المؤلفون: Qingchun Zhou, Juan Yu, Qingyou Zheng, Tao Wu, Ziliang Ji, Yumin Zhuo

المصدر: FEBS Open Bio, Vol 11, Iss 5, Pp 1487-1496 (2021)

مصطلحات موضوعية: bladder cancer, KIF3A, kinesin, migration, proliferation, therapeutic target, Biology (General), QH301-705.5

الوصف: Bladder cancer is one of the most common malignant tumors of the urinary system, with high morbidity and mortality. At present, the survival rates and prognosis of patients with bladder cancer are still relatively low; thus, there remains a need to improve prognosis by identifying novel targets. Kinesins (kinesin superfamily proteins) are a series of microtubule‐based motor proteins that mediate various types of cellular processes. Kinesin family member 3A (KIF3A) is critical for cytoplasm separation in mitosis, and it has been reported to be misexpressed in multiple types of cancer. However, its effects on the progression and development of bladder cancer remain unclear. Herein, we report that KIF3A is highly expressed in human bladder cancer. We identified a significant correlation between KIF3A and clinical features, including clinical stage (P = 0.047), pathological tumor status (P = 0.045), lymph node status (P = 0.041) and metastasis (P = 0.035). KIF3A expression was also correlated with poor prognosis of patients with bladder cancer. Our results further indicated that KIF3A ablation resulted in cell cycle arrest; blocked the proliferation, migration and invasion of bladder cancer cells in vitro; and restrained tumor growth in mice in a microtubule‐dependent manner. In summary, our findings suggest that KIF3A is a potential therapeutic target for bladder cancer.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2211-5463Test

الوصول الحر: https://doaj.org/article/85cfe60dc6d84b9eaf08faae67a71b2fTest

المؤلفون: YANG Lili, WANG Yaping, XUE Kunjiao, RUAN Lingying, FU Zhou, GENG Gang

المصدر: Di-san junyi daxue xuebao, Vol 43, Iss 6, Pp 496-502 (2021)

مصطلحات موضوعية: kif3a, β-arrestin, wnt/β-catenin pathway, asthma, bronchial inflammation, Medicine (General), R5-920

الوصف: Objective To investigate the possible mechanism of kinesin family member 3A (KIF3A) taking part in the regulation of asthma airway inflammation, so as to provide a new target and direction for asthma treatment. Methods Female C57BL/6 mice were randomly divided into asthma group (n=10) and control group (n=10). Western blotting and immunohistochemistry (IHC) were performed to detect the expression of KIF3A in the 2 groups. After human bronchial epithelial 16HBE cells were intervened using phosphate buffer solution (PBS) and house dust mite (HDM), Western blotting and RT-PCR were adopted to detect the KIF3A expression. Moreover, the lentiviral vectors of KIF3A overexpression (LV-KIF3A-45894-J2, LV-KIF3A) and knock-down (LV-KIF3A-RNAi-81183-1, RNAi) were constructed and then transfected into 16HBE cells, and the blank lentiviral vectors and those containing negative control sequence served as controls, respectively. The binding of KIF3A to β-arrestin in the overexpressed cells was detected by immunoprecipitation, while the expression level of β-catenin in each group of cells was determined by Western blotting and RT-PCR. The effect of differential expression of KIF3A on the expression of chemokines CCL-17 and CCL-26 was also determined. Results In animal models, the expression of KIF3A was significantly lower in the asthma mice than the control mice (P < 0.05). In vitro study indicated that HDM intervention decreased the expression of KIF3A at protein and mRNA levels in 16HBE cells, though there was no statistical difference (P>0.05). The RT-PCR and Western blotting results showed that the expression of KIF3A were increased in the LV-KIF3A transfected cells (P < 0.05) and decreased in the RNAi treated cells (P < 0.05). Immunoprecipitation confirmed the binding of KIF3A to β-arrestin. No significant difference was found in the total amount of β-catenin protein between the LV-KIF3A transfected cells and the RNAi treated cells. Compared with the corresponding cells, the mRNA level of β-catenin was significantly lower in the RNAi treated cells (P < 0.0001), but no such difference was seen in the LV-KIF3A transfected cells. The RT-PCR results suggested that the levels of chemokines CCL-17 and CCL-26 were increased in the RNAi treated cells (P < 0.001), while decreased in the LV-KIF3A transfected cells (P < 0.05) as compared with their control cells. Conclusion KIF3A binds to β-arrestin in the Wnt/β-catenin pathway, and is involved in asthmatic airway epithelial inflammation by regulating the expression of chemokines CCL-17 and CCL-26.

