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The optimized priming effect of FGF-1 and FGF-2 enhances preadipocyte lineage commitment in human adipose-derived mesenchymal stem cells FGF-1和FGF-2的优化引物效应增强了人脂肪间充质干细胞的前脂肪细胞系承诺。
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-01-22 DOI: 10.1111/gtc.13095
Tanakorn Tarapongpun, Nattawat Onlamoon, Kouichi Tabu, Suebwong Chuthapisith, Tetsuya Taga

The cell-assisted lipotransfer technique, integrating adipose-derived mesenchymal stem cells (ADMSCs), has transformed lipofilling, enhancing fat graft viability. However, the multipotent nature of ADMSCs poses challenges. To improve safety and graft vitality and to reduce unwanted lineage differentiation, this study refines the methodology by priming ADMSCs into preadipocytes—unipotent, self-renewing cells. We explored the impact of fibroblast growth factor-1 (FGF-1), fibroblast growth factor-2 (FGF-2), and epidermal growth factor (EGF), either alone or in combination, on primary human ADMSCs during the proliferative phase. FGF-2 emerged as a robust stimulator of cell proliferation, preserving stemness markers, especially when combined with EGF. Conversely, FGF-1, while not significantly affecting cell growth, influenced cell morphology, transitioning cells to a rounded shape with reduced CD34 expression. Furthermore, co-priming with FGF-1 and FGF-2 enhanced adipogenic potential, limiting osteogenic and chondrogenic tendencies, and possibly promoting preadipocyte commitment. These preadipocytes exhibited unique features: rounded morphology, reduced CD34, decreased preadipocyte factor 1 (Pref-1), and elevated C/EBPα and PPARγ, alongside sustained stemness markers (CD73, CD90, CD105). Mechanistically, FGF-1 and FGF-2 activated key adipogenic transcription factors—C/EBPα and PPARγ—while inhibiting GATA3 and Notch3, which are adipogenesis inhibitors. These findings hold the potential to advance innovative strategies for ADMSC-mediated lipofilling procedures.

结合脂肪间充质干细胞(ADMSCs)的细胞辅助脂肪移植技术改变了脂肪填充,提高了脂肪移植的存活率。然而,ADMSCs的多能性带来了挑战。为了提高安全性和移植物的活力,减少不必要的系分化,本研究通过将 ADMSCs 引导成前绒毛膜细胞(单能、自我更新细胞)来改进方法。我们探讨了成纤维细胞生长因子-1(FGF-1)、成纤维细胞生长因子-2(FGF-2)和表皮生长因子(EGF)单独或联合使用对处于增殖期的原代人类 ADMSCs 的影响。FGF-2是细胞增殖的强大刺激因子,能保留干性标记,尤其是与表皮生长因子结合使用时。相反,FGF-1虽然对细胞生长没有显著影响,却影响了细胞形态,使细胞转变为圆形,CD34表达减少。此外,与 FGF-1 和 FGF-2 联合诱导可增强成脂潜能,限制成骨和软骨倾向,并可能促进前脂肪细胞的形成。这些前脂肪细胞表现出独特的特征:圆形形态、CD34减少、前脂肪细胞因子1(Pref-1)减少、C/EBPα和PPARγ升高,同时干性标志物(CD73、CD90、CD105)持续存在。从机理上讲,FGF-1和FGF-2激活了关键的脂肪生成转录因子-C/EBPα和PPARγ,同时抑制了抑制脂肪生成的GATA3和Notch3。这些发现有望推动 ADMSC 介导的脂肪填充程序的创新战略。
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引用次数: 0
Mouse transient receptor potential melastatin 2 (TRPM2) isoform 7 attenuates full-length mouse TRPM2 activity through reductions in its expression by targeting it to ER-associated degradation 小鼠瞬时受体电位美司他丁 2(TRPM2)异构体 7 通过靶向 ER 相关降解减少小鼠 TRPM2 的表达,从而削弱全长 TRPM2 的活性。
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-01-21 DOI: 10.1111/gtc.13097
Shinichiro Yamamoto, Naoto Kiyatake, Akihiro Kaneko, Masanao Shimamura, Takashi Yoshida, Shunichi Shimizu

