Cell structure and function最新文献

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Zebrafish imaging reveals hidden oncogenic-normal cell communication during primary tumorigenesis. 斑马鱼成像揭示了原发性肿瘤发生过程中隐藏的致癌细胞与正常细胞之间的交流。
IF 1.5 4区 生物学
Cell structure and function Pub Date : 2023-06-16 Epub Date: 2023-05-11 DOI: 10.1247/csf.23026
Yukinari Haraoka, Mai Miyake, Tohru Ishitani
{"title":"Zebrafish imaging reveals hidden oncogenic-normal cell communication during primary tumorigenesis.","authors":"Yukinari Haraoka, Mai Miyake, Tohru Ishitani","doi":"10.1247/csf.23026","DOIUrl":"10.1247/csf.23026","url":null,"abstract":"<p><p>Oncogenic mutations drive tumorigenesis, and single cells with oncogenic mutations act as the tumor seeds that gradually evolve into fully transformed tumors. However, oncogenic cell behavior and communication with neighboring cells during primary tumorigenesis remain poorly understood. We used the zebrafish, a small vertebrate model suitable for in vivo cell biology, to address these issues. We describe the cooperative and competitive communication between oncogenic cells and neighboring cells, as revealed by our recent zebrafish imaging studies. Newly generated oncogenic cells are actively eliminated by neighboring cells in healthy epithelia, whereas oncogenic cells cooperate with their neighbors to prime tumorigenesis in unhealthy epithelia via additional mutations or inflammation. In addition, we discuss the potential of zebrafish in vivo imaging to determine the initial steps of human tumorigenesis.Key words: zebrafish, imaging, cell-cell communication, cell competition, EDAC, senescence, primary tumorigenesis.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10721949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9663700","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
Cell biology of protein-lipid conjugation. 蛋白质与脂质结合的细胞生物学。
IF 1.5 4区 生物学
Cell structure and function Pub Date : 2023-05-11 Epub Date: 2023-04-06 DOI: 10.1247/csf.23016
Jun-Ichi Sakamaki, Noboru Mizushima
{"title":"Cell biology of protein-lipid conjugation.","authors":"Jun-Ichi Sakamaki, Noboru Mizushima","doi":"10.1247/csf.23016","DOIUrl":"10.1247/csf.23016","url":null,"abstract":"<p><p>Protein-lipid conjugation is a widespread modification involved in many biological processes. Various lipids, including fatty acids, isoprenoids, sterols, glycosylphosphatidylinositol, sphingolipids, and phospholipids, are covalently linked with proteins. These modifications direct proteins to intracellular membranes through the hydrophobic nature of lipids. Some of these membrane-binding processes are reversible through delipidation or by reducing the affinity to membranes. Many signaling molecules undergo lipid modification, and their membrane binding is important for proper signal transduction. The conjugation of proteins to lipids also influences the dynamics and function of organellar membranes. Dysregulation of lipidation has been associated with diseases such as neurodegenerative diseases. In this review, we first provide an overview of diverse forms of protein-lipid conjugation and then summarize the catalytic mechanisms, regulation, and roles of these modifications.Key words: lipid, lipidation, membrane, organelle, protein modification.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10721952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9446792","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: 1
A conserved WXXE motif is an apical delivery determinant of ABC transporter C subfamily isoforms. 保守的 WXXE 基序是 ABC 转运体 C 亚家族同种异构体的顶端输送决定因素。
IF 1.5 4区 生物学
Cell structure and function Pub Date : 2023-03-09 Epub Date: 2023-01-25 DOI: 10.1247/csf.22049
Md Shajedul Haque, Yoshikazu Emi, Masao Sakaguchi