وصف الملف: electronic resource

العلاقة: https://aammt.tmmu.edu.cn/Upload/rhtml/202009180.htmTest; https://doaj.org/toc/1000-5404Test

الوصول الحر: https://doaj.org/article/23d4fce097e44f24b3c4d55241121945Test

المؤلفون: Chun-Jung Lin, Andrew Dang, Elizabeth Hernandez, Jer-Tsong Hsieh

المصدر: Neoplasia: An International Journal for Oncology Research, Vol 23, Iss 1, Pp 169-180 (2021)

مصطلحات موضوعية: DAB2IP, KIF3a, Primary cilia, Renal cell carcinoma, Tumor suppressor gene, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Primary cilium is a microtubule-based organelle that projects from the surfaces of most mammalian cell types and protrudes into the extracellular milieu as an antenna-like sensor to senses extracellular physical and biochemical signals, and then transmits signals into cytoplasm or nucleus to regulate numerous physical and developmental processes. Therefore, loss of primary cilia is associated to multiple cancer progression, including skin, breast, pancreas, ovarian, prostate, and kidney cancers. Our previous studies demonstrate that high prevalent loss of DAB2 Interacting Protein (DAB2IP) is associated with renal cell carcinoma, and we found a kinesin-like protein, kinesin family member 3A (KIF3a), was significantly increased in DAB2IP-interacting protein fraction. KIF3 is one of the most abundant kinesin-2 family proteins expressed in cells, and it is necessary for ciliogenesis. In this study, we observed that loss of DAB2IP in normal kidney epithelial cell significantly impair primary cilia formation. We unveiled a new mechanism of primary cilia stability via DAB2IP and KIF3a physical interaction at DAB2IP-PH domain. Furthermore, we found that KIF3a also act as a tumor suppressor in renal cell carcinoma, affect tumor development and patient survival.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S1476558620301834Test; https://doaj.org/toc/1476-5586Test

الوصول الحر: https://doaj.org/article/18e39db5315a493cb16a4b050f7d6fc3Test

المؤلفون: Lin Ding, Erica A. Sontz, Milena Saqui-Salces, Juanita L. Merchant

المصدر: Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 5, Pp 1251-1266 (2021)

مصطلحات موضوعية: Helicobacter, Hedgehog Signaling, IFN-γ, Gastric Cancer, KIF3A, Diseases of the digestive system. Gastroenterology, RC799-869

الوصف: Background & Aims: Helicobacter pylori infection in humans typically begins with colonization of the gastric antrum. The initial Th1 response occasionally coincides with an increase in gastrin secretion. Subsequently, the gastritis segues to chronic atrophic gastritis, metaplasia, dysplasia and distal gastric cancer. Despite these well characterized clinical events, the link between inflammatory cytokines and non-cardia gastric cancer remains difficult to study in mouse models. Prior studies have demonstrated that overexpression of the Hedgehog (HH) effector GLI2 induces loss of gastrin (atrophy) and antral hyperplasia. To determine the link between specific cytokines, HH signaling and pre-neoplastic changes in the gastric antrum. Methods: Mouse lines were created to conditionally direct IL1β or IFN-γ to the antrum using the Gastrin-CreERT2 and Tet activator. Primary cilia, which transduces HH signaling, on G cells were disrupted by deleting the ciliary motor protein KIF3a. Phenotypic changes were assessed by histology and western blots. A subclone of GLUTag enteroendocrine cells selected for gastrin expression and the presence of primary cilia was treated with recombinant SHH, IL1β or IFN-γ with or without kif3a siRNA. Results: IFN-γ increased gastrin and induced antral hyperplasia. However, antral expression of IL1β suppressed tissue and serum gastrin, while also inducing antral hyperplasia. IFN-γ treatment of GLUTAg cells suppressed GLI2 and induced gastrin, without affecting cilia length. By contrast, IL1β treatment doubled primary cilia length, induced GLI2 and suppressed gastrin gene expression. Knocking down kif3a in GLUTAg cells mitigated SHH or IL1β suppression of gastrin. Conclusions: Overexpression of IL1β in the antrum was sufficient to induce antral hyperplasia coincident with suppression of gastrin via primary cilia. ORCID: #0000-0002-6559-8184

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2352345X20302071Test; https://doaj.org/toc/2352-345XTest

الوصول الحر: https://doaj.org/article/8383de67d32d4ac88b613f959de6be78Test

المؤلفون: Duan, S., Sawyer, T.W., Sontz, R.A., Wieland, B.A., Diaz, A.F., Merchant, J.L.