Transient receptor potential melastatin 2 (TRPM2) assembles into tetramers to function as an oxidative stress-sensitive Ca2+ channel at the surface membrane. Limited information is currently available on the 10 protein isoforms of mouse TRPM2 (mTRPM2) identified. This study investigated whether these isoforms function as Ca2+ channels and examined their effects on full-length mTRPM2 activity using the HEK 293 cell exogenous expression system. Only full-length mTRPM2, isoform 1 localized to the surface membrane and was activated by oxidative stress. Isoform 7 was clearly recognized by protein quality control systems and degraded by endoplasmic reticulum-associated degradation after transmembrane proteolysis. In the co-expression system, the activation and expression of full-length mTRPM2 were attenuated by its co-expression with isoform 7, but not with the other isoforms. This decrease in the expression of full-length mTRPM2 was recovered by the proteasomal inhibitor. The present results suggest that isoforms other than isoform 1 did not function as oxidative stress-sensitive channels and also that only isoform 7 attenuated the activation of full-length mTRPM2 by targeting it to endoplasmic reticulum-associated degradation. The present study will provide important information on the functional nature of mTRPM2 isoforms for the elucidation of their roles in physiological and patho-physiological responses in vivo using mouse models.

瞬时受体电位美司他丁 2(TRPM2)组装成四聚体,在表膜上发挥氧化应激敏感性 Ca2+ 通道的功能。目前关于小鼠 TRPM2(mTRPM2)的 10 种蛋白同工形式的信息有限。本研究利用 HEK 293 细胞外源表达系统研究了这些异构体是否具有 Ca2+ 通道功能,并考察了它们对全长 mTRPM2 活性的影响。只有全长 mTRPM2 的异构体 1 定位于表面膜,并被氧化应激激活。异构体 7 被蛋白质质量控制系统明确识别,并在跨膜蛋白水解后被内质网相关降解。在共表达系统中,全长 mTRPM2 与同工酶 7 共表达后,其活化和表达量减少,而与其他同工酶共表达后,其活化和表达量则没有减少。蛋白酶体抑制剂可恢复全长 mTRPM2 的表达。本研究结果表明,除同工酶体 1 外,其他同工酶体并不具有氧化应激敏感通道的功能,而且只有同工酶体 7 通过将全长 mTRPM2 靶向内质网相关降解而削弱了其激活作用。本研究将为利用小鼠模型阐明 mTRPM2 异构体在体内生理和病理生理反应中的作用提供有关 mTRPM2 异构体功能性质的重要信息。
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引用次数: 0
GTP-dependent regulation of heterochromatin fluctuations at subtelomeric regions in Saccharomyces cerevisiae GTP 依赖性调控酿酒酵母中副基因组区域的异染色质波动。
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-01-16 DOI: 10.1111/gtc.13094
Takahito Ayano, Takuma Yokosawa, Masaya Oki

In eukaryotes, single cells in a population display different transcriptional profiles. One of the factors regulating this heterogeneity is the chromatin state in each cell. However, the mechanisms of epigenetic chromatin regulation of specific chromosomal regions remain unclear. Therefore, we used single-cell tracking system to analyze IMD2. IMD2 is located at the subtelomeric region of budding yeast, and its expression is epigenetically regulated by heterochromatin fluctuations. Treatment with mycophenolic acid, an inhibitor of de novo GTP biosynthesis, triggered a decrease in GTP, which caused heterochromatin fluctuations at the IMD2 locus. Interestingly, within individually tracked cells, IMD2 expression state underwent repeated switches even though IMD2 is positioned within the heterochromatin region. We also found that 30% of the cells in a population always expressed IMD2. Furthermore, the addition of nicotinamide, a histone deacetylase inhibitor, or guanine, the GTP biosynthesis factor in salvage pathway of GTP biosynthesis, regulated heterogeneity, resulting in IMD2 expression being uniformly induced or suppressed in the population. These results suggest that gene expression heterogeneity in the IMD2 region is regulated by changes in chromatin structure triggered by slight decreases in GTP.

