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Y. Peng Loh - One of the best experts on this subject based on the ideXlab platform.

  • NEurotrophic, GEnE REgulation, and CognitivE Functions of CarboxypEptidasE E-NEurotrophic Factor-α1 and Its Variants.
    Frontiers in neuroscience, 2019
    Co-Authors: Lan Xiao, Xuyu Yang, Y. Peng Loh
    Abstract:

    CarboxypEptidasE E, also known as nEurotrophic factor-α1 (CPE-NFα1), was first discovErEd as an ExopEptidasE and is known to work by clEaving C-tErminal basic amino acids from prohormonE intErmEdiatEs to producE maturE pEptidE hormonEs and nEuropEptidEs in thE EndocrinE and cEntral nErvous systEms, rEspEctivEly. CPE-NFα1 also plays a critical rolE in prohormonE sorting and sEcrEtory vEsiclE transportation. REcEntly, EmErging studiEs havE indicatEd that CPE-NFα1 ExErts multiplE non-Enzymatic physiological rolEs in maintaining normal cEntral nErvous systEm function and in nEurodEvElopmEnt. This includEs potEnt nEuroprotEctivE and anti-dEprEssant activitiEs, as wEll as stEm cEll diffErEntiation functions. In addition, N-tErminal truncatEd variants of CPE-NFα1 havE bEEn idEntifiEd to rEgulatE ExprEssion of important nEurodEvElopmEntal gEnEs. This mini-rEviEw summarizEs rEcEnt advancEs in undErstanding thE mEchanisms undErlying CPE-NFα1's function in nEuroprotEction during strEss and aspEcts of nEurodEvElopmEnt.

  • Cloning, gEnE rEgulation, and nEuronal prolifEration functions of novEl N-tErminal-truncatEd CarboxypEptidasE E/nEurotrophic factor-αl variants in Embryonic mousE brain.
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2018
    Co-Authors: Lan Xiao, Xuyu Yang, Vinay Kumar Sharma, Y. Peng Loh
    Abstract:

    CarboxypEptidasE E (CPE), an ExopEptidasE involvEd in pronEuropEptidE procEssing, is also a nEurotrophic factor, namEd nEurotrophic factor-α1 (NF-α1) and has important rolEs in nEuroprotEction, stEm cEll diffErEntiation, and nEuritE outgrowth, indEpEndEnt of Enzymatic activity. Additionally, an N-tErminal-truncatEd CPE/NF-α1 variant, (CPE/NF-α1)-ΔN, proposEd from bioinformatic analysis of GEnBank (National CEntEr for BiotEchnology Information, BEthEsda, MD, USA) DNA sEquEncEs and Encoding a 40-kDa protEin, has bEEn found to bE ExclusivEly ExprEssEd in Embryonic nEurons. To invEstigatE thE function of (CPE/NF-α1)-ΔN in nEurodEvElopmEnt, wE first clonEd (CPE/NF-α1)-ΔN transcripts from an Embryonic mousE brain. A rapid amplification of cDNA Ends assay, DNA sEquEncing, and NorthErn blot rEvEalEd 1.9- and 1.73-kb transcripts, which EncodEd 47- and 40-kDa (CPE/NF-α1)-ΔN protEins, rEspEctivEly. ThosE protEins wErE ExprEssEd in Embryonic mousE brain. ExprEssion of thE 2 (CPE/NF-α1)-ΔN mRNAs surgEd at Embryonic d 10.5, corrElating with thE timE of nEurogEnEsis in thE dEvEloping brain and also at postnatal d 1. HT22 cElls, a mousE hippocampal cEll linE, transducEd with 40 kDa (CPE/NF-α1)-ΔN up-rEgulatEd ExprEssion of gEnEs involvEd in Embryonic nEurodEvElopmEnt: insulin-likE growth factor binding protEin 2 ( IGFBP2), dEath-associatEd protEin 1, and Ephrin A1, which rEgulatE prolifEration, programmEd cEll dEath, and nEuronal migration, rEspEctivEly. HT22 cElls and Embryonic cortical nEurons ovErExprEssing 40 kDa (CPE/NF-α1)-ΔN ExhibitEd EnhancEd prolifEration, which was inhibitEd by IGFBP2 short intErfEring RNA trEatmEnt. Thus, 40 kDa (CPE/NF-α1)-ΔN has an important, Enzymatically indEpEndEnt rolE in thE rEgulation of gEnEs critical for nEurodEvElopmEnt.-Xiao, L., Yang, X., Sharma, V. K., Loh, Y. P. Cloning, gEnE rEgulation, and nEuronal prolifEration functions of novEl N-tErminal-truncatEd CarboxypEptidasE E/nEurotrophic factor-αl variants in Embryonic mousE brain.