المساهمون: University of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology, Wyant College of Optical Sciences, University of Arizona

المصدر: Cellular and Molecular Gastroenterology and Hepatology

مصطلحات موضوعية: Enteric Glia, Gastrinomas, Hedgehog Signaling, KIF3A, Primary Cilia, SOX10

الوصف: Background & Aims: Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis. Methods: Transgenic GFAPΔMen1 mice were generated by conditional GFAP-directed Men1 deletion in GFAP-expressing cells. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. Small interfering RNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel. Results: GFAPΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAPΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Men1 deletion induced loss of glial-restricted progenitor lineage markers and an increase in neuroendocrine genes, suggesting a reprogramming of GFAP+ cells. Deleting Kif3a, a mediator of Hedgehog signaling, in GFAP-expressing cells attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate. Similar results in the pancreas were observed when Sox10 was used to delete Men1. Conclusions: GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation. © 2022 The Authors ; Open access journal ; This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.

العلاقة: Duan, S., Sawyer, T. W., Sontz, R. A., Wieland, B. A., Diaz, A. F., & Merchant, J. L. (2022). GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming. Cellular and Molecular Gastroenterology and Hepatology, 14(5), 1025–1051.; http://hdl.handle.net/10150/666872Test; Cellular and Molecular Gastroenterology and Hepatology

الإتاحة: https://doi.org/10.1016/j.jcmgh.2022.06.009Test
http://hdl.handle.net/10150/666872Test

المؤلفون: ZHOU Tao, WU Peiyao, YANG Yuqing, CAO Zhiwei, XIE Liang

المصدر: 口腔疾病防治, Vol 28, Iss 5, Pp 318-321 (2020)

مصطلحات موضوعية: primary cilia, odontogenesis, distribution, wnt signaling pathway, hedgehog signaling pathway, kif3a gene, evc/evc2 gene, ift gene, Medicine

الوصف: Primary cilia are organelles present on most mammalian cells that sense environmental changes and transduce signaling, and they are the key coordinators of various signaling pathways during tissue development. This article reviews the progress of research on the distribution of primary cilia in tooth development and the related signaling pathways. A literature review shows that in odontogenesis, primary cilia play an important role in the mutual induction of the epithelium and mesenchyme; during the continuous proliferation and differentiation of cells, the distribution of primary cilia is temporally and spatially dependent. Although the reason for this distribution is still unclear, some experimental evidence indicates that this phenomenon is compatible with the function of cells and tissues in which primary cilia are distributed. Primary cilia are involved in the regulation of two important signaling pathways, Hedgehog and Wnt, in odontogenesis. Genes encoding cilia (such as Kif3a, Evc/Evc2 and Ift) can affect the development of teeth by regulating these two signaling pathways, and there is an interaction between the two signaling pathways. Deletion of related genes (such as Ofd1 and Bbs) can damage the transmission of upstream and downstream signals by damaging the structure or function of cilia, thereby causing various types of dental dysplasia, including small teeth, enamel hypoplasia, missing teeth, or craniofacial deformities.

وصف الملف: electronic resource

العلاقة: http://www.kqjbfz.com/CN/10.12016/j.issn.2096-1456.2020.05.009Test; https://doaj.org/toc/2096-1456Test

الوصول الحر: https://doaj.org/article/df3cbfe0dc9e474fbeef40e2142a25d0Test

المؤلفون: LI Haiyan, ZHOU Xuan, CHEN Yunqing, JI Huihui, SHI Weiping, WANG Chengqin, XIANG Fenggang

المصدر: Zhongliu Fangzhi Yanjiu, Vol 45, Iss 12, Pp 985-990 (2018)

مصطلحات موضوعية: kif3a, stomach neoplasm, adenocarcinoma, invasion, metastasis, prognosis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Objective To investigate the expression of KIF3A in different gastric mucosal lesions and corresponding metastatic lymph nodes, and to explore its relationship with the occurrence, clinicopathologic characteristics, metastasis and prognosis of gastric adenocarcinoma. Methods The expression of KIF3A was detected immunohistochemically in different gastric mucosal lesions and corresponding metastatic lymph nodes. SPSS23.0 software package was used for statistical analysis. Results The expression of KIF3A was higher in gastric adenocarcinoma tissues than that in corresponding adjacent tissues(P < 0.01), and it was also higher in metastatic lymph nodes than that in corresponding primary lesions(P < 0.01). The expression of KIF3A both in low- and high-grade intraepithelial neoplasia were significantly higher than that in chronic gastritis(P < 0.01). In addition, KIF3A expression in advanced gastric adenocarcinoma was correlated with TNM grade, lymph node metastasis and vascular invasion(P < 0.05). Patients with high expression of KIF3A had shorter overall survival and disease-free survival than those with low expression of KIF3A(P < 0.01), and patients with both cytoplasm and nuclear expression of KIF3A had shorter overall survival than those with exclusively cytoplasmic distribution(P < 0.05). COX multivariate analysis showed that high expression of KIF3A was an independent risk factor for overall survival and disease-free survival of patients with gastric adenocarcinoma(P < 0.05). Conclusion KIF3A may be correlated with intraepithelial neoplasia of gastric mucosa. Both the up-regulation of KIF3A and nuclear expression of KIF3A may be related to poor prognosis of advanced gastric adenocarcinoma patients. KIF3A may be an independent prognostic factor for advanced gastric adenocarcinoma.