在真核生物中,群体中的单个细胞显示出不同的转录特征。调节这种异质性的因素之一是每个细胞的染色质状态。然而,特定染色体区域的表观遗传染色质调控机制仍不清楚。因此,我们利用单细胞追踪系统分析了IMD2。IMD2位于芽殖酵母的副染色质区,其表达受异染色质波动的表观遗传调控。霉酚酸是一种新GTP生物合成抑制剂,它能导致GTP减少,从而引起IMD2基因座的异染色质波动。有趣的是,在单独跟踪的细胞中,即使 IMD2 位于异染色质区域内,IMD2 的表达状态也会发生反复切换。我们还发现,群体中有 30% 的细胞始终表达 IMD2。此外,添加组蛋白去乙酰化酶抑制剂烟酰胺或 GTP 生物合成途径中的 GTP 生物合成因子鸟嘌呤可调节异质性,从而使 IMD2 的表达在群体中均匀地被诱导或抑制。这些结果表明,IMD2 区域的基因表达异质性是由 GTP 的轻微下降引发的染色质结构变化调控的。
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引用次数: 0
Extracellular α-synuclein impairs sphingosine 1-phosphate receptor type 3 (S1PR3)-regulated lysosomal delivery of cathepsin D in HeLa cells 细胞外的α-突触核蛋白会损害HeLa细胞中由1-磷酸鞘氨醇受体3型(S1PR3)调控的溶酶体中猫毒素D的输送。
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2024-01-01 DOI: 10.1111/gtc.13093
Susumu Nishida, Shubi Ambwene Matovelo, Taketoshi Kajimoto, Shun-ichi Nakamura, Taro Okada

α-Synuclein (α-Syn)-positive intracellular fibrillar protein deposits, known as Lewy bodies, are thought to be involved in the pathogenesis of Parkinson's disease (PD). Although recent lines of evidence suggested that extracellular α-Syn secreted from pathogenic neurons contributes to the propagation of PD pathology, the precise mechanism of action remains unclear. We have reported that extracellular α-Syn caused sphingosine 1-phosphate (S1P) receptor type 1 (S1PR1) uncoupled from Gi and inhibited downstream G-protein signaling in SH-SY5Y cells, although its patho/physiological role remains to be clarified. Here we show that extracellular α-Syn caused S1P receptor type 3 (S1PR3) uncoupled from G protein in HeLa cells. Further studies indicated that α-Syn treatment reduced cathepsin D activity while enhancing the secretion of immature pro-cathepsin D into cell culture medium, suggesting that lysosomal delivery of cathepsin D was disturbed. Actually, extracellular α-Syn attenuated the retrograde trafficking of insulin-like growth factor-II/mannose 6-phosphate (IGF-II/M6P) receptor, which is under the regulation of S1PR3. These findings shed light on the understanding of dissemination of the PD pathology, that is, the mechanism underlying how extracellular α-Syn secreted from pathogenic cells causes lysosomal dysfunction of the neighboring healthy cells, leading to propagation of the disease.

α-突触核蛋白(α-Syn)阳性的细胞内纤维蛋白沉积物,即路易体,被认为与帕金森病(PD)的发病机制有关。尽管最近有证据表明,致病神经元分泌的细胞外α-Syn有助于帕金森病病理的传播,但其确切的作用机制仍不清楚。我们曾报道细胞外的α-Syn会导致1-磷酸鞘磷脂(S1P)受体1型(S1PR1)与Gi脱钩,并抑制SH-SY5Y细胞中的下游G蛋白信号转导,但其病理/生理作用仍有待明确。在这里,我们发现细胞外的α-Syn导致HeLa细胞中的S1P受体3型(S1PR3)与G蛋白脱钩。进一步的研究表明,α-Syn 处理降低了 cathepsin D 的活性,同时增强了细胞培养基中未成熟原 cathepsin D 的分泌,这表明溶酶体输送 cathepsin D 的过程受到了干扰。实际上,细胞外的α-Syn减弱了胰岛素样生长因子-II/6-磷酸甘露糖(IGF-II/M6P)受体的逆向运输,而IGF-II/M6P受体是受S1PR3调控的。这些发现有助于理解帕金森病病理的传播,即致病细胞分泌的细胞外α-Syn如何导致邻近健康细胞的溶酶体功能障碍,从而导致疾病传播的机制。
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引用次数: 0
Metastatic potentials classified with hypoxia-inducible factor 1 downstream genes in pan-cancer cell lines 根据泛癌细胞系中的低氧诱导因子 1 下游基因对转移潜力进行分类。
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2023-12-29 DOI: 10.1111/gtc.13092
Kazuya Nakamichi, Yusuke Yamamoto, Kentaro Semba, Jun Nakayama

Hypoxia-inducible factor 1 (HIF1) is a transcription factor that is stabilized under hypoxia conditions via post-translational modifications. HIF1 regulates tumor malignancy and metastasis by gene transcriptions, such as Warburg effect and angiogenesis-related genes, in cancer cells. However, the HIF1 downstream genes show varied expressional patterns in different cancer types. Herein, we performed the hierarchical clustering based on the HIF1 downstream gene expression patterns using 1406 cancer cell lines crossing 30 types of cancer to understand the relationship between HIF1 downstream genes and the metastatic potential of cancer cell lines. Two types of cancers, including bone and breast cancers, were classified based on HIF1 downstream genes with significantly altered metastatic potentials. Furthermore, different HIF1 downstream gene subsets were extracted to discriminate each subtype for these cancer types. HIF1 downstream subtyping classification will help to understand the novel insight into tumor malignancy and metastasis in each cancer type.