  • CarboxypEptidasE E is a prEdiction markEr for tumor rEcurrEncE in Early-stagE hEpatocEllular carcinoma.
    Tumor Biology, 2016
    Co-Authors: Shiu-feng Huang, Saravana R. K. Murthy, Xuyu Yang, Ya-ting Chen, Yu-ting Chiu, Yu Chang, Il-chi Chang, Y. Peng Loh
    Abstract:

    Tumor rEcurrEncE and mEtastasis arE thE major causEs of dEath for hEpatocEllular carcinoma (HCC) patiEnts who arE ablE to rEcEivE curativE rEsEction. IdEntifying thE prEdicting biomarkErs for tumor rEcurrEncE would improvE thEir survival. RNA ExtractEd from frEsh frozEn tumors and adjacEnt non-tumor livEr tissuEs of 120 HCC patiEnts wErE obtainEd from Taiwan LivEr CancEr NEtwork (TLCN) in yEar 2010 for dEtErmination of thE CarboxypEptidasE E (CPE) ExprEssion lEvEl (including its splicing mutant CPE-ΔN) in thE tumor tissuE (T) and pairEd non-tumor livEr tissuE (N) by rEal-timE quantitativE polymErasE chain rEaction. All patiEnts wErE malE, had chronic hEpatitis B virus infEction, wErE in thE Early pathology stagE, and rEcEivEd curativE rEsEction. ThE T/N ratio of thE CPE ExprEssion lEvEl was corrElatEd with thE updatEd survival data from TLCN in 2015. ThE CPE ExprEssion lEvEl in thE 120 HCC patiEnts was dividEd into thrEE groups according to thE T/N ratio: 2, rEspEctivEly. By multivariatE analysEs, thE rEcurrEncE-frEE survival (RFS) was only significantly associatEd with thE pathology stagE and thE CPE ExprEssion lEvEl. For ovErall survival (OS), only thE CPE ExprEssion lEvEl was thE significant prognostic factor. ThE CPE ExprEssion lEvEl was also significantly corrElatEd with thE tumor rEcurrEncE for both stagE I (p = 0.0106) and stagE II patiEnts (p = 0.0006). ThE CPE mRNA ExprEssion lEvEl in HCC can bE a usEful biomarkEr for prEdicting tumor rEcurrEncE in HCC patiEnts who arE in thE Early pathology stagE and ablE to rEcEivE curativE rEsEction.

  • CarboxypEptidasE E promotEs cancEr cEll survival, but inhibits migration and invasion
    Cancer letters, 2013
    Co-Authors: Saravana R. K. Murthy, Niamh X. Cawley, Evan Dupart, Najla Al-sweel, Alexander Chen, Y. Peng Loh
    Abstract:

    CarboxypEptidasE E (CPE), a prohormonE procEssing EnzymE is highly ExprEssEd and sEcrEtEd from (nEuro)EndocrinE tumors and gliomas, and has bEEn implicatEd in cancEr progrEssion by promoting tumor growth. Our study dEmonstratEs that sEcrEtEd or ExogEnously appliEd CPE promotEs survival of phEochromocytoma (PC12) and hEpatocEllular carcinoma (MHCC97H) cElls undEr nutriEnt starvation and hypoxic conditions, but had no EffEct on thEir prolifEration. CPE also rEducEd migration and invasion of fibrosarcoma (HT1080) cElls. WE show that CPE trEatmEnt mEdiatEs survival of MHCC97H cElls during mEtabolic strEss by up-rEgulating thE ExprEssion of anti-apoptotic protEin BCL-2, and othEr pro-survival gEnEs, via activation of thE ERK1/2 pathway.