وصف الملف: electronic resource

العلاقة: http://html.rhhz.net/ZLFZYJ/html/8578.2018.18.0627.htmTest; https://doaj.org/toc/1000-8578Test

الوصول الحر: https://doaj.org/article/1766c26ac7d4408e99c3fc34e8851c12Test

المؤلفون: Ding, L., Sontz, E.A., Saqui-Salces, M., Merchant, J.L.

المساهمون: Department of Medicine-Gastroenterology, University of Arizona

المصدر: Cellular and Molecular Gastroenterology and Hepatology

مصطلحات موضوعية: Gastric Cancer, Hedgehog Signaling, Helicobacter, IFN-γ, KIF3A

الوصف: Background & Aims: Helicobacter pylori infection in humans typically begins with colonization of the gastric antrum. The initial Th1 response occasionally coincides with an increase in gastrin secretion. Subsequently, the gastritis segues to chronic atrophic gastritis, metaplasia, dysplasia and distal gastric cancer. Despite these well characterized clinical events, the link between inflammatory cytokines and non-cardia gastric cancer remains difficult to study in mouse models. Prior studies have demonstrated that overexpression of the Hedgehog (HH) effector GLI2 induces loss of gastrin (atrophy) and antral hyperplasia. To determine the link between specific cytokines, HH signaling and pre-neoplastic changes in the gastric antrum. Methods: Mouse lines were created to conditionally direct IL1β or IFN-γ to the antrum using the Gastrin-CreERT2 and Tet activator. Primary cilia, which transduces HH signaling, on G cells were disrupted by deleting the ciliary motor protein KIF3a. Phenotypic changes were assessed by histology and western blots. A subclone of GLUTag enteroendocrine cells selected for gastrin expression and the presence of primary cilia was treated with recombinant SHH, IL1β or IFN-γ with or without kif3a siRNA. Results: IFN-γ increased gastrin and induced antral hyperplasia. However, antral expression of IL1β suppressed tissue and serum gastrin, while also inducing antral hyperplasia. IFN-γ treatment of GLUTAg cells suppressed GLI2 and induced gastrin, without affecting cilia length. By contrast, IL1β treatment doubled primary cilia length, induced GLI2 and suppressed gastrin gene expression. Knocking down kif3a in GLUTAg cells mitigated SHH or IL1β suppression of gastrin. Conclusions: Overexpression of IL1β in the antrum was sufficient to induce antral hyperplasia coincident with suppression of gastrin via primary cilia. ORCID: #0000-0002-6559-8184 © 2021 The Authors ; Open access journal ; This item from the UA Faculty Publications collection is made available by the University of Arizona with ...

العلاقة: Ding, L., Sontz, E. A., Saqui-Salces, M., & Merchant, J. L. (2021). Interleukin-1β suppresses gastrin via primary cilia and induces antral hyperplasia. Cellular and Molecular Gastroenterology and Hepatology, 11(5), 1251-1266.; http://hdl.handle.net/10150/659934Test; Cellular and Molecular Gastroenterology and Hepatology

الإتاحة: https://doi.org/10.1016/j.jcmgh.2020.12.008Test
http://hdl.handle.net/10150/659934Test

المؤلفون: Kotsis, Fruzsina, Janusch, Heike, Li, Yujie, Viau, Amandine, Epting, Daniel, Kramer-Zucker, Albrecht, Walz, Gerd, Nitschke, Roland, Lorentzen, Esben, Ganner, Athina, Neumann-Haefelin, Elke, Kuehn, E. Wolfgang, Boehlke, Christopher

