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Regulation of cytohesins by their interactors in the nervous system

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Neural Regeneration Research 2023年第10期18卷 2186-2187页

作者： Yuqi Zhai King To Leung kwok-fai lau School of Life Sciences Faculty of ScienceThe Chinese University of Hong KongHong Kong Special Administrative RegionChina

Adenosine diphosphate ribosylation factors(ARFs) are small GTP-binding proteins of the Ras superfamily which are involved in membrane trafficking and actin cytoskeleton *** other small GTPases,their functions are attributed to the cycling of ARF between GTP(active) and GDP (inactive) states through the actions of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins,respectively.

关键词： Adenosine cycling attributed

FE65:a hub for neurodevelopment

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Neural Regeneration Research 2024年第9期19卷 1883-1884页

作者： Yuqi Zhai laura Lok-Haang Ng Dennis Dik-Long Chau kwok-fai lau School of Life Sciences Faculty of ScienceThe Chinese University of Hong KongHong Kong Special Administrative RegionChina

FE65,initially identified as a binding partner of amyloid precursor protein(APP),is an adaptor protein enriched in the brain and regulated during ***65 belongs to the FE65 protein *** family is comprised of three memb... 详细信息

关键词： family development partner

Emerging roles of the neural adaptor FE65 in neurite outgrowth

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Neural Regeneration Research 2018年第12期13卷 2085-2086页

作者： Wen Li Wai Wa Ray Chan Jacky Chi Ki Ngo kwok-fai lau Shenzhen Institute of Advanced Technology Chinese Academy of Sciences School of Life Sciences Chinese University of Hong Kong

The brain is the third largest organ in the human body and consists of over80 billion neurons（Herculano-Houzel,2009）.Neurons are interconnected by neurite to form a complex neural network that allows the communicati... 详细信息

关键词： FE Emerging roles of the neural adaptor FE65 in neurite outgrowth GEF

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer’s disease

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5481-5494页

作者： Ashok Iyaswamy Abhimanyu Thakur Xin-Jie Guan Senthilkumar Krishnamoorthi Tsz Yan Fung Kejia Lu Isha Gaurav Zhijun Yang Cheng-Fu Su kwok-fai lau Kui Zhang Roy Chun-Laam Ng Qizhou Lian King-Ho Cheung Keqiang Ye Huanhuan Joyce Chen Min Li Mr.&Mrs.Ko Chi-Ming Centre for Parkinson’s Disease Research School of Chinese MedicineHong Kong Baptist UniversityHong Kong SARChina Pritzker School of Molecular Engineering The University of ChicagoChicagoILUSA Ben May Department for Cancer Research The University of ChicagoChicagoILUSA School of Chinese Medicine Hong Kong Baptist UniversityHong Kong SARChina School of Life Sciences The Chinese University of Hong KongHong Kong SARChina Division of Neuroscience School of Biological SciencesFaculty of BiologyMedicine and HealthManchester Academic Health Science CentreUniversity of ManchesterManchesterUnited Kingdom Department of Medicine Li Ka Shing Faculty of MedicineThe University of Hong KongPok Fu LamHong Kong SARChina Prenatal Diagnostic Center and Cord Blood Bank Guangzhou Women and Children’s Medical CenterGuangzhou Medical UniversityGuangzhouChina HKUMed Laboratory of Cellular Therapeutics the University of Hong KongPok Fu LamHong Kong SARChina Faculty of Life and Health Sciences Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhenChina

Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques,hyperphosphorylated tau protein,and neurofibrillary tangles in the *** overexpression of amyloid-βprecursor protein(APP)in an AD brain results in the binding of APP intracellular domain(AICD)to Fe65 protein via the C-terminal Fe65-PTB2 interaction,which then triggers the secretion of amyloid-βand the consequent pathogenesis of ***,targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for ***,exosome,a type of extracellular vesicle with diameter around 30–200 nm,has gained much attention as a potential delivery tool for brain diseases,including AD,due to their ability to cross the blood–brain barrier,their efficient uptake by autologous cells,and their ability to be surface-modified with target-specific receptor ***,the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65,enabled the development of a novel exosome-based targeted drug delivery system,which carried Corynoxine-B(Cory-B,an autophagy inducer)to the APP overexpressed-neuron cells in the brain of AD *** Fe65-engineered HT22 hippocampus neuron cell-derived exosomes(Fe65-EXO)loaded with Cory-B(Fe65-EXO-Cory-B)hijacked the signaling and blocked the natural interaction between Fe65 and APP,enabling APP-targeted delivery of ***,Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells,leading to amelioration of the cognitive decline and pathogenesis in AD mice,demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.