  • CarboxypEptidasE E: ElEvatEd ExprEssion corrElatEd with tumor growth and mEtastasis in phEochromocytomas and othEr cancErs.
    Cellular and molecular neurobiology, 2010
    Co-Authors: Saravana R. K. Murthy, Karel Pacak, Y. Peng Loh
    Abstract:

    ExprEssion of CarboxypEptidasE E (CPE), a prohormonE procEssing EnzymE in diffErEnt cancEr typEs, was analyzEd from data in thE GEO profilE databasE (http://www.ncbi.nlm.nih.gov/gEo/) and ExpErimEntally in phEochromocytomas. Analysis of microarray data dEmonstratEd that significantly ElEvatEd lEvEls of CPE mRNA was found in many mEtastatic non-EndocrinE cancErs: cErvical, colon rEctal, rEnal cancErs, Ewing sarcomas (bonE cancEr), and various typEs of astrocytomas and oligodEndrogliomas, whErEas ExprEssion of CPE mRNA was virtually absEnt in thEir rEspEctivE countErpart normal tissuEs. MorEovEr, thErE was highEr CPE mRNA ExprEssion in cElls from thE mEtastatic tumor comparEd to thosE from thE primary tumor in colorEctal cancEr. ElEvatEd CPE mRNA ExprEssion was found in nEuroEndocrinE tumors in lung and pituitary adEnomas, although thE significancE is unclEar sincE EndocrinE and nEuroEndocrinE cElls normally ExprEss CPE. HowEvEr, studiEs of nEuroEndocrinE tumors, phEochromocytomas, rEvEalEd ExprEssion of not only wild-typE CPE, but a variant which was corrElatEd with tumor bEhavior. ExtrEmEly high CPE mRNA copy numbErs of thE variant wErE found in vEry largE or invasivE tumors, both of which usually indicatE poor prognosis. Thus, collEctivEly thE data suggEst that CPE may play a rolE in promoting tumor growth and invasion. CPE could potEntially sErvE as a diagnostic and prognostic biomarkEr for mEtastasis in diffErEnt cancEr typEs.

Lloyd D. Fricker - One of the best experts on this subject based on the ideXlab platform.

  • Affinity Purification of NEuropEptidE PrEcursors from MicE Lacking CarboxypEptidasE E Activity.
    Methods in molecular biology (Clifton N.J.), 2018
    Co-Authors: Lloyd D. Fricker
    Abstract:

    PEptidomic tEchniquEs arE powErful tools to idEntify pEptidEs in a biological samplE. This protocol dEscribEs a targEtEd pEptidomic approach that usEs affinity chromatography to purify pEptidEs that arE substratEs of CarboxypEptidasE E (CPE), an EnzymE prEsEnt in thE sEcrEtory pathway of nEuroEndocrinE cElls. Many CPE products function as nEuropEptidEs and/or pEptidE hormonEs, and thErEforE rEprEsEnt an important subsEt of thE pEptidomE. BEcausE CPE rEmovEs C-tErminal Lys and Arg rEsiduEs from pEptidE-procEssing intErmEdiatEs, organisms lacking CPE show a largE dEcrEasE in thE lEvEls of thE maturE forms of most nEuropEptidEs and pEptidE hormonEs, and a vEry largE incrEasE in thE lEvEls of thE procEssing intErmEdiatEs that contain C-tErminal Lys and/or Arg (i.E., thE CPE substratEs). ThEsE CPE substratEs can bE purifiEd on an anhydrotrypsin-agarosE affinity rEsin, which spEcifically binds pEptidEs with C-tErminal basic rEsiduEs. Not all pEptidEs with basic C-tErminal rEsiduEs within a cEll arE CPE substratEs, and thEsE othEr pEptidEs will also bE purifiEd on thE anhydrotrypsin affinity column. HowEvEr, a comparison of pEptidEs purifiEd from wild-typE micE and from micE lacking CPE allows for thE rapid idEntification of CPE substratEs basEd on thEir largE incrEasE in thE absEncE of CPE.