{"title":"A conserved WXXE motif is an apical delivery determinant of ABC transporter C subfamily isoforms.","authors":"Md Shajedul Haque, Yoshikazu Emi, Masao Sakaguchi","doi":"10.1247/csf.22049","DOIUrl":"10.1247/csf.22049","url":null,"abstract":"<p><p>ATP-binding cassette transporter isoform C7 (ABCC7), also designated as cystic fibrosis transmembrane conductance regulator (CFTR), is exclusively targeted to the apical plasma membrane of polarized epithelial cells. Although the apical localization of ABCC7 in epithelia is crucial for the Cl<sup>-</sup> excretion into lumens, the mechanism regulating its apical localization is poorly understood. In the present study, an apical localization determinant was identified in the N-terminal 80-amino acid long cytoplasmic region of ABCC7 (NT80). In HepG2 cells, overexpression of NT80 significantly disturbed the apical expression of ABCC7 in a competitive manner, suggesting the presence of a sorting determinant in this region. Deletion analysis identified a potential sorting information within a 20-amino acid long peptide (aa 41-60) of NT80. Alanine scanning mutagenesis of this region in full-length ABCC7 further narrowed down the apical localization determinant to four amino acids, W<sup>57</sup>DRE<sup>60</sup>. This WDRE sequence was conserved among vertebrate ABCC7 orthologs. Site-directed mutagenesis showed that W<sup>57</sup> and E<sup>60</sup> were critical for the apical expression of ABCC7, confirming a novel apical sorting determinant of ABCC7. Furthermore, a WXXE motif (tryptophan and glutamic acid residues with two-amino acid spacing) was found to be conserved among the N-terminal regions of apically localized ABCC members with 12-TM configuration. The significance of the WXXE motif was demonstrated for proper trafficking of ABCC4 to the apical plasma membrane.Key words: apical plasma membrane, sorting, ATP-binding cassette transporter, CFTR, MRP4.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10721954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9135259","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
A non-nucleotide agonist that binds covalently to cysteine residues of STING. 一种非核苷酸激动剂,能与 STING 的半胱氨酸残基共价结合。
IF 1.5 4区 生物学
Cell structure and function Pub Date : 2023-02-16 Epub Date: 2022-12-28 DOI: 10.1247/csf.22085
Kentaro Matsumoto, Shenwei Ni, Hiroyuki Arai, Takashi Toyama, Yoshiro Saito, Takehiro Suzuki, Naoshi Dohmae, Kojiro Mukai, Tomohiko Taguchi
{"title":"A non-nucleotide agonist that binds covalently to cysteine residues of STING.","authors":"Kentaro Matsumoto, Shenwei Ni, Hiroyuki Arai, Takashi Toyama, Yoshiro Saito, Takehiro Suzuki, Naoshi Dohmae, Kojiro Mukai, Tomohiko Taguchi","doi":"10.1247/csf.22085","DOIUrl":"10.1247/csf.22085","url":null,"abstract":"<p><p>Stimulator of interferon genes (STING) is an ER-localized transmembrane protein and the receptor for 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which is a second messenger produced by cGAMP synthase (cGAS), a cytosolic double-stranded DNA sensor. The cGAS-STING pathway plays a critical role in the innate immune response to infection of a variety of DNA pathogens through the induction of the type I interferons. Pharmacological activation of STING is a promising therapeutic strategy for cancer, thus the development of potent and selective STING agonists has been pursued. Here we report that mouse STING can be activated by phenylarsine oxide (PAO), a membrane permeable trivalent arsenic compound that preferentially reacts with thiol group of cysteine residue (Cys). The activation of STING with PAO does not require cGAS or cGAMP. Mass spectrometric analysis of the peptides generated by trypsin and chymotrypsin digestion of STING identifies several PAO adducts, suggesting that PAO covalently binds to STING. Screening of STING variants with single Cys to serine residues (Ser) reveals that Cys88 and Cys291 are critical to the response to PAO. STING activation with PAO, as with cGAMP, requires the ER-to-Golgi traffic and palmitoylation of STING. Our results identify a non-nucleotide STING agonist that does not target the cGAMP-binding pocket, and demonstrate that Cys of STING can be a novel target for the development of STING agonist.Key words: STING agonist, cysteine modification, innate immunity, phenylarsine oxide.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10721953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10736938","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