缺氧诱导因子 1(HIF1)是一种转录因子,在缺氧条件下通过翻译后修饰而稳定。HIF1 通过癌细胞中的基因转录(如沃伯格效应和血管生成相关基因)调控肿瘤的恶性程度和转移。然而,HIF1 下游基因在不同癌症类型中的表达模式各不相同。在此,我们利用跨越30种癌症的1406个癌细胞株,根据HIF1下游基因的表达模式进行了分层聚类,以了解HIF1下游基因与癌细胞株转移潜力之间的关系。根据转移潜能显著改变的 HIF1 下游基因对骨癌和乳腺癌等两类癌症进行了分类。此外,还提取了不同的 HIF1 下游基因子集,以区分这些癌症类型的各个亚型。HIF1下游亚型分类将有助于了解各癌症类型中肿瘤恶性程度和转移的新见解。
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引用次数: 0
Generation of inducible mitophagy mice 诱导性有丝分裂小鼠的产生。
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2023-12-22 DOI: 10.1111/gtc.13091
Toshiyuki Nishiji, Atsushi Hoshino, Yuki Uchio, Satoaki Matoba

Mitophagy is programmed selective autophagy of mitochondria and is important for mitochondrial quality control and cellular homeostasis. Mitochondrial dysfunction and impaired mitophagy are closely associated with various diseases, including heart failure and diabetes. To better understand the pathophysiological role of mitophagy, we generated doxycycline-inducible mitophagy mice using a synthetic mitophagy adaptor protein consisting of an outer mitochondrial membrane targeting sequence and an engineered LIR. To evaluate the activation of mitophagy upon doxycycline treatment, we also generated mitophagy reporter mito-QC mice in which mitochondria tandemly express mCherry and GFP, and only GFP signals are lost in acidic lysosomes subjected to mitophagy. With the ROSA26 promoter-driven rtTA, mitophagy was observed at least in heart, liver, and skeletal muscle. We investigated the relationship between mitophagy activation and pressure overload heart failure or high fat diet-induced obesity. Unexpectedly, we were unable to confirm the protective effect of mitophagy in these two pathological models. Further titration of the level of mitophagy induction is required to demonstrate the potency of the protective effects of mitophagy in disease models.

有丝分裂是线粒体的程序性选择性自噬,对线粒体质量控制和细胞稳态非常重要。线粒体功能障碍和有丝分裂受损与包括心力衰竭和糖尿病在内的多种疾病密切相关。为了更好地了解有丝分裂的病理生理作用,我们利用由线粒体外膜靶向序列和工程化 LIR 组成的合成有丝分裂适配蛋白生成了强力霉素诱导的有丝分裂小鼠。为了评估多西环素处理后有丝分裂的激活情况,我们还产生了有丝分裂报告基因 mito-QC 小鼠,其中线粒体串联表达 mCherry 和 GFP,只有 GFP 信号在有丝分裂的酸性溶酶体中消失。通过 ROSA26 启动子驱动的 rtTA,至少在心脏、肝脏和骨骼肌中观察到了有丝分裂。我们研究了有丝分裂活化与压力超负荷心衰或高脂饮食诱发肥胖之间的关系。出乎意料的是,我们无法证实有丝分裂在这两种病理模型中的保护作用。要证明有丝分裂在疾病模型中的保护作用的有效性,还需要进一步滴定有丝分裂的诱导水平。
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引用次数: 0
Insertion sequence excision is enhanced by a protein that catalyzes branch migration and promotes microhomology-mediated end joining 一种能催化分支迁移并促进微结构介导的末端连接的蛋白质能增强插入序列切除功能
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2023-12-14 DOI: 10.1111/gtc.13090
Ren Kishino, Takashi Saito, Shuntaro Muto, Yuzuka Tomita, Yasuhiko Sekine