  • CarboxypEptidasE E and thE IdEntification of NovEl NEuropEptidEs as PotEntial ThErapEutic TargEts.
    Advances in pharmacology (San Diego Calif.), 2017
    Co-Authors: Lloyd D. Fricker
    Abstract:

    PEptidEs and small molEculEs that bind to pEptidE rEcEptors arE important classEs of drugs that arE usEd for a widE variEty of diffErEnt applications. ThE sEarch for novEl nEuropEptidEs traditionally involvEd a timE-consuming approach to purify Each pEptidE to homogEnEity and dEtErminE its amino acid sEquEncE. ThE discovEry in thE 1980s of EnkEphalin convErtasE/CarboxypEptidasE E (CPE), and thE obsErvation that this EnzymE was involvEd in thE production of nEarly EvEry known nEuropEptidE lEd to thE idEa for a onE-stEp affinity purification of CPE substratEs. This approach was succEssfully usEd to isolatE hundrEds of known nEuropEptidEs in mousE brain, as wEll as ovEr a dozEn novEl pEptidEs. SomE of thE novEl pEptidEs found using this approach arE among thE most abundant pEptidEs prEsEnt in brain, but had not bEEn prEviously idEntifiEd by traditional approachEs. REcEntly, rEcEptors for two of thE novEl pEptidEs havE bEEn idEntifiEd, confirming thEir rolE as nEuropEptidEs that function in cEll-cEll signaling. Small molEculEs that bind to onE of thEsE rEcEptors havE bEEn dEvElopEd and found to significantly rEducE food intakE and anxiEty-likE bEhavior in an animal modEl. This rEviEw dEscribEs thE EntirE projEct, from discovEry of CPE to thE novEl pEptidEs and thEir rEcEptors.

  • 248 – CarboxypEptidasE E
    Handbook of Proteolytic Enzymes, 2004
    Co-Authors: Lloyd D. Fricker
    Abstract:

    PublishEr Summary This chaptEr ExaminEs activity, spEcificity and structural chEmistry of CarboxypEptidasE E (CPE). CPE rEmovEs C-tErminal basic rEsiduEs from a variEty of substratEs, with no dEtEctablE activity towards nonbasic rEsiduEs. All rEsiduEs arE tolEratEd in thE PI position, although thE Pro–Arg bond is clEavEd sEvEral ordErs of magnitudE morE slowly than substratEs with othEr rEsiduEs in PI. Amongst N-tErminally blockEd small pEptidEs, CPE shows lowEr activity with dipEptidEs than with tri- or tEtrapEptidEs. ThE optimal pH for CPE activity is 5.0–5.5, and activity falls off dramatically with incrEasing pH. ThE sEnsitivity of CPE to pH ovEr thE rangE 5.5–7 may sErvE as a mEchanism to kEEp CPE inactivE in thE Golgi and allow for thE activation of CPE in maturE sEcrEtory vEsiclEs. As found with othEr mEtalloCarboxypEptidasEs, CPE is stimulatEd by millimolar concEntrations of Co2+ and inhibitEd by 1,10-phEnanthrolinE. CPE is potEntly inhibitEd by somE thiol-dirEctEd rEagEnts. CPE is a singlE-chain protEin of 52–56 kDa, with a pi around 5. It is likEly that CPE contains lmol of zinc pEr mol of protEin basEd on thE homology bEtwEEn CPE and othEr mEtalloCarboxypEptidasEs.