关键词： Alzheimer gained loaded

The human and mouse sex-determining SRY genes repress the Rspo1/β-catenin signaling

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Journal of Genetics and Genomics 2009年第4期36卷 193-202页

作者： Yun-fai Chris lau Division of Cell and Developmental Genetics Department of Medicine VA Medical Center University of CaliforniaSan Francisco CA 94121 USA

The sex-determining region Y （SRY） is the gene on the Y chromosome responsible for switching on male sex determination during mammalian embryogenesis. In its absence, ovaries develop in the embryo. Hence, ovarian determination and differentiation is considered to be a default, or passive, developmental pathway. Recently this classical paradigm of sex determination has been challenged with the discovery of the R-spondin 1 （RSPO1） as an active ovarian determinant. Mutations of RSPO1 cause a female-to-male sex reversal. RSPO1 synergizes with WNT4 in activating an ovarian development in the bipotential gonad via the canonical Wnt signaling. Early studies showed that SRY represses such Wnt signaling, but also generated discrepancies on whether only mouse Sry is capable of inhibiting such Wnt signaling and whether both human and mouse SRY proteins are able to interact with β-catenin, the intracellular messenger responsible for executing the Wnt signals. Our studies show that both human SRY and mouse Sry are capable of repressing the Rspol/Wnt/β-catenin signaling. However, the repression activities vary among different SRY/Sry proteins and paradoxically related to the presence and/or size of an acidic/glutamine-rich domain. The HMG box of human SRY could bind directly to β-catenin while the mouse Sry binds to β-catenin via its HMG box and glutamine-rich domain. The results clarify some of the initial discrepancies, and raise the possibility that SRY interacts with β-catenin in the nucleus and represses the transcriptional activation of the Rspol/Wnt target genes involved in ovarian determination, thereby switching on testis determination.

关键词： SRY sex determination R-spondin 1 canonical Wnt signaling β-catenin protein interaction

Roles of the Y chromosome genes in human cancers

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Asian Journal of Andrology 2015年第3期17卷 373-380页

作者： Tatsuo Kido Yun-fai Chris lau Division of Cell and Developmental Genetics Department of Medicine Veterans Affairs Medical Center Institute for Human Genetics University of California San Francisco California 94121 USA

Male and female differ genetically by their respective sex chromosome composition, that is, XY as male and XX as female. Although both X and Y chromosomes evolved from the same ancestor pair of autosomes, the Y chromosome harbors male-specific genes, which play pivotal roles in male sex determination, germ cell differentiation, and masculinization of various tissues. Deletions or translocation of the sex-determining gene, SRY, from the Y chromosome causes disorders of sex development （previously termed as an intersex condition） with dysgenic gonads. failure of gonadal development results not only in infertility, but also in increased risks of germ cell tumor （GCT）, such as gonadoblastoma and various types of testicular GCT. Recent studies demonstrate that either loss of Y chromosome or ectopic expression of Y chromosome genes is closely associated with various male-biased diseases, including selected somatic cancers. These observations suggest that the Y-linked genes are involved in male health and diseases in more frequently than expected. Although only a small number of protein-coding genes are present in the male-specific region of Y chromosome, the impacts of Y chromosome genes on human diseases are still largely unknown, due to lack of in vivo models and differences between the Y chromosomes of human and rodents. In this review, we highlight the involvement of selected Y chromosome genes in cancer development in men.