Insertion sequence (IS)-excision enhancer (IEE) promotes the excision of ISs in the genome of enterohemorrhagic Escherichia coli O157. Because IEE-dependent IS excision occurs in the presence of transposase, the process of IS transposition may be involved in IS excision; however, little is understood about the molecular mechanisms of IS excision. Our in vitro analysis revealed that IEE exhibits DNA-dependent ATPase activity, which is activated by branched DNA. IEE also catalyzes the branch migration of fork-structured DNA. These results suggest that IEE remodels branched structures of the IS transposition intermediate. Sequence analysis of recombination sites in IS-excision products suggested that microhomologous sequences near the ends of the IS are involved in IS excision. IEE promoted microhomology-mediated end joining (MMEJ), in which base pairing between 6-nucleotides complementary ends of two 3′-protruding DNAs and subsequent elongation of the paired DNA strand occurred. IS-excision frequencies were significantly decreased in cells producing IEE mutants that had lost either branch migration or MMEJ activity, which suggests that these activities of IEE are required for IS excision. Based on our results, we propose a model for IS excision triggered by IEE and transposase.

插入序列(IS)-切除增强子(IEE)促进了肠出血性大肠杆菌 O157 基因组中 IS 的切除。由于IEE依赖的IS切除是在转座酶存在的情况下发生的,因此IS转座过程可能参与了IS切除;然而,人们对IS切除的分子机制知之甚少。我们的体外分析表明,IEE具有依赖于DNA的ATP酶活性,它被支化的DNA激活。IEE 还能催化叉形结构 DNA 的分支迁移。这些结果表明,IEE 能重塑 IS 转座中间体的分叉结构。对IS切除产物中重组位点的序列分析表明,IS末端附近的微同源序列参与了IS切除。IEE促进了微同源序列介导的末端连接(MMEJ),其中两个3′突起DNA的6核苷酸互补末端发生碱基配对,随后配对的DNA链发生伸长。在产生失去分支迁移或MMEJ活性的IEE突变体的细胞中,IS切除频率明显降低,这表明IEE的这些活性是IS切除所必需的。根据我们的研究结果,我们提出了一个由IEE和转座酶引发的IS切割模型。
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引用次数: 0
Acidic growth conditions stabilize the ribosomal RNA gene cluster and extend lifespan through noncoding transcription repression 酸性生长条件可稳定核糖体 RNA 基因簇,并通过非编码转录抑制延长寿命
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2023-12-08 DOI: 10.1111/gtc.13089
Yo Hasegawa, Hiroyuki Ooka, Tsuyoshi Wakatsuki, Mariko Sasaki, Ayumi Yamamoto, Takehiko Kobayashi

Blackcurrant (Ribes nigrum L.) is a classical fruit that has long been used to make juice, jam, and liqueur. Blackcurrant extract is known to relieve cells from DNA damage caused by hydrogen peroxide (H2O2), methyl methane sulfonate (MMS), and ultraviolet (UV) radiation. We found that blackcurrant extract (BCE) stabilizes the ribosomal RNA gene cluster (rDNA), one of the most unstable regions in the genome, through repression of noncoding transcription in the intergenic spacer (IGS) which extended the lifespan in budding yeast. Reduced formation of extrachromosomal circles (ERCs) after exposure to fractionated BCE suggested that acidity of the growth medium impacted rDNA stability. Indeed, alteration of the acidity of the growth medium to pH ~4.5 by adding HCl increased rDNA stability and extended the lifespan. We identified RPD3 as the gene responsible for this change, which was mediated by the RPD3L histone deacetylase complex. In mammals, as inflammation sites in a tissue are acidic, DNA maintenance may be similarly regulated to prevent genome instability from causing cancer.

黑加仑(Ribes nigrum L.)是一种经典的水果,长期以来被用来制作果汁、果酱和利口酒。众所周知,黑加仑提取物可以缓解过氧化氢(H2O2)、甲烷磺酸甲酯(MMS)和紫外线(UV)辐射造成的细胞DNA损伤。我们发现黑加仑提取物(BCE)通过抑制基因间间隔区(IGS)的非编码转录来稳定基因组中最不稳定的区域之一核糖体RNA基因簇(rDNA),从而延长出芽酵母的寿命。暴露于分离的BCE后,染色体外环(ERCs)的形成减少,表明生长培养基的酸度影响了rDNA的稳定性。事实上,通过添加HCl将生长介质的酸度改变为pH ~4.5,增加了rDNA的稳定性并延长了寿命。我们确定RPD3是导致这种变化的基因,这种变化是由RPD3L组蛋白脱乙酰酶复合物介导的。在哺乳动物中,由于组织中的炎症部位是酸性的,DNA维护可能受到类似的调节,以防止基因组不稳定导致癌症。
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引用次数: 0
CD271 promotes proliferation and migration in bladder cancer CD271促进膀胱癌的增殖和迁移。
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2023-11-28 DOI: 10.1111/gtc.13087
Shingo Myoen, Mai Mochizuki, Rie Shibuya-Takahashi, Haruna Fujimori, Norihisa Shindo, Kazunori Yamaguchi, Jun Yasuda, Jiro Abe, Takayuki Imai, Ikuro Sato, Hisanobu Adachi, Sadafumi Kawamura, Akihiro Ito, Keiichi Tamai

