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From cell signaling to cancer therapy

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Acta Pharmacologica Sinica 2007年第9期28卷 1494-1498页

作者： Jin DING Yun FENG Hong-yang WANG The International Cooperation Laboratory on Signal Transduction,Eastern Hepatobiliary Surgery Institute,Second Military Medical University,Shanghai 200438,China The International Cooperation Laboratory on Signal Transduction EasternHepatobiliary Surgery InstituteSecond Military Medical UniversityShanghai 200438China

Cancer has been seriously threatening the health and life of humans for a *** the intensive effort put into revealing the underlying mechanismsof cancer,the detailled machinery of carcinogenesis is still far from fully *** studies have illustrated that cell signaling is extensively involved intumor initiation,promotion and ***,targeting the key mol-ecules in the oncogenic signaling pathway might be one of the most promisingways to conquer *** targeted drugs,such as imatinib mesylate (Gleevec),herceptin,gefitinib (Iressa),sorafenib (Nexavar) and sunitinib (Sutent),whichevolve from monotarget drug into multitarget ones,have been developed withencouraging effects.

关键词： cell signaling cancer therapy chemotherapy

PAQR family members in cell signaling and development

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PAQR family members in cell signaling and development

JAK/STAT signaling regulates tissue outgrowth and male germline stem cell fate in Drosophila

第三届细胞结构与功能的信号基础研讨会

作者：陈雁中国科学院上海生命科学学院营养研究所

Ras plays a pivotal role in many cellular activities and subcellular compartmentation of Ras as well as its downstream signaling components controls the information flow and output in the context of stimulus and cell ***,how Ras signaling is modulated by subcellular compartmentation at the Golgi apparatus as well as its physiological significance are largely *** we report a mode of spatial regulation of Ras signaling by two highly homologous proteins RasTG1 and RasTG2(Ras Trapping to Golgi 1 and 2) of the PAQR *** RasTGs are membrane proteins specifically localized at the Golgi *** interacts with HRas and NRas and mobilizes them onto the Golgi apparatus,in which Ras is activated in situ,leading to activation of MEK,ERK,and other downstream targets. RasTG also engages a guanine nucleotide exchange protein RasGRP1 onto the Golgi, contributing to the activation of Ras at the *** zebrafish,knockdown of RasTG2 leads to defects in the development of atrioventricular canal and formation of heart ***,MEK inhibitors and a dominant negative HRas can mimic RasTG2 knockdown in inducing cardiac developmental *** active HRas is able to rescue the cardiac defects caused by RasTG2 *** together,these data uncover a new paradigm of Ras signaling,whereby RasTG serves as an organelle-restricted protein that tethers Ras to the Golgi apparatus and such spatial regulation of Ras plays an important role in cardiac valve development.

关键词： cell signaling Ras MAPK heart development

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cell Research 2005年第1期15卷 1-5页

作者： Shree Ram SINGH,Steven X. HOU The Laboratory of Immunobiology National Institutes of Health National Cancer Institute at Frederick Frederick MD 21702 USA The Laboratory of Immunobiology National Institutes of Health National Cancer Institute at Frederick Frederick MD 21702 USA

In multicellular organisms, biological activities are regulated by cell signaling. The various signal transduction path- ways regulate cell fate, proliferation, migration, and polarity. Miscoordination of the communicative signals will lead to disasters like cancer and other fatal diseases. The JAK/STAT signal transduction pathway is one of the pathways, which was first identified in vertebrates and is highly conserved throughout evolution. Studying the JAK/STAT signal transduc- tion pathway in Drosophila provides an excellent opportunity to understand the molecular mechanism of the cell regu- lation during development and tumor formation. In this review, we discuss the general overview of JAK/STAT signaling in Drosophila with respect to its functions in the eye development and stem cell fate determination.