关键词： germ cell tumors RBMY, Y-linked somatic cancers TSPY Y chromosome

Identification of a TSPY co-expression network associated with DNA hypomethylation and tumor gene expression in somatic cancers

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Journal of Genetics and Genomics 2016年第10期43卷 577-585页

作者： Tatsuo Kido Yun-fai Chris lau Division of Cell and Developmental Genetics Department of Medicine Veterans Affairs Medical Center and Institute for Human Genetics University of California

Testis specific protein Y-encoded（TSPY） is a Y-located proto-oncogene predominantly expressed in normal male germ cells and various types of germ cell tumor. Significantly, TSPY is frequently expressed in somatic cancers including liver cancer but not in adjacent normal tissues, suggesting that ectopic TSPY expression could be associated with oncogenesis in non-germ cell cancers. Various studies demonstrated that TSPY expression promotes growth and proliferation in cancer cells; however, its relationship to other oncogenic events in TSPY-positive cancers remains unknown. The present study seeks to correlate TSPY expression with other molecular features in clinical cancer samples, by analyses of RNA-seq transcriptome and DNA methylation data in the Cancer Genome Atlas（TCGA） database. A total of 53 genes,including oncogenic lineage protein 28 homolog B（LIN28B） gene and RNA-binding motif protein Y-linked（RBMY） gene, are identified to be consistently co-expressed with TSPY, and have been collectively designated as the TSPY co-expression network（TCN）. TCN genes were simultaneously activated in subsets of liver hepatocellular carcinoma（30%） and lung adenocarcinoma（10%） regardless of pathological stage, but only minimally in other cancer types. Further analysis revealed that the DNA methylation level was globally lower in the TCN-active than TCN-silent cancers. The specific expression and methylation patterns of TCN genes suggest that they could be useful as biomarkers for the diagnosis,prognosis and clinical management of cancers, especially those for liver and lung cancers, associated with TSPY co-expression network genes.

关键词： Co-expression network DNA methylation Gene expression signature Cancer subclassification Y chromosome genes TSPY Cancer/testis antigens

Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

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Asian Journal of Andrology 2019年第3期21卷 260-269页

作者： Yun-fai Chris lau Yunmin Li Tatsuo Kido Division of Cell and Developmental Genetics Department of Medicine VA Medical Center and Institute for Human Genetics University of California San Francisco CA 94121 USA

The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.

关键词： androgen receptor AR-V7 cell cycle regulation cyclin B-CDK1 oncogene sex chromosomes sex differences TSPX TSPY tumor suppressor

Lycium barbarum polysaccharides promotes in vivo proliferation of adult rat retinal progenitor cells

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Neural Regeneration Research 2015年第12期10卷 1976-1981页

作者： Hua Wang Benson Wui-Man lau Ning-li Wang Si-ying Wang Qing-jun Lu Raymond Chuen-Chung Chang kwok-fai So Beijing Tongren Eye Center Beijing Tongren HospitalCapital Medical University Beijing Ophthalmology & Visual Sciences Key Laboratory Department of Rehabilitation Science The Hong Kong Polytechnic University Department of Anatomy Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulam The State Key Laboratory of Brain and Cognitive Sciences The University of Hong Kong Research Centre of Heart BrainHormone and Healthy AgingFaculty of MedicineThe University of Hong Kong Department of Ophthalmology Li Ka Shing Faculty of MedicineThe University of Hong KongPokfulam GMH Institute of Central Nervous System Regeneration Jinan University

Lycium barbarum is a widely used Chinese herbal medicine prescription for protection of optic ***,it remains unclear regarding the effects of Lycium barbarum polysaccharides,the main component of Lycium barbarum,on in vivo proliferation of adult ciliary body *** this study,adult rats were intragastrically administered low-and high-dose Lycium barbarum polysaccharides（1 and 10 mg/kg）for 35 days and those intragastrically administered phosphate buffered saline served as *** number of Ki-67-positive cells in rat ciliary body in the Lycium barbarum polysaccharides groups,in particular low-dose Lycium barbarum polysaccharides group,was significantly greater than that in the phosphate buffered saline ***-67-positive rat ciliary body cells expressed nestin but they did not express glial fibrillary acidic *** findings suggest that Lycium barbarum polysaccharides can promote the proliferation of adult rat retinal progenitor cells and the proliferated cells present with neuronal phenotype.

关键词： nerve regeneration traditional Chinese medicine Lycium barbarum polysaccharides Lycium barbarum (wolJberry) retinal disease neurogenesis adult neural regeneration