المصدر: Kotsis , F , Janusch , H , Li , Y , Viau , A , Epting , D , Kramer-Zucker , A , Walz , G , Nitschke , R , Lorentzen , E , Ganner , A , Neumann-Haefelin , E , Kuehn , E W & Boehlke , C 2021 , ' Ift88, but not Kif3a, is required for establishment of the periciliary membrane compartment ' , Biochemical and Biophysical Research Communications , vol. 584 , pp. 19-25 . https://doi.org/10.1016/j.bbrc.2021.10.075Test

مصطلحات موضوعية: Ciliary pocket, Ift88, Kif3a, Periciliary membrane compartment, Primary cilia

الوصف: The primary cilium is a sensory organelle at the cell surface with integral functions in cell signaling. It contains a microtubular axoneme that is rooted in the basal body (BB) and serves as a scaffold for the movement of intraflagellar transport (IFT) particles by Kinesin-2 along the cilium. Ift88, a member of the anterograde moving IFT-B1 complex, as well as the Kinesin-2 subunit Kif3a are required for cilia formation. To facilitate signaling, the cilium restricts the access of molecules to its membrane (“ciliary gate”). This is thought to be mediated by cytoskeletal barriers (“subciliary domains”) originating from the BB subdistal/distal appendages, the periciliary membrane compartment (PCMC) as well as the transition fibers and zone (TF/TZ). The PCMC is a poorly characterized membrane domain surrounding the ciliary base with exclusion of certain apical membrane proteins. Here we describe that Ift88, but not Kinesin-2, is required for the establishment of the PCMC in MDCK cells. Likewise, in C. elegans mutants of the Ift88 ortholog osm-5 fail to establish the PCMC, while Kinesin-2 deficient osm-3 mutants form PCMCs normally. Furthermore, disruption of IFT-B1 into two subcomplexes, while disrupting ciliogenesis, does not interfere with PCMC formation. Our findings suggest that cilia are not a prerequisite for the formation of the PCMC, and that separate machineries with partially overlapping functions are required for the establishment of each.

وصف الملف: application/pdf

الإتاحة: https://doi.org/10.1016/j.bbrc.2021.10.075Test
https://pure.au.dk/portal/da/publications/ift88-but-notTest-kif3a-is-required-for-establishment-of-the-periciliary-membrane-compartment(ad713663-b2c5-4f3b-9ee1-b55a9d0ec82a).html
https://pure.au.dk/ws/files/285206922/1_s2.0_S0006291X21014984_main.pdfTest
http://www.scopus.com/inward/record.url?scp=85118540306&partnerID=8YFLogxKTest

المؤلفون: D'Amico, Eva, Gayral, Stéphanie, Massart, Claude, Van Sande, Jacqueline, Reiter, Jeremy F, Dumont, Jacques E, Robaye, Bernard, Schurmans, Stéphane

المصدر: Journal of Molecular Endocrinology. 50(3)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Metabolic and endocrine, Animals, Hypothyroidism, Kinesins, Mice, Mice, Mutant Strains, PAX8 Transcription Factor, Paired Box Transcription Factors, Signal Transduction, Thyroid Gland, Thyrotropin, thyroid, hypothyroidism, genetically-modified mouse, Kif3a, molecular motor, kinesin 2, Kinesin, Veterinary Sciences, Paediatrics and Reproductive Medicine, Endocrinology & Metabolism, Clinical sciences

الوصف: Kinesins, including the kinesin 2/KIF3 molecular motor, play an important role in intracellular traffic and can deliver vesicles to distal axon terminals, to cilia, to nonpolarized cell surfaces or to epithelial cell basolateral membranes, thus taking part in the establishment of cellular polarity. We report here the consequences of kinesin 2 motor inactivation in the thyroid of 3-week-old Kif3a(Δ)(/flox) Pax8(Cre/)(+) mutant mice. Our results indicate first that 3-week-old Pax8(Cre/)(+) mice used in these experiments present minor thyroid functional defects resulting in a slight increase in circulating bioactive TSH and intracellular cAMP levels, sufficient to maintain blood thyroxine levels in the normal range. Second, Kif3a inactivation in thyrocytes markedly amplified the phenotype observed in Pax8(Cre/)(+) mice, resulting in altered TSH signaling upstream of the second messenger cAMP and mild hypothyroidism. Finally, our results in mouse embryonic fibroblasts indicate that Kif3a inactivation in the absence of any Pax8 gene alteration leads to altered G protein-coupled receptor plasma membrane expression, as shown for the β2 adrenergic receptor, and we suggest that a similar mechanism may explain the altered TSH signaling and mild hypothyroidism detected in Kif3a(Δ)(/flox) Pax8(Cre/)(+) mutant mice.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4hx190wnTest