关键词： cell signaling JAK/STAT signal transduction pathway cell regulation Drosophila stem cell fate tissue outgrowth.

mTORC1 signaling:what we still don’t know

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Journal of Molecular cell Biology 2011年第4期3卷 206-220页

作者： Xuemin Wang Christopher G.Proud School of Biological Sciences Life Sciences BuildingUniversity of SouthamptonSouthampton SO171BJUK

The mammalian target of rapamycin(mTOR)is a protein kinase that plays key roles in cellular *** forms complexes with additional *** best-understood one is mTOR complex 1(mTORC1).The regulation and cellular functions of mTORC1 have been the subjects of intense study;despite this,many questions remain to be *** include questions about the actual mechanisms by which mTORC1 signaling is stimulated by hormones and growth factors,which involves the small GTPase Rheb,and by amino acids,which involves other GTPase *** control of Rheb and the mechanism by which it activates mTORC1 remain incompletely *** it has been known for many years that rapamycin interferes with some functions of mTORC1,it is not known how it does this,or why only some functions of mTORC1 are ***1 regulates diverse cellular *** mTORC1 substrates are now known,although in several cases their physiological roles are poorly or incompletely *** the case of several processes,although it is clear that they are regulated by mTORC1,it is not known how mTORC1 does ***,mTORC1 is implicated in ageing,but again it is unclear what mechanisms account for *** the importance of mTORC1 signaling both for cellular functions and in human disease,it is a high priority to gain further insights into the control of mTORC1 signaling and the mechanisms by which it controls cellular functions and animal physiology.

关键词： mTORC1 protein synthesis cell signaling transcription cell growth autophagy metabolism

Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling

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Neural Regeneration Research 2022年第6期17卷 1172-1182页

作者： Bart Nieuwenhuis Richard Eva John van Geest Center for Brain Repair Department of Clinical NeurosciencesUniversity of CambridgeCambridgeUK

Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous *** in the central nervous system fail to regenerate,meaning that injuries or diseases that cause loss of axonal connectivity have life-changing *** 2008,genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic *** is a phosphatase that opposes the actions of PI3-kinase,a family of enzymes that function to generate the membrane phospholipid PIP_(3) from PIP_(2)(phosphatidylinositol(3,4,5)-trisphosphate from phosphatidylinositol(4,5)-bisphosphate).Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase,and was initially demonstrated to promote axon regeneration by signaling through *** recently,additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative *** review describes neuronal signaling pathways downstream of PI3-kinase and PIP3,and considers them in relation to both developmental and regenerative axon *** briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability,and describe how these are affected by signaling through *** highlight the recent finding of a developmental decline in the generation of PIP_(3) as a key reason for regenerative failure,and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous ***,we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.

关键词： axon cytoskeleton axon regeneration axon transport cell signaling central nervous system growth cone neuroprotection PI3-kinase PI3K PTEN trafficking transcription translation

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Adiponectin signaling and function in insulin target tissues

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Journal of Molecular cell Biology 2016年第2期8卷 101-109页

作者： Hong Ruan Lily Q.Dong Department of Pharmacology University of Texas Health Science Center at San Antonio7703 Floyd Curl DriveSan AntonioTX 78229USA Department of cell and Structural Biology University of Texas Health Science Center at San Antonio7703 Floyd Curl DriveSan AntonioTX 78229USA

Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide,posing a major threat on human health,productivity,and quality of *** great progressmadetowards a better understanding of the molecular basis of diabetes,the available clinical counter-measures against insulin resistance,a defect that is central to obesity-linked type 2 diabetes,remain ***,an abundant adipocyte-secreted factor with a wide-range of biological activities,improves insulin sensitivity in major insulin target tissues,modulates inflammatory responses,and plays a crucial role in the regulation of energy ***,adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention,and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation,and reveal therapeutic ***,we discuss tissue-and cell-specific functions of adiponectin,with an emphasis on the regulation of adiponectin signaling pathways,and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic *** better just why and how adiponectin and its downstream effector molecules work will be essential,together with empirical trials,to guide us to therapies that target the root cause(s)of type 2 diabetes and insulin resistance.