Suppression of P-cadherin expression as a key regulatory element for embryonic stem cell stemness. 抑制 P-cadherin 的表达是胚胎干细胞干性的关键调控因素。
IF 1.5 4区 生物学
Cell structure and function Pub Date : 2023-02-08 Epub Date: 2022-12-28 DOI: 10.1247/csf.22060
Yuka Takeda, Shuji Matsuguchi, Sae Nozaki, Taisei Mihara, Junya Abe, Yohei Hirai
{"title":"Suppression of P-cadherin expression as a key regulatory element for embryonic stem cell stemness.","authors":"Yuka Takeda, Shuji Matsuguchi, Sae Nozaki, Taisei Mihara, Junya Abe, Yohei Hirai","doi":"10.1247/csf.22060","DOIUrl":"10.1247/csf.22060","url":null,"abstract":"<p><p>In embryonic stem (ES) cell colonies, a small subpopulation that changes cell shape and loses pluripotency often appears in two-dimensional (2D) cultures, even in the presence of a stemness factor. We have previously shown that membrane translocation of the syntaxin4, t-SNARE protein contributes to this phenomenon. Here, we show that ES cells in three-dimensional (3D) aggregates do not succumb to extruded syntaxin4 owing to suppressed expression of P-cadherin protein. While extracellular expression of syntaxin4 led to the striking upregulation of P-cadherin mRNA in both 2D and 3D-ES cells, morphological changes and appreciable expression of P-cadherin protein were detected only in 2D-ES cells. Importantly, the introduction of an expression cassette for P-cadherin practically reproduced the effects induced by extracellular syntaxin4, where the transgene product was clearly detected in 2D-, but not 3D-ES cells. An expression construct for P-cadherin-Venus harboring an in-frame insertion of the P2A sequence at the joint region gave fluorescent signals only in the cytoplasm of 2D-ES cells, demonstrating translational regulation of P-cadherin. These results provide the mechanistic insight into the uncontrollable differentiation in 2D-ES cells and shed light on the validity of the \"embryoid body protocol commonly used for ES cell handling\" for directional differentiation.Key words: differentiation, embryoid body, ES cells, P-cadherin, syntaxin4.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10721948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10680262","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: 1
Enhancement of Vivid-based photo-activatable Gal4 transcription factor in mammalian cells. 增强哺乳动物细胞中基于 Vivid 的可光激活 Gal4 转录因子。
IF 1.5 4区 生物学
Cell structure and function Pub Date : 2023-02-08 Epub Date: 2022-12-16 DOI: 10.1247/csf.22074
Shinji C Nagasaki, Tomonori D Fukuda, Mayumi Yamada, Yusuke Iii Suzuki, Ryo Kakutani, Adam T Guy, Itaru Imayoshi
{"title":"Enhancement of Vivid-based photo-activatable Gal4 transcription factor in mammalian cells.","authors":"Shinji C Nagasaki, Tomonori D Fukuda, Mayumi Yamada, Yusuke Iii Suzuki, Ryo Kakutani, Adam T Guy, Itaru Imayoshi","doi":"10.1247/csf.22074","DOIUrl":"10.1247/csf.22074","url":null,"abstract":"<p><p>The Gal4/UAS system is a versatile tool to manipulate exogenous gene expression of cells spatially and temporally in many model organisms. Many variations of light-controllable Gal4/UAS system are now available, following the development of photo-activatable (PA) molecular switches and integration of these tools. However, many PA-Gal4 transcription factors have undesired background transcription activities even in dark conditions, and this severely attenuates reliable light-controlled gene expression. Therefore, it is important