{"title":"ATP2B4 is an essential gene for epidermal growth factor-induced macropinocytosis in A431 cells","authors":"Shunsuke Yoshie, Masashi Kuriyama, Masashi Maekawa, Wei Xu, Takuro Niidome, Shiroh Futaki, Hisaaki Hirose","doi":"10.1111/gtc.13118","DOIUrl":"10.1111/gtc.13118","url":null,"abstract":"<p>Macropinocytosis (MPC) is a large-scale endocytosis pathway that involves actin-dependent membrane ruffle formation and subsequent ruffle closure to generate macropinosomes for the uptake of fluid-phase cargos. MPC is categorized into two types: constitutive and stimuli-induced. Constitutive MPC in macrophages relies on extracellular Ca<sup>2+</sup> sensing by a calcium-sensing receptor. However, the link between stimuli-induced MPC and Ca<sup>2+</sup> remains unclear. Here, we find that both intracellular and extracellular Ca<sup>2+</sup> are required for epidermal growth factor (EGF)-induced MPC in A431 human epidermoid carcinoma cells. Through investigation of mammalian homologs of coelomocyte uptake defective (CUP) genes, we identify <i>ATP2B4</i>, encoding for a Ca<sup>2+</sup> pump called the plasma membrane calcium ATPase 4 (PMCA4), as a Ca<sup>2+</sup>-related regulator of EGF-induced MPC. Knockout (KO) of <i>ATP2B4</i>, as well as depletion of extracellular/intracellular Ca<sup>2+</sup>, inhibited ruffle closure and macropinosome formation, without affecting ruffle formation. We demonstrate the importance of PMCA4 activity itself, independent of interactions with other proteins via its C-terminus known as a PDZ domain-binding motif. Additionally, we show that <i>ATP2B4</i>-KO reduces EGF-stimulated Ca<sup>2+</sup> oscillation during MPC. Our findings suggest that EGF-induced MPC requires <i>ATP2B4</i>-dependent Ca<sup>2+</sup> dynamics.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 6","pages":"512-520"},"PeriodicalIF":2.1,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140592620","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}
Genes to CellsPub Date : 2024-03-29DOI: 10.1111/gtc.13114
Rieko Ohki, Koji Itahana, Tomoo Iwakuma
{"title":"“The 10th International MDM2 Workshop”: Opening up new avenues for MDM2 and p53 research, the First International MDM2 Workshop in Asia","authors":"Rieko Ohki, Koji Itahana, Tomoo Iwakuma","doi":"10.1111/gtc.13114","DOIUrl":"10.1111/gtc.13114","url":null,"abstract":"<p>The 10th International MDM2 Workshop was held at the National Cancer Center Research Institute (NCCRI) in Tokyo, Japan, from October 15 to 18, 2023. It attracted 166 participants from 12 countries. The meeting featured 52 talks and 41 poster presentations. In the first special session, six invited speakers gave educational and outstanding talks on breakthroughs in MDM2 research. Three keynote speakers presented emerging p53-independent functions of MDM2/MDM4, functional association of MDM2/p53 with cancer immunity, and drug discovery targeting the MDM2/MDM4-p53 pathway. Additionally, 19 invited speakers introduced their new findings. Twenty-one presenters, many of whom were young investigators, postdocs, and students, were selected from submitted abstracts and reported their exciting and unpublished results. For poster presenters, outstanding poster awards were given to the best presenters. There were many inspiring questions and discussions throughout the meeting. Social events like a welcome party, a workshop dinner, and an optional tour enabled further scientific interactions among the participants. The meeting successfully provided an exciting platform for scientific exchange. The experience gained from organizing this meeting will be handed over to the next organizers of the 11th International MDM2 Workshop.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 6","pages":"451-455"},"PeriodicalIF":2.1,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326532","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":"Role of Wnt5b-Ror1 signaling in the proliferation of pancreatic ductal adenocarcinoma cells","authors":"Natsuko Yamauchi, Mako Otsuka, Tomohiro Ishikawa, Yoshihiro Kakeji, Akira Kikuchi, Atsuhiro Masuda, Yuzo Kodama, Yasuhiro Minami, Koki Kamizaki","doi":"10.1111/gtc.13115","DOIUrl":"10.1111/gtc.13115","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory cancers with the worst prognosis. Although several molecules are known to be associated with the progression of PDAC, the molecular