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Biochemical mechanisms of the RNA-induced silencing complex

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Cell Research 2007年第3期17卷 187-194页

作者： Zain Paroo~1 Qinghua Liu~1 Xiaodong Wang~(1,2) ~1department of biochemistry,~2Howard Hughes medical institute,university of texas southwestern medical center 5323 Harry Hines Blvd,dallas,TX 75390,USA department of biochemistry University of Texas Southwestern Medical Center Dallas USA Howard Hughes medical Institute University of Texas Southwestern Medical Center Dallas USA

In less than 10 years since its inception,RNA interference(RNAi)has had extraordinary impact on biomedical *** has been demonstrated to influence numerous biological and disease *** and adoptionof RNAi technologies have been prolific ranging from basic loss-of-function tools,genome-wide screening libraries topharmaceutical target validation and therapeutic ***,understanding of the molecular mechanismsof RNAi is far from *** purpose of this brief review is to highlight key achievements in elucidating the bio-chemical mechanisms of the RNA-induced silencing complex and to outline major challenges for the field.

关键词： Argonaute Dicer dsRBR RISC RNA interference

Design of synthetic materials for intracellular delivery of RNAs： From siRNA-mediated gene silencing to CRISPR/Cas gene editing

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Nano Research 2018年第10期11卷 5310-5337页

作者： Jason B. Miller Daniel J. Siegwart Simmons Comprehensive Cancer center University of Texas Southwestern Medical Center Dallas TX 75390 USA department of biochemistry University of Texas Southwestern Medical Center Dallas TX 75390 USA

Ribonucleic acids （RNAs） possess great therapeutic potential and can be used to treat a variety of diseases. The unique biophysical properties of RNAs, such as high molecular weight, negative charge, hydrophilicity, low stability, and potential immunogenicity, require chemical modification and development of carriers to enable intracellular delivery of RNAs for clinical use. A variety of nanornaterials have been developed for the effective in vivo delivery of short/ small RNAs, messenger RNAs, and RNAs required for gene editing technologies including clustered regularly interspaced palindromic repeat （CRISPR）/Cas. This review outlines the challenges of delivering RNA therapeutics, explores the chemical synthesis of RNA modifications and carriers, and describes the efforts to design nanomaterials that can be used for a variety of clinical indications.

关键词： nucleic acid therapeutics nanoparticles synthetic nanomaterials RNA interference (RNAi) messenger RNA (mRNA) clustered regularly inter-spaced palindromic repeat(CRISPR)/Cas

Crystal Structure of the MAP3K TAO2 Kinase Domain Bound by an Inhibitor Staurosporine

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Acta Biochimica et Biophysica Sinica 2006年第6期38卷 385-392页

作者： Elizabeth J.GOLDSMITH USA TX 75390-9038 department of biochemistry university of texas southwestern medical center at dallas

Mitogen-activated protein kinase (MAPK) signal transduction pathways are ubiquitous ineukaryotic cells,which transfer signals from the cell surface to the nucleus,controlling multiple *** are activated by MAPK kinases [MAP2Ks or MAP/extracellular signal-regulated kinase(ERK) kinases (MEK)],which in turn are activated by MAPK kinase kinases (MAP3Ks).TAO2 is a MAP3Klevel kinase that activates the MAP2Ks MEK3 and MEK6 to activate p38 *** p38 MAPKs arekey regulators of expression of inflammatory cytokines,they appear to be involved in human diseases suchas asthma and *** an upstream activator of p38s,TAO2 represents a potential drug *** we report the crystal structure of active TAO2 kinase domain in complex with staurosporine,a broad-range protein kinase inhibitor that inhibits TAO2 with an ICof 3 μ*** structure reveals that staurosporineoccupies the position where the adenosine of ATP binds in TAO2,and the binding of the inhibitor mimicsmany features of ATP *** polar and nonpolar interactions contribute to the *** induces conformational changes in TAO2 residues that surround the inhibitormolecule,but causes very limited global changes in the *** structure provides atomic details forTAO2-staurosporine interactions,and explains the relatively low potency of staurosporine against *** structure presented here should aid in the design of inhibitors specific to TAO2 and related kinases.