to develop reliable PA-Gal4 transcription factors with robust light-induced gene expression and limited background activity. By optimization of synthetic PA-Gal4 transcription factors, we have validated configurations of Gal4 DNA biding domain, transcription activation domain and blue light-dependent dimer formation molecule Vivid (VVD), and applied types of transcription activation domains to develop a new PA-Gal4 transcription factor we have named eGAV (enhanced Gal4-VVD transcription factor). Background activity of eGAV in dark conditions was significantly lower than that of hGAVPO, a commonly used PA-Gal4 transcription factor, and maximum light-induced gene expression levels were also improved. Light-controlled gene expression was verified in cultured HEK293T cells with plasmid-transient transfections, and in mouse EpH4 cells with lentivirus vector-mediated transduction. Furthermore, light-controlled eGAV-mediated transcription was confirmed in transfected neural stem cells and progenitors in developing and adult mouse brain and chick spinal cord, and in adult mouse hepatocytes, demonstrating that eGAV can be applied to a wide range of experimental systems and model organisms.Key words: optogenetics, Gal4/UAS system, transcription, gene expression, Vivid.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10721950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9324635","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: 1
Role of phosphatidylserine in the localization of cell surface membrane proteins in yeast. 磷脂酰丝氨酸在酵母细胞表面膜蛋白定位中的作用
IF 1.5 4区 生物学
Cell structure and function Pub Date : 2023-01-28 Epub Date: 2022-12-15 DOI: 10.1247/csf.22081
Ryutaro Kashikuma, Makoto Nagano, Hiroki Shimamura, Kouya Nukaga, Ikumi Katsumata, Junko Y Toshima, Jiro Toshima
{"title":"Role of phosphatidylserine in the localization of cell surface membrane proteins in yeast.","authors":"Ryutaro Kashikuma, Makoto Nagano, Hiroki Shimamura, Kouya Nukaga, Ikumi Katsumata, Junko Y Toshima, Jiro Toshima","doi":"10.1247/csf.22081","DOIUrl":"10.1247/csf.22081","url":null,"abstract":"<p><p>Phosphatidylserine (PS) is a constituent of the cell membrane, being especially abundant in the cytoplasmic leaflet, and plays important roles in a number of cellular functions, including the formation of cell polarity and intracellular vesicle transport. Several studies in mammalian cells have suggested the role of PS in retrograde membrane traffic through endosomes, but in yeast, where PS is localized primarily at the plasma membrane (PM), the role in intracellular organelles remains unclear. Additionally, it is reported that polarized endocytic site formation is defective in PS-depleted yeast cells, but the role in the endocytic machinery has not been well understood. In this study, to clarify the role of PS in the endocytic pathway, we analyzed the effect of PS depletion on endocytic internalization and post-endocytic transport. We demonstrated that in cell lacking the PS synthase Cho1p (cho1Δ cell), binding and internalization of mating pheromone α-factor into the cell was severely impaired. Interestingly, the processes of endocytosis were mostly unaffected, but protein transport from the trans-Golgi network (TGN) to the PM was defective and localization of cell surface proteins was severely impaired in cho1Δ cells. We also showed that PS accumulated in intracellular compartments in cells lacking Rcy1p and Vps52p, both of which are implicated in endosome-to-PM transport via the TGN, and that the number of Snx4p-residing endosomes was increased in cho1Δ cells. These results suggest that PS plays a crucial role in the transport and localization of cell surface membrane proteins.Key words: phosphatidylserine, endocytosis, recycling, vesicle transport.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10725852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10655171","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: 1