关键词： adiponectin insulin resistance cell signaling APPL1 APPL2 adiponectin receptor

Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells

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Cancer Communications 2021年第12期41卷 1275-1313页

作者： Valdenizia R.Silva Luciano de S.Santos Rosane B.Dias Claudio A.Quadros Daniel P.Bezerra Gonçalo Moniz Institute Oswaldo Cruz Foundation(IGM-FIOCRUZ/BA)SalvadorBahia 40296-710Brazil São Rafael Hospital Rede D’Or/São LuizSalvadorBahia 41253-190Brazil Bahia State University SalvadorBahia 41150-000Brazil

Colorectal cancer(CRC)represents the third most commonly diagnosed cancer and the second leading cause of cancer death *** modern concept of cancer biology indicates that cancer is formed of a small population of cells called cancer stem cells(CSCs),which present both pluripotency and self-renewal *** cells are considered responsible for the progression of the disease,recurrence and tumor ***,some cell signaling pathways participate in CRC survival,proliferation,and selfrenewal properties,and most of them are dysregulated in CSCs,including the Wingless(Wnt)/β-catenin,Notch,Hedgehog,nuclear factor kappa B(NF-κB),Janus kinase/signal transducer and activator of transcription(JAK/STAT),peroxisome proliferator-activated receptor(PPAR),phosphatidyl-inositol-3-kinase/Akt/mechanistic target of rapamycin(PI3K/Akt/mTOR),and transforming growth factor-β(TGF-β)/Smad *** this review,we summarize the strategies for eradicating CRC stem cells by modulating these dysregulated pathways,which will contribute to the study of potential therapeutic schemes,combining conventional drugs with CSC-targeting drugs,and allowing better cure rates in anti-CRC therapy.

关键词： colorectal cancer stem cells cell signaling Wnt/β-catenin pathway Notch Hedgehog NF-κB JAK/STAT signaling PI3K/Akt/mTOR signaling targeted therapy

DNA origami nanodevice with spatial regulation of CD95 signaling for rheumatoid arthritis treatment

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3777-3779页

作者： Miao Mao Zhe Pu Yuanqing Zhang School of Pharmaceutical Sciences Sun Yat-Sen UniversityGuangzhou 510006China

Recently,a work jointly studied by Ling Li and coworkers1 was published in Nature Materials,describing a reconfigurable DNA origami nanodevice designed to regulate CD95 death-inducing signaling of immune *** researchers utilized the DNA origami nanodevice to establish selective local immune tolerance and demonstrated its ability to alleviate rheumatoid arthritis(RA)in the inflamed synovial tissue of mice without causing any obvious side effects(Fig.1).This approach presents a novel idea for the development of drug interventions involving ligandreceptor interactions.

关键词： DNA origami Rheumatoid arthritis CD95 death-inducing signaling DNA nanostructure Drug delivery Receptoreligand interaction cell signaling Drug intervention

Conformational dynamics in GPCR signaling by NMR

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Magnetic Resonance Letters 2022年第3期2卷 139-146页

作者： Yunfei Hu Changwen Jin Joint Laboratory of the National Centers for Magnetic Resonance in Wuhan and in Beijing Wuhan430071China Beijing Nuclear Magnetic Resonance Center College of Chemistry and Molecular EngineeringPeking UniversityBeijing100871China State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics National Center for Magnetic Resonance in WuhanKey Laboratory of Magnetic Resonance in Biological SystemsInnovation Academy for Precision Measurement Science and TechnologyChinese Academy of SciencesWuhan430071China

G-protein-coupled receptors(GPCRs)mediate a wide range of cellular responses to various ligands or stimuli,and are the most important drug targets associated with human *** major advances in GPCR structural biology have greatly deepened our understanding of its activation mechanism,the highly complex changes in the structural dynamics of GPCRs during activation remain underdetermined and their links to physiological functions largely *** nuclear magnetic resonance(NMR)spectroscopy is an essential technique that allows the characterization of protein structural dynamics at atomic level,and has been applied in the studies of GPCR structural-function relationship in the past ***,we summarize a few specific studies in which solution NMR methods were employed and provided novel insights into questions difficult to be addressed by other methods.

关键词： G-protein-coupled receptor(GPCR) Membrane protein Dynamics Nuclear magnetic resonance(NMR) cell signaling

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