mechanisms underlying the progression of PDAC remain largely elusive. The Ror-family receptors, Ror1 and Ror2, which act as a receptor(s) for Wnt-family ligands, particularly Wnt5a, are involved in the progression of various types of cancers. Here, we show that higher expression of <i>Ror1</i> and <i>Wnt5b</i>, but not <i>Ror2</i>, are associated with poorer prognosis of PDAC patients, and that Ror1 and Wnt5b are expressed highly in a type of PDAC cell lines, PANC-1 cells. Knockdown of either <i>Ror1</i> or <i>Wnt5b</i> in PANC-1 cells inhibited their proliferation significantly in vitro, and knockout of <i>Ror1</i> in PANC-1 cells resulted in a significant inhibition of tumor growth in vivo. Furthermore, we show that Wnt5b-Ror1 signaling in PANC-1 cells promotes their proliferation in a cell-autonomous manner by modulating our experimental setting in vitro. Collectively, these findings indicate that Wnt5b-Ror1 signaling might play an important role in the progression of some if not all of PDAC by promoting proliferation.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 6","pages":"503-511"},"PeriodicalIF":2.1,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293350","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":"Changes in brain proteasome dynamics associated with aging","authors":"Nodoka Nago, Shigeo Murata, Keiji Tanaka, Nobuyuki Tanahashi","doi":"10.1111/gtc.13113","DOIUrl":"10.1111/gtc.13113","url":null,"abstract":"<p>In the nervous system, proteasomes are important for proteolysis and cellular homeostasis of neurons and glial cells and for brain health. Proteasome function declines with age in many tissues, including the nervous system, and this decline affects many of the nervous system processes important to brain health and may be related to age-related cognitive decline. Therefore, we analyzed the factors that contribute to this decline in function using the brain of mice from different months of life. Peptidase activity of proteasomes in crude extracts decreased with aging, while ubiquitinated proteins increased with aging. Additionally, there was a tendency for the number of subunits that form proteasomes to decrease slightly with age. On the other hand, ump1, which is required for proteasome formation, accumulated with age. Therefore, analysis of proteasome dynamics in each month revealed that proteasome formation decreased with aging. This study suggests that with aging, not only 20S proteasome function but also 26 proteasome function decreases, the decline in proteasome function is due to the lack of proteasome formation, the PA28-20S-PA700 complex, which is involved in immunity, increases in the brain, and one factor in this lack of proteasome formation is that the proteins called UMP1.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 5","pages":"438-445"},"PeriodicalIF":2.1,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140287363","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":"Long-term sorbitol consumption affects the hippocampus and alters cognitive function in aged mice","authors":"Haruna Yokoi, Jingshu Wang, Yoriko Ikuyo, Mitsuyoshi Yamada, Yosuke Shikama, Masae Furukawa, Kenji Matsushita","doi":"10.1111/gtc.13112","DOIUrl":"10.1111/gtc.13112","url":null,"abstract":"<p>The systemic effects of the artificial sweetener sorbitol on older adult individuals have not been elucidated. We assessed the effects of sorbitol consumption on cognitive and gingival health in a mouse model. Aged mice were fed 5% sorbitol for 3 months before their behavior was assessed, and brain and gingival tissues were collected. Long-term sorbitol consumption inhibited gingival tissue aging in aged mice. However, it caused cognitive decline and decreased brain-derived neurotrophic factor (BDNF) in the hippocampus. Sorbitol consumption did not affect homeostatic function; however, it may exert effects within the brain, particularly in the hippocampus.