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

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

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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

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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

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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

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Expression of the human TSPY gene in the brains of transgenic mice suggests a potential role of this Y chromosome gene in neural functions

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Journal of Genetics and Genomics 2011年第5期38卷 181-191页

作者： Tatsuo Kido Stephanie Schubert Jrg Schmidtke yun-fai chris lau Division of Cell and Developmental Genetics Department of MedicineVA Medical Centerand Institute for Human GeneticsUniversity of California Institute of Human Genetics Hannover Medical School

The testis specific protein Y-encoded （TSPY） is a member of TSPY/SET/NAP1 superfamily, encoded within the gonadoblastoma locus on the Y chromosome. TSPY shares a highly conserved SET/NAP-domain responsible for protein--protein interaction among TSPY/SET/NAP 1 proteins. Accumulating data, so far, support the role of TSPYas the gonadoblastoma gene, involved in germ cell tumorigenesis. The X-chromosome homolog of TSPY, TSPX is expressed in various tissues at both fetal and adult stages, including the brain, and is capable of interacting with the multi-domain adapter protein CASK, thereby influencing the synaptic and transcriptional functions and developmental regulation of CASK in the brain and other neural tissues. Similar to TSPX, we demonstrated that TSPY could interact with CASK at its SET/NAP-domain in cultured cells. Transgenic mice harboring a human TSPYgene and flanking sequences showed specific expression of the human TSPYtransgene in both testis and brain. The neural expression pattern of the human TSPYgene overlapped with those of the endogenous mouse Cask and Tspx gene. Similarly with TSPX, TSPY was co-localized with CASK in neuronal axon fibers in the brain, suggesting a potential role（s） of TSPY in development and/or physiology of the nervous system.

关键词： TSPY TSPX CASK Y chromosome Neuron Testis

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Developmental staging of male murine embryonic gonad by SAGE analysis

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Journal of Genetics and Genomics 2009年第4期36卷 215-227页

作者： Tin-Lap Lee yunmin Li Diana Alba Queenie R Vong Shao-Ming Wu Vanessa Baxendale Owen M. Rennert yun-fai chris lau Wai-Yee Chan Section on Developmental Genomics Laboratory of Clinical Genomics Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD 20892 USA Department of Medicine VA Medical Center University of California San Francisco CA 94121 USA Department of Pediatrics Biochemistry Molecular & Cellular Biology Georgetown University Washington DC 20007 USA

Despite the identification of key genes such as Sry integral to embryonic gonadal development, the genomic classification and identification of chromosomal activation of this process is still poorly understood. To better understand the genetic regulation of gonadal development, we performed Serial Analysis of Gene Expression （SAGE） to profile the genes and novel transcripts, and an average of 152,000 tags from male embryonic gonads at E10.5 （embryonic day 10.5）, E11.5, E12.5, E13.5, E15.5 and E17.5 were analyzed. A total of 275,583 non-singleton tags that do not map to any annotated sequence were identified in the six gonad libraries, and 47,255 tags were mapped to 24,975 annotated sequences, among which 987 sequences were uncharacterized. Utilizing an unsupervised pattern identification technique, we established molecular staging of male gonadal development. Rather than providing a static descriptive analysis, we developed algorithms to cluster the SAGE data and assign SAGE tags to a corresponding chromosomal position; these data are displayed in chromosome graphic format. A prominent increase in global genomic activity from E10.5 to E17.5 was observed. Important chromosomal regions related to the developmental processes were identified and validated based on established mouse models with developmental disorders. These regions may represent markers for early diagnosis for disorders of male gonad development as well as potential treatment targets.

关键词： SAGE transcriptome male gonads gene tag novel transcripts cluster analysis chromosome transcription hotspot

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Y染色体和雄性生殖细胞生物学在健康与疾病中的作用

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国外科技新书评介 2008年第9期 19-20页

作者： yun-fai chris lau 吴少伟不详北京大学公共卫生学院硕士

由人类基因组计划（Human Genome Project）所带来的人类基因组和相关研究技术方面的进步已经深刻地改变了我们对雄性干细胞发育和分化机制的理解，并提高了我们对此类机制进行研究的能力。本书对后基因组时代雄性生殖腺及干细胞研究所... 详细信息

由人类基因组计划（Human Genome Project）所带来的人类基因组和相关研究技术方面的进步已经深刻地改变了我们对雄性干细胞发育和分化机制的理解，并提高了我们对此类机制进行研究的能力。本书对后基因组时代雄性生殖腺及干细胞研究所取得的成果进行了总结，着重介绍了精子发生生物学的发展，试图建立一个干细胞发生模型，并对与基因在干细胞发生中的作用有关的一系列问题进行了阐述，主要内容包括Y染色体基因在雄性生殖中的作用、精原干细胞和雄性干细胞的基因表达及生殖过程和干细胞肿瘤中干细胞基因表达的调节等。

关键词：雄性生殖细胞生物学 Y染色体人类基因组计划精原干细胞疾病健康后基因组时代

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A prospective cohort of men with localized prostate cancer on active surveillance protocol in Hong Kong,China:what did we learn?