关键词： TAO2 MAP3K inhibitor staurosporine crystal structure

Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer's disease pathogenesis

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Science China(Life Sciences) 2011年第8期54卷 744-751页

作者： Charlene SUPNET Ilya BEZPROZVANNY department of Physiology University of Texas Southwestern Medical Center at Dallas

Alzheimer disease(AD) is the most common neurodegenerative disorder worldwide and is at present,*** accumulation of toxic amyloid-beta(Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline,an idea that underlies the'amyloid hypothesis'of AD etiology in both the familal(FAD) and sporadic forms of the *** mutations causing FAD also result in the dysregulation of neuronal calcium(Ca2+) handling and may contribute to AD pathogenesis,an idea termed the'calcium hypothesis'of *** in presenilin proteins account for majority of FAD *** function as catalytic subunit ofγ-secretase involved in generation of Aβ peptide Recently,we discovered that presenilns function as low-conductance,passive ER Ca2+ leak channels,independent of γ-secretase *** further discovered that many FAD mutations in presenilins result in loss of ER Ca2+ leak function activity and Ca2+ overload in the *** results provided potential explanation for abnormal Ca2+ signaling observed in FAD cells with mutations in *** latest work on studies of ER Ca2+ leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.

关键词： calcium signaling neurodegeneration presenilins Alzheimer's disease gamma-secretase amyloid

Apoer2/Lrp8:the undercover cop of synaptic homeostasis

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Neural Regeneration Research 2024年第12期19卷 2563-2564页

作者： Gordon C.Werthmann Joachim Herz department of Molecular Genetics and center for Translational Neurodegeneration Research University of Texas Southwestern Medical Center at DallasDallasTXUSA department of Neuroscience department of Neurology university of texas southwestern medical center at dallas DallasTXUSA

Apolipoprotein E receptor 2(ApoER2)is a receptor for the protein ApoE,the most common genetic risk factor for late-onset Alzheimer's disease(AD).It is also a key modulator of syna ptic homeostasis,in part through its effect on the expression of neuronal genes including those implicated in AD and other neuropsychiatric *** this perspective,we highlight several genes affected by ApoER2 and its alternatively spliced forms and how aberrant expression can be rescued by the reintroduction of the ApoER2 intracellular domain in the mouse hippocampus.

关键词： homeostasis ApoE Alzheimer

Von Hippel-Lindau tumor suppressor pathways&corresponding therapeutics in kidney cancer

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Journal of Genetics and Genomics 2021年第7期48卷 552-559页

作者： Maxwell Shulman Rachel Shi Qing Zhang department of Pathology University of Texas Southwestern Medical CenterDallasTXUSA

The identification and application of the Von Hippel-Lindau(VHL)gene is a seminal breakthrough in kidney cancer *** and its protein p VHL are the root cause of most kidney cancers,and the cascading pathway below them is crucial for understanding hypoxia,in addition to the aforementioned tumorigenesis routes and *** reviewed the history and functions of VHL/pVHL and Hypoxia-inducible factor(HIF),their well-known activities under low-oxygen environments as an E3 ubiquitin ligase and as a transcription factor,respectively,as well as their non-canonical functions revealed ***,we discussed how their dysregulation promotes tumorigenesis:beginning with chromosome 3 p-arm(3p)loss/epigenetic methylation,followed by two-allele knockout,before the loss of complimentary tumor suppressor genes leads cells down predictable oncological *** different pathways can ultimately determine the grade,outcome,and severity of the deadliest genitourinary *** finished by investigating current and proposed schemes to therapeutically treat clear cell renal cell carcinoma(cc RCC)by manipulating the hypoxic pathway utilizing Vascular Endothelial Growth Factor(VEGF)inhibitors,mammalian target of rapamycin complex 1(mTORC1)inhibitors,small molecule HIF inhibitors,immune checkpoint blockade therapy,and synthetic lethality.