  • 248 CarboxypEptidasE E
    Handbook of Proteolytic Enzymes (Second Edition)#R##N#Aspartic and Metallo Peptidases, 2004
    Co-Authors: Lloyd D. Fricker
    Abstract:

    PublishEr Summary This chaptEr ExaminEs activity, spEcificity and structural chEmistry of CarboxypEptidasE E (CPE). CPE rEmovEs C-tErminal basic rEsiduEs from a variEty of substratEs, with no dEtEctablE activity towards nonbasic rEsiduEs. All rEsiduEs arE tolEratEd in thE PI position, although thE Pro–Arg bond is clEavEd sEvEral ordErs of magnitudE morE slowly than substratEs with othEr rEsiduEs in PI. Amongst N-tErminally blockEd small pEptidEs, CPE shows lowEr activity with dipEptidEs than with tri- or tEtrapEptidEs. ThE optimal pH for CPE activity is 5.0–5.5, and activity falls off dramatically with incrEasing pH. ThE sEnsitivity of CPE to pH ovEr thE rangE 5.5–7 may sErvE as a mEchanism to kEEp CPE inactivE in thE Golgi and allow for thE activation of CPE in maturE sEcrEtory vEsiclEs. As found with othEr mEtalloCarboxypEptidasEs, CPE is stimulatEd by millimolar concEntrations of Co2+ and inhibitEd by 1,10-phEnanthrolinE. CPE is potEntly inhibitEd by somE thiol-dirEctEd rEagEnts. CPE is a singlE-chain protEin of 52–56 kDa, with a pi around 5. It is likEly that CPE contains lmol of zinc pEr mol of protEin basEd on thE homology bEtwEEn CPE and othEr mEtalloCarboxypEptidasEs.

  • ProcEssing of proCarboxypEptidasE E into CarboxypEptidasE E occurs in sEcrEtory vEsiclEs.
    Journal of neurochemistry, 2002
    Co-Authors: Lixin Song, Lloyd D. Fricker
    Abstract:

    CarboxypEptidasE E (CPE) functions in thE posttranslational procEssing of bioactivE pEptidEs. LikE othEr pEptidE procEssing EnzymEs, CPE is initially producEd as a prEcursor ("proCPE") that undErgoEs posttranslational procEssing at a sitE containing fivE adjacEnt Arg rEsiduEs nEar thE N-tErminus and at othEr sitEs nEar thE C-tErminus of proCPE. ThE timE coursE of thE N-tErminal procEssing stEp suggEsts that this convErsion occurs in EithEr thE Golgi apparatus or thE sEcrEtory vEsiclEs. To dElinEatE furthEr thE sitE of proCPE procEssing, pulsE/chasE analysis was pErformEd undEr conditions that block transit out of thE Golgi apparatus (brEfEldin A, carbonyl cyanidE m-chlorophEnylhydrazonE, or 20 dEgrEEs C) or that block acidification of vEsiclEs (chloroquinE, monEnsin, or ammonium chloridE). ThE rEsults of thEsE analysis suggEst that EfficiEnt proCPE procEssing rEquirEs an acidic post-Golgi compartmEnt. To tEst whEthEr known procEssing EnzymEs can pErform this clEavagE, purifiEd proCPE was incubatEd with furin, prohormonE convErtasE 1, or a dynorphin convErting EnzymE, and thE products wErE analyzEd on dEnaturing polyacrylamidE gEls. Furin clEavEs proCPE within thE N-tErminal rEgion, although thE rEaction is not vEry EfficiEnt, rEquiring rElativEly largE amounts of furin or long incubation timEs. ThE othEr two pEptidE procEssing EnzymEs did not clEavE proCPE, whErEas a rElativEly small amount of sEcrEtory granulE Extract was ablE to convErt proCPE into CPE. TakEn togEthEr, thEsE findings suggEst that thE convErsion of proCPE into CPE occurs primarily in sEcrEtory vEsiclEs.

Niamh X. Cawley - One of the best experts on this subject based on the ideXlab platform.

  • CarboxypEptidasE E nf α1 a nEw trophic factor in nEuroprotEction
    Neuroscience Bulletin, 2014
    Co-Authors: Yong Cheng, Niamh X. Cawley
    Abstract:

    CarboxypEptidasE E (CPE) is a prohormonE-procEssing EnzymE and sorting rEcEptor that functions intracEllularly. HowEvEr, rEcEnt studiEs havE dEmonstratEd that CPE acts as a trophic factor ExtracEllularly to up-rEgulatE thE ExprEssion of a pro-survival gEnE. This mini-rEviEw summarizEs thE rolEs of CPE in nEuroprotEction and thE implications for nEurodEgEnErativE disEasEs.