Bladder cancer is a urothelial cancer and effective therapeutic strategies for its advanced stages are limited. Here, we report that CD271, a neurotrophin receptor, promotes the proliferation and migration of bladder cancer cells. CD271 knockdown decreased proliferation in both adherent and spheroid cultures, and vice versa when CD271 was overexpressed in bladder cancer cell lines. CD271 depletion impaired tumorigenicity in vivo. Migration activity was reduced by CD271 knockdown and TAT-Pep5, a known CD271-Rho GDI-binding inhibitor. Apoptosis was induced by CD271 knockdown. Comprehensive gene expression analysis revealed alterations in E2F- and Myc-related pathways upon CD271 expression. In clinical cases, patients with high CD271 expression showed significantly shortened overall survival. In surgically resected specimens, pERK, a known player in proliferation signaling, colocalizes with CD271. These data indicate that CD271 is involved in bladder cancer malignancy by promoting cell proliferation and migration, resulting in poor prognosis.

膀胱癌是一种泌尿上皮肿瘤,其晚期的有效治疗策略有限。在这里,我们报道了CD271,一种神经营养因子受体,促进膀胱癌细胞的增殖和迁移。当CD271在膀胱癌细胞系中过表达时,CD271敲低可降低贴壁和球形培养中的增殖,反之亦然。CD271缺失在体内损害了致瘤性。CD271敲除和TAT-Pep5(一种已知的CD271- rho gdi结合抑制剂)降低了迁移活性。CD271敲低诱导细胞凋亡。综合基因表达分析显示,E2F和myc相关通路在CD271表达上发生改变。在临床病例中,CD271高表达患者的总生存期明显缩短。在手术切除的标本中,已知的增殖信号参与者pERK与CD271共定位。这些数据表明,CD271通过促进细胞增殖和迁移参与膀胱癌恶性,导致预后不良。
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引用次数: 0
IMPDH2 forms spots at branching sites and distal ends of astrocyte stem processes IMPDH2在星形胶质细胞干突的分支位点和远端形成斑点。
IF 2.1 4区 生物学 Q4 CELL BIOLOGY Pub Date : 2023-11-27 DOI: 10.1111/gtc.13088
Saori Toyoda, Takehisa Handa, Huang Yong, Hidehiko Takahashi, Hiroki Shiwaku

Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in the de novo GTP biosynthesis pathway. Recent studies suggest that IMPDH2, an isoform of IMPDH, can localize to specific subcellular compartments under certain conditions and regulate site-specific GTP availability and small GTPase activity in invasive cancer cells. However, it is unclear whether IMPDH2 plays a site-specific regulatory role in subcellular functions in healthy cells. In this study, we focused on brain cells and examined the localization pattern of IMPDH2. We discovered that IMPDH2 forms localized spots in the astrocytes of the adult mouse hippocampus. Further analysis of spot distribution in primary astrocyte cultures revealed that IMPDH2 spots are predominantly localized on branching sites and distal ends of astrocyte stem processes. Our findings suggest a potential unidentified role for IMPDH2 and GTP synthesis specifically at specialized nodes of astrocyte branches.

肌苷单磷酸脱氢酶(IMPDH)是GTP生物合成新途径中的限速酶。最近的研究表明,IMPDH2是IMPDH的一种异构体,可以在一定条件下定位到特定的亚细胞区室,并调节侵袭性癌细胞中特定位点的GTP可用性和小GTPase活性。然而,目前尚不清楚IMPDH2是否在健康细胞的亚细胞功能中发挥位点特异性调节作用。在本研究中,我们以脑细胞为研究对象,研究了IMPDH2的定位模式。我们发现,IMPDH2在成年小鼠海马的星形胶质细胞中形成局部斑点。进一步分析星形胶质细胞原代培养中的斑点分布,发现IMPDH2斑点主要位于星形胶质细胞干突的分支位点和远端。我们的研究结果表明,IMPDH2和GTP合成在星形胶质细胞分支的特定节点上具有潜在的未知作用。
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引用次数: 0
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