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Asian Journal of Andrology 2024年第3期26卷 245-249页

作者： Xiaobo Wu Ivan Ching-Ho Ko Cindy Yeuk-Lam Hong Samuel Chi-Hang Yee Jeremy Yuen-Chun Teoh Samson yun-Sang Chan Ho-Man Tam Chi-Kwok Chan Chi-fai Ng Peter Ka-Fung Chiu SH Ho Urology Centre Department of SurgeryFaculty of MedicineThe Chinese University of Hong KongHong KongChina

This study aimed to report the outcomes of active surveillance(AS)in the management of low-risk prostate cancer(PCa).It recruited87 men who were prospectively followed up according to the Prostate Cancer Research International Active Surveillance(PRIAS)protocol with local adaptation at SH Ho Urology Centre,Prince of Wales Hospital,Hong Kong,*** investigated the predictorsof disease progression and found that baseline prostate-specific antigen density(PSAD)and the presence of the highest ProstateImaging-Reporting and Data System(PI-RADS)score 5 lesion on magnetic resonance imaging(MRI)are significantly correlatedwith disease ***,men with PSAD>0.2 ng ml^(−2)or PI-RADS 4 or 5 lesions had significantly worse upgradingfree survival compared to those with PSAD≤0.2 ng ml−2 and PI-RADS 2 or 3 *** study concludes that AS is a safe andeffective management strategy for selected patients to defer radical treatment and that most disease progression can be detectedafter the first repeated *** combination of PSAD>0.2 ng ml^(−2)and PI-RADS 4 or 5 lesions may serve as a useful predictorof early disease progression and provide a guide to optimize follow-up protocols for men in different risk groups.

关键词： active surveillance cohort localized prostate cancer

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Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4028-4044页

作者： chris Chun-Yiu Chan Qian Guo Jasper Fuk-Woo Chan Kaiming Tang Jian-Piao Cai Kenn Ka-Heng Chik Yixin Huang Mei Dai Bo Qin Chon Phin Ong Allen Wing-Ho Chu Wan-Mui Chan Jonathan Daniel Ip Lei Wen Jessica Oi-Ling Tsang Tong-yun Wang Yubin Xie Zhenzhi Qin Jianli Cao Zi-Wei Ye Hin Chu Kelvin Kai-Wang To Xing-Yi Ge Tao Ni Dong-Yan Jin Sheng Cui Kwok-yung Yuen Shuofeng Yuan State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China Department of Infectious Diseases and Microbiology the University of Hong Kong-Shenzhen HospitalShenzhen 518000China Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong SAR 999077China Academician Workstation of Hainan Province Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesHaikou 571100China School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen Biology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China College of Biology Hunan Provincial Key Laboratory of Medical VirologyHunan UniversityChangsha 410082China

There are only eight approved small molecule antiviral drugs for treating *** them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous *** there is a dearth of new treatment options for *** this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 *** compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of *** studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in *** vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 ***,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-CoV-2 High throughput screening Broad-spectrum antiviral treatment 3CLpro inhibitor Allosteric-site inhibitor Animal models Chemical genetics Reverse genetics

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Coupling Enhancement of a Flexible BiFeO_(3) Film-Based Nanogenerator for Simultaneously Scavenging Light and Vibration Energies

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Nano-Micro Letters 2022年第12期14卷 137-150页

作者： Xiao Han yun Ji Li Wu Yanlong Xia chris RBowen Ya Yang CAS Center for Excellence in Nanoscience Beijing Key Laboratory of Micro-Nano Energy and SensorBeijing Institute of Nanoenergy and NanosystemsChinese Academy of SciencesBeijing 101400People’s Republic of China Department of Mechanical Engineering University of BathBath BA27AKUK School of Nanoscience and Technology University of Chinese Academy of SciencesBeijing 100049People’s Republic of China Center On Nanoenergy Research School of Physical Science and TechnologyGuangxi UniversityNanning 530004People’s Republic of China

Coupled nanogenerators have been a research hotspot due to their ability to harvest a variety of forms of energy such as light,mechanical and thermal energy and achieve a stable direct current *** films are frequently investigated for photovoltaic applications due to their unique photovoltaic properties and bandgap-independent photovoltage,while the flexoelectric effect is an electromechanical property commonly found in solid ***,we effectively construct a new form of coupled nanogenerator based on a flexible BiFeO_(3) ferroelectric film that combines both flexoelectric and photovoltaic effects to successfully harvest both light and vibration *** device converts an alternating current into a direct current and achieves a 6.2% charge enhancement and a 19.3%energy enhancement to achieve a multi-dimensional"1+1>2"coupling enhancement in terms of current,charge and *** work proposes a new approach to the coupling of multiple energy harvesting mechanisms in ferroelectric nanogenerators and provides a new strategy to enhance the transduction efficiency of flexible functional devices.

关键词： Ferroelectric film Coupled nanogenerators Photovoltaic effect Flexoelectric effect Energy collection

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