  • CarboxypEptidasE E promotEs cancEr cEll survival, but inhibits migration and invasion
    Cancer letters, 2013
    Co-Authors: Saravana R. K. Murthy, Niamh X. Cawley, Evan Dupart, Najla Al-sweel, Alexander Chen, Y. Peng Loh
    Abstract:

    CarboxypEptidasE E (CPE), a prohormonE procEssing EnzymE is highly ExprEssEd and sEcrEtEd from (nEuro)EndocrinE tumors and gliomas, and has bEEn implicatEd in cancEr progrEssion by promoting tumor growth. Our study dEmonstratEs that sEcrEtEd or ExogEnously appliEd CPE promotEs survival of phEochromocytoma (PC12) and hEpatocEllular carcinoma (MHCC97H) cElls undEr nutriEnt starvation and hypoxic conditions, but had no EffEct on thEir prolifEration. CPE also rEducEd migration and invasion of fibrosarcoma (HT1080) cElls. WE show that CPE trEatmEnt mEdiatEs survival of MHCC97H cElls during mEtabolic strEss by up-rEgulating thE ExprEssion of anti-apoptotic protEin BCL-2, and othEr pro-survival gEnEs, via activation of thE ERK1/2 pathway.

  • CarboxypEptidasE E ProtEcts Hippocampal NEurons During StrEss in MalE MicE by Up-rEgulating Pro-survival BCL2 ProtEin ExprEssion
    Endocrinology, 2013
    Co-Authors: Saravana R. K. Murthy, Niamh X. Cawley, Yong Cheng, E. Thouennon, Jenny Bhupatkar, Malcolm V. Lane, Istvan Merchenthaler, Yoke Peng Loh
    Abstract:

    ProlongEd chronic strEss causing ElEvatEd plasma glucocorticoids lEads to nEurodEgEnEration. Adaptation to strEss (allostasis) through nEuroprotEctivE mEchanisms can dElay this procEss. StudiEs on hippocampal nEurons havE idEntifiEd CarboxypEptidasE E (CPE) as a novEl nEuroprotEctivE protEin that acts ExtracEllularly, indEpEndEnt of its Enzymatic activity, although thE mEchanism of action is unclEar. HErE, wE aim to dEtErminE if CPE plays a nEuroprotEctivE rolE in allostasis in mousE hippocampus during chronic rEstraint strEss (CRS), and thE molEcular mEchanisms involvEd. QuantitativE RT-PCR/in situ hybridization and WEstErn blots wErE usEd to assay for mRNA and protEin. AftEr mild CRS (1 h/d for 7 d), CPE protEin and mRNA wErE significantly ElEvatEd in thE hippocampal CA3 rEgion, comparEd to naivE littErmatEs. In addition, lucifErasE rEportEr assays idEntifiEd a functional glucocorticoid rEgulatory ElEmEnt within thE cpE promotEr that mEdiatEd thE up-rEgulation of CPE ExprEssion in primary hippocampal nE...

  • nEw rolEs of CarboxypEptidasE E in EndocrinE and nEural function and cancEr
    Endocrine Reviews, 2012
    Co-Authors: Niamh X. Cawley, Joshua J. Park, William C Wetsel, Saravana R K Murthy, Saravana R. K. Murthy, Karel Pacak
    Abstract:

    CarboxypEptidasE E (CPE) or CarboxypEptidasE H was first discovErEd in 1982 as an EnkEphalin-convErtasE that clEavEd a C-tErminal basic rEsiduE from EnkEphalin prEcursors to gEnEratE EnkEphalin. SincE thEn, CPE has bEEn shown to bE a multifunctional protEin that subsErvEs many EssEntial nonEnzymatic rolEs in thE EndocrinE and nErvous systEms. HErE, wE rEviEw thE phylogEny, structurE, and function of CPE in hormonE and nEuropEptidE sorting and vEsiclE transport for sEcrEtion, altErnativE splicing of thE CPE transcript, and singlE nuclEotidE polymorphisms in humans. With this and thE analysis of mutant and knockout micE, thE data collEctivEly support important rolEs for CPE in thE modulation of mEtabolic and glucosE homEostasis, bonE rEmodEling, obEsity, fErtility, nEuroprotEction, strEss, sExual bEhavior, mood and Emotional rEsponsEs, lEarning, and mEmory. REcEntly, a splicE variant form of CPE has bEEn found to bE an inducEr of tumor growth and mEtastasis and a prognostic biomarkEr for mEtastasis in Endoc...

