results suggest that APAP-induced cell death in hepatoma cell lines may be partly mediated by protein denaturation and that the expression level of HSP70 has an inhibitory effect.</p>","PeriodicalId":15234,"journal":{"name":"Journal of biochemistry","volume":" ","pages":"133-139"},"PeriodicalIF":2.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828734","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}