关键词： VHL HIF ccRCC Kidney cancer Hypoxia

Cytokines that target immune killer cells against tumors

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Cellular & Molecular Immunology 2020年第7期17卷 722-727页

作者： Jian Qiao Yang-Xin Fu The department of Pathology University of Texas Southwestern Medical CenterDallasTX 75235USA

T-cell-stimulating cytokines have shown promise as monotherapies or in combination with other therapeutic modalities for immunotherapy of ***,their efficacy is limited due to their short half-life,pleiotropic roles,and induction of severe toxicity even at therapeutic *** overcome these major therapeutic barriers,cytokine-based products are being further developed to improve their therapeutic *** approaches include manipulating their activity to preferentially bind to effector immune cells rather than immune-suppressive cells,prolonging their half-life in vivo and modifying them to target *** review focuses on IL-2,IL-15,and IL-10,which have potent effects on immune cells that mediate effective antitumor *** will summarize the recent progress of these cytokines in both preclinical studies and selective clinical applications and will discuss our perspectives on the development of new strategies to potentiate cytokine-based immunotherapy.

关键词： IL-2 IL-15 IL-10 cytokine therapy cancer

Molecular mechanisms of cardiac aging

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Journal of Geriatric Cardiology 2010年第3期7卷 184-188页

作者： Tian-Jun Zhou Yan Gao department of biochemistry University of Texas Southwestern Medical Center at Dallas Dallas TX 75390-9038 USA

Age-associated changes in cardiovascular structure/ function are implicated in the markedly increased risk for cardiovascular disease in older persons. Aging not only prolongs exposure to several other cardiovascular risks, but also leads to intrinsic cardiac changes, which reduces cardiac functional reserve, predisposes the heart to stress and contributes to increased cardiovascular mortality in the elderly. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans, includ- ing left ventricular hypertrophy, fibrosis and diastolic dysfunction. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations, increased mitochondrial biogenesis, as well as decreased cardiac SERCA2 protein. All of these age-related changes are significantly attenu- ated in mice overexpressing catalase targeted to mitochondria （mCAT）. These findings demonstrate the critical role of rnitochondrial reactive oxygen species （ROS） in cardiac ag ing and support the potential antioxidants to cardiac aging lar diseases. application of mitochondrial and age-related cardiovascular diseases.

关键词： cardiac aging molecular mechanisms reactive oxygen species

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3063-3072页

作者： Yi Zhu Na Li Mingyang Huang Xi Chen Yu AAn Jianping Li Shangang Zhao Jan-Bernd Funck Jianhong Cao Zhenyan He Qingzhang Zhu Zhuzhen Zhang Zhao VWang Lin Xu Kevin W.Williams Chien Li Kevin Grove Philipp E.Scherer Touchstone Diabetes center Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Division of Cardiology Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Division of Hypothalamic Research Department of Internal Medicinethe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Quantitative Biomedical Research center Department of Population and Data Sciencesthe University of Texas Southwestern Medical Center at DallasDallasTX 75390USA department of Pediatrics the University of Texas Southwestern Medical Center at DallasDallasTX 75390USA Novo Nordisk Research center SeattleWA 98109USA Children’s Nutrition Research center Department of PediatricsBaylor College of MedicineHoustonTX 77030USA department of Cell Biology the University of Texas Southwestern Medical Center at DallasDallasTX 75390USA

Adipose tissue is a promising target for treating obesity and metabolic ***,pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization,especially in obese *** have previously shown that during cold exposure,connexin43(Cx43)gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple *** reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose *** an adipose tissue-specific Cx43 overexpression mouse model,we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of theβ_(3)-adrenergic receptor agonist Mirabegron and ***,combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced *** light of these findings,we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage ***,Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.

关键词： GJA1 Adipose tissue Gap junction Connexin43 FGF21 β3-Adrenergic receptor agonist Obesity Type 2 diabetes