Reconstitution of functional tight junctions with individual claudin subtypes in epithelial cells. 用上皮细胞中的单个 claudin 亚型重建功能性紧密连接。
IF 1.5 4区 生物学
Cell structure and function Pub Date : 2023-01-20 Epub Date: 2022-12-09 DOI: 10.1247/csf.22068
Mikio Furuse, Daiki Nakatsu, Wendy Hempstock, Shiori Sugioka, Noriko Ishizuka, Kyoko Furuse, Taichi Sugawara, Yugo Fukazawa, Hisayoshi Hayashi
{"title":"Reconstitution of functional tight junctions with individual claudin subtypes in epithelial cells.","authors":"Mikio Furuse, Daiki Nakatsu, Wendy Hempstock, Shiori Sugioka, Noriko Ishizuka, Kyoko Furuse, Taichi Sugawara, Yugo Fukazawa, Hisayoshi Hayashi","doi":"10.1247/csf.22068","DOIUrl":"10.1247/csf.22068","url":null,"abstract":"<p><p>The claudin family of membrane proteins is responsible for the backbone structure and function of tight junctions (TJs), which regulate the paracellular permeability of epithelia. It is thought that each claudin subtype has its own unique function and the combination of expressed subtypes determines the permeability property of each epithelium. However, many issues remain unsolved in regard to claudin functions, including the detailed functional differences between claudin subtypes and the effect of the combinations of specific claudin subtypes on the structure and function of TJs. To address these issues, it would be useful to have a way of reconstituting TJs containing only the claudin subtype(s) of interest in epithelial cells. In this study, we attempted to reconstitute TJs of individual claudin subtypes in TJ-deficient MDCK cells, designated as claudin quinKO cells, which were previously established from MDCK II cells by deleting the genes of claudin-1, -2, -3, -4, and -7. Exogenous expression of each of claudin-1, -2, -3, -4, and -7 in claudin quinKO cells resulted in the reconstitution of functional TJs. These TJs did not contain claudin-12 and -16, which are endogenously expressed in claudin quinKO cells. Furthermore, overexpression of neither claudin-12 nor claudin-16 resulted in the reconstitution of TJs, demonstrating the existence of claudin subtypes lacking TJ-forming activity in epithelial cells. Exogenous expression of the channel-forming claudin-2, -10a, -10b, and -15 reconstituted TJs with reported paracellular channel properties, demonstrating that these claudin subtypes form paracellular channels by themselves without interaction with other subtypes. Thus, the reconstitution of TJs in claudin quinKO cells is advantageous for further investigation of claudin functions.Key words: tight junction, claudin, paracellular permeability, epithelial barrier.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10721951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9138393","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: 1
Role of CRP2-MRTF interaction in functions of myofibroblasts. CRP2-MRTF 相互作用在肌成纤维细胞功能中的作用
IF 1.5 4区 生物学
Cell structure and function Pub Date : 2023-01-01 DOI: 10.1247/csf.23004
Ken'ichiro Hayashi, Shinri Horoiwa, Kotaro Mori, Hiroshi Miyata, Reuben Jacob Labios, Tsuyoshi Morita, Yuka Kobayashi, Chiemi Yamashiro, Fumiaki Higashijima, Takuya Yoshimoto, Kazuhiro Kimura, Yoshiaki Nakagawa
{"title":"Role of CRP2-MRTF interaction in functions of myofibroblasts.","authors":"Ken'ichiro Hayashi, Shinri Horoiwa, Kotaro Mori, Hiroshi Miyata, Reuben Jacob Labios, Tsuyoshi Morita, Yuka Kobayashi, Chiemi Yamashiro, Fumiaki Higashijima, Takuya Yoshimoto, Kazuhiro Kimura, Yoshiaki Nakagawa","doi":"10.1247/csf.23004","DOIUrl":"10.1247/csf.23004","url":null,"abstract":"<p><p>Inflammatory response induces phenotypic modulation of fibroblasts into myofibroblasts. Although transforming growth factor-βs (TGF-βs) evoke such transition, the details of the mechanism are still unknown. Here, we report that a LIM domain protein, cysteine-and glycine-rich