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 5","pages":"432-437"},"PeriodicalIF":2.1,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101438","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":"Staphylococcal superantigen-like protein 3 triggers murine mast cell adhesion by binding to CD43 and augments mast cell activation","authors":"Sae Kawano, Chisaki Noda, Saotomo Itoh, Ayaka Urabe, Chifumi Fujii, Isamu Ogawa, Ryo Suzuki, Shigeaki Hida","doi":"10.1111/gtc.13111","DOIUrl":"10.1111/gtc.13111","url":null,"abstract":"<p><i>Staphylococcus aureus</i> is a noteworthy pathogen in allergic diseases, as four staphylococcal exotoxins activate mast cells, a significant contributor to inflammation, in an IgE-independent manner. Although the adhesion of mast cells is an essential process for their immune responses, only a small number of exotoxins have been reported to affect the process. Here, we demonstrated that staphylococcal superantigen-like (SSL) 3, previously identified as a toll-like receptor 2 agonist, induced the adhesion of murine bone marrow-derived mast cells to culture substratum. SSL3-induced adhesion was mediated by fibronectin in an Arg-Gly-Asp (RGD) sequence-dependent manner, suggesting the integrins were involved in the process. Additionally, SSL3 was found to bind to an anti-adhesive surface protein CD43. SSL3 induced the adhesion of HEK293 cells expressing exogenous CD43, suggesting that CD43 is the target molecule for adhesion induced by SSL3. Evaluation of SSL3-derived mutants showed that the C-terminal region (253–326), specifically T285 and H307, are necessary to induce adhesion. SSL3 augmented the IL-13 production of mast cells in response to immunocomplex and SSL12. These findings reveal a novel function of SSL3, triggering cell adhesion and enhancing mast cell activation. This study would clarify the correlation between <i>S. aureus</i> and allergic diseases such as atopic dermatitis.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 5","pages":"397-416"},"PeriodicalIF":2.1,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059127","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":"Left–right Myosin-Is, Myosin1C, and Myosin1D exhibit distinct single molecule behaviors on the plasma membrane of Drosophila macrophages","authors":"Sosuke Utsunomiya, Kazutoshi Takebayashi, Asuka Yamaguchi, Takeshi Sasamura, Mikiko Inaki, Masahiro Ueda, Kenji Matsuno","doi":"10.1111/gtc.13110","DOIUrl":"10.1111/gtc.13110","url":null,"abstract":"<p>Left–right (LR) asymmetry is crucial for animal development, particularly in <i>Drosophila</i> where LR-asymmetric morphogenesis of organs hinges on cellular-level chirality, termed cell chirality. In this species, two class I myosins, Myosin1D (Myo1D), and Myosin1C (Myo1C), respectively determine dextral (wild type) and sinistral (mirror image) cell chirality. Previous studies demonstrated Myo1D's ability to propel F-actin in leftward circles during in vitro gliding assays, suggesting its mechanochemical role in defining dextral chirality. Conversely, Myo1C propels F-actin without exhibiting LR-directional preference in this assay, suggesting at other properties governing sinistral chirality. Given the interaction of Myo1D and Myo1C with the membrane, we hypothesized that differences in their membrane behaviors might be critical in dictating their dextral or sinistral activities. In this study, employing single-molecule imaging analyses, we investigated the dynamic behaviors of Myo1D and Myo1C on the plasma membrane. Our findings revealed that Myo1C exhibits a significantly greater proportion of slow-diffusing population compared to Myo1D. Importantly, this characteristic was contingent upon both head and tail domains of Myo1C. The distinct diffusion patterns of Myo1D and Myo1C did not exert mutual influence on each other. This divergence in membrane diffusion between Myo1D and Myo1C may be crucial for dictating cell and organ chirality.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 5","pages":"380-396"},"PeriodicalIF":2.1,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059126","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":"Mode of SUV420H2 heterochromatin localization through multiple HP1 binding motifs in the heterochromatic targeting module","authors":"Masaru Nakao, Yuko Sato, Arisa Aizawa, Hiroshi Kimura","doi":"10.1111/gtc.13109","DOIUrl":"10.1111/gtc.13109","url":null,"abstract":"<p>Constitutive heterochromatin is transcriptionally repressed and densely packed chromatin, typically harboring histone H3 Lys9 trimethylation (H3K9me3) and heterochromatin protein 1 (HP1). SUV420H2, a histone H4 Lys20 methyltransferase, is recruited to heterochromatin by binding to HP1 through its Heterochromatic Targeting Module (HTM). Here, we have identified three HP1 binding motifs within