  • ObEsE CarboxypEptidasE E knockout micE Exhibit multiplE dEfEcts in pEptidE hormonE procEssing contributing to low bonE minEral dEnsity
    American journal of physiology. Endocrinology and metabolism, 2010
    Co-Authors: Niamh X. Cawley, Tulin Yanik, Alicja Woronowicz, Weizhong Chang, Joan C. Marini, Y. Peng Loh
    Abstract:

    CarboxypEptidasE E (CPE) is a prohormonE/pronEuropEptidE procEssing EnzymE, and micE bEaring CPE mutations Exhibit an obEsE and diabEtic phEnotypE. StudiEs on CPE knockout (KO) micE rEvEalEd poor p...

Lars-inge Larsson - One of the best experts on this subject based on the ideXlab platform.

  • CarboxypEptidasE E in rat antropyloric mucosa: distribution in progEnitor and maturE EndocrinE cEll typEs
    Histochemistry and Cell Biology, 2004
    Co-Authors: David M. Hougaard, Lars-inge Larsson
    Abstract:

    ProcEssing of most gut hormonEs involvEs clEavagE bEtwEEn dibasic amino acids followEd by CarboxypEptidasE-catalyzEd rEmoval of thE COOH-tErminal basic rEsiduE, rEsulting in pEptidEs with a COOH-tErminal glycinE. Such pEptidEs may subsEquEntly bE convErtEd to amidatEd pEptidEs or can bE dirEctly sEcrEtEd. It is bEliEvEd that CarboxypEptidasE E (CPE) is involvEd in gut hormonE procEssing but its prEsEncE in gut EndocrinE cElls has nEvEr bEEn studiEd. WE havE analyzEd thE distribution of CPE in thE antropyloric mucosa of rat stomach and rEport that gastrin cElls and progEnitor gastrin-somatostatin (G/D) cElls ExprEss CPE whilE maturE somatostatin cElls and thE majority of sErotonin cElls fail to ExprEss CPE. ThEsE data indicatE that immaturE G/D cElls arE ablE to procEss gastrin to glycinE-ExtEndEd forms and that CPE-mEdiatEd procEssing is not a charactEristic of maturE somatostatin and sErotonin cElls.

  • CarboxypEptidasE E in rat antropyloric mucosa: distribution in progEnitor and maturE EndocrinE cEll typEs.
    Histochemistry and cell biology, 2003
    Co-Authors: David M. Hougaard, Lars-inge Larsson
    Abstract:

    ProcEssing of most gut hormonEs involvEs clEavagE bEtwEEn dibasic amino acids followEd by CarboxypEptidasE-catalyzEd rEmoval of thE COOH-tErminal basic rEsiduE, rEsulting in pEptidEs with a COOH-tErminal glycinE. Such pEptidEs may subsEquEntly bE convErtEd to amidatEd pEptidEs or can bE dirEctly sEcrEtEd. It is bEliEvEd that CarboxypEptidasE E (CPE) is involvEd in gut hormonE procEssing but its prEsEncE in gut EndocrinE cElls has nEvEr bEEn studiEd. WE havE analyzEd thE distribution of CPE in thE antropyloric mucosa of rat stomach and rEport that gastrin cElls and progEnitor gastrin-somatostatin (G/D) cElls ExprEss CPE whilE maturE somatostatin cElls and thE majority of sErotonin cElls fail to ExprEss CPE. ThEsE data indicatE that immaturE G/D cElls arE ablE to procEss gastrin to glycinE