protein 2 (CSRP2 [CRP2]) plays a vital role in the functional expression profile in myofibroblasts and cancer-associated fibroblasts (CAFs). Knock-down of CRP2 severely inhibits the expression of smooth muscle cell (SMC) genes, cell motility, and CAF-mediated collective invasion of epidermoid carcinoma. We elucidate the following molecular bases: CRP2 directly binds to myocardin-related transcription factors (MRTF-A/B [MRTFs]) and serum response factor (SRF) and stabilizes the MRTF/SRF/CArG-box complex to activate SMC gene expression. Furthermore, a three-dimensional structural analysis of CRP2 identifies the amino acids required for the CRP2-MRTF-A interaction. Polar amino acids in the C-terminal half (serine-152, glutamate-154, serine-155, threonine-156, threonine-157, and threonine-159 in human CRP2) are responsible for direct binding to MRTF-A. On the other hand, hydrophobic amino acids outside the consensus sequence of the LIM domain (tryptophan-139, phenylalanine-144, leucine-153, and leucine-158 in human CRP2) play a role in stabilizing the unique structure of the LIM domain.Key words: CRP2, 3D structure, myocardin-related transcription factor, myofibroblast, cancer-associated fibroblasts.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10721955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9837874","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: 1
Significance of the p38MAPK-CRP2 axis in myofibroblastic phenotypic transition. p38MAPK-CRP2轴在肌成纤维细胞表型转变中的意义。
IF 2 4区 生物学
Cell structure and function Pub Date : 2023-01-01 DOI: 10.1247/csf.23060
Ken'ichiro Hayashi, Reuben Jacob Labios, Tsuyoshi Morita, Atsushige Ashimori, Ren Aoki, Masanori Mikuni, Kazuhiro Kimura
{"title":"Significance of the p38MAPK-CRP2 axis in myofibroblastic phenotypic transition.","authors":"Ken'ichiro Hayashi, Reuben Jacob Labios, Tsuyoshi Morita, Atsushige Ashimori, Ren Aoki, Masanori Mikuni, Kazuhiro Kimura","doi":"10.1247/csf.23060","DOIUrl":"10.1247/csf.23060","url":null,"abstract":"<p><p>We have recently demonstrated that a LIM domain protein, cysteine and glycine-rich protein 2 (CSRP2 [CRP2]), plays a vital role in the functional expression of myofibroblasts and cancer-associated fibroblasts. CRP2 binds directly to myocardin-related transcription factors (MRTF [MRTF-A or MRTF-B]) and serum response factor (SRF) to stabilize the MRTF/SRF/CArG-box complex, leading to the expression of smooth muscle cell (SMC) genes such as α-smooth muscle actin (α-SMA) and collagens. These are the marker genes for myofibroblasts. Here, we show that the adhesion of cultured human skin fibroblasts (HSFs) to collagen reduces the myofibroblastic features. HSF adhesion to collagen suppresses the expression of CRP2 and CSRP2-binding protein (CSRP2BP [CRP2BP]) and reduces the expression of SMC genes. Although CRP2BP is known as an epigenetic factor, we find that CRP2BP also acts as an adaptor protein to enhance the function of CRP2 mentioned above. This CRP2BP function does not depend on its histone acetyltransferase activity. We also addressed the molecular mechanism of the reduced myofibroblastic features of HSFs on collagen. HSF adhesion to collagen inhibits the p38MAPK-mediated pathway, and reducing the p38MAPK activity decreases the expression of CRP2 and SMC genes. Thus, the activation of p38MAPK is critical for the myofibroblastic features. We also show evidence that CRP2 plays a role in the myofibroblastic transition of retinal pigment epithelial cells (RPEs). Like HSFs, such phenotypic modulation of RPEs depends on the p38MAPK pathway.Key words: CRP2, p38MAPK, MRTF, myofibroblasts, retinal pigment epithelial cells.</p>","PeriodicalId":9927,"journal":{"name":"Cell structure and function","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71410928","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
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