the HTM. Both the full-length HTM and its N-terminal region (HTM-N), which contains the first and second motifs, stabilized HP1 on heterochromatin. The intervening region between the first and second HP1 binding motifs in HTM-N was also crucial for HP1 binding. In contrast, the C-terminal region of HTM (HTM-C), containing the third motif, destabilized HP1 on chromatin. An HTM V374D mutant, featuring a Val374 to Asp substitution in the second HP1 binding motif, localizes to heterochromatin without affecting HP1 stability. These data suggest that the second HP1 binding motif in the SUV420H2 HTM is critical for locking HP1 on H3K9me3-enriched heterochromatin. HTM V374D, tagged with a fluorescent protein, can serve as a live-cell probe to visualize HP1-bound heterochromatin.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 5","pages":"361-379"},"PeriodicalIF":2.1,"publicationDate":"2024-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139968905","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}
Genes to CellsPub Date : 2024-02-22DOI: 10.1111/gtc.13106
Shota Torigoe, Douglas W. Lowman, Toshihiko Sugiki, David L. Williams, Sho Yamasaki
{"title":"Self-recognition through Dectin-1 exacerbates liver inflammation","authors":"Shota Torigoe, Douglas W. Lowman, Toshihiko Sugiki, David L. Williams, Sho Yamasaki","doi":"10.1111/gtc.13106","DOIUrl":"10.1111/gtc.13106","url":null,"abstract":"<p>Dectin-1 is a well-characterized C-type lectin receptor involved in anti-fungal immunity through the recognition of polysaccharides; however, molecular mechanisms and outcomes initiated through self-recognition have not been fully understood. Here, we purified a water-soluble fraction from mouse liver that acts as a Dectin-1 agonist. To address the physiological relevance of this recognition, we utilized sterile liver inflammation models. The CCl<sub>4</sub>-induced hepatitis model showed that Dectin-1 deficiency led to reduced inflammation through decreased inflammatory cell infiltration and lower pro-inflammatory cytokine levels. Moreover, in a NASH model induced by streptozotocin and a high-fat diet, hepatic inflammation and fibrosis were ameliorated in Dectin-1-deficient mice. The Dectin-1 agonist activity was increased in the water-soluble fraction from NASH mice, suggesting a potential pathogenic cycle between Dectin-1 activation and hepatitis progression. In vivo administration of the fraction into mice induced hepatic inflammation. These results highlight a role of self-recognition through Dectin-1 that triggers hepatic innate immune responses and contributes to the exacerbation of inflammation in pathogenic settings. Thus, the blockade of this axis may provide a therapeutic option for liver inflammatory diseases.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 4","pages":"316-327"},"PeriodicalIF":2.1,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139930817","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":"Premature gray hair development in the interbrow region owing to the loss of maxillary first molars in young mice","authors":"Masae Furukawa, Haruna Yokoi, Jingshu Wang, Yoriko Ikuyo, Hirobumi Tada, Mitsuyoshi Yamada, Yosuke Shikama, Kenji Matsushita","doi":"10.1111/gtc.13107","DOIUrl":"10.1111/gtc.13107","url":null,"abstract":"<p>The exact sites of premature hair graying and whether tooth loss causes this condition remain unknown. In this study, we aimed to explore the effect of reduced mastication on premature hair graying. Maxillary first molars were extracted from young mice, and the mice were observed for 3 months, along with non-extraction control group mice. After 3 months, gray hair emerged in the interbrow region of mice in the tooth extraction group but not in the control group. The expression of <i>tyrosinase-related protein-2</i> (<i>TRP-2</i>) mRNA was lower in the interbrow tissues of young mice without maxillary molars than in those with maxillary molars. Tooth loss leads to interbrow gray hair growth, possibly because of weakened trigeminal nerve input, suggesting that reduced mastication causes premature graying. Thus, prompt prosthetic treatment after molar loss is highly recommended.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 5","pages":"417-422"},"PeriodicalIF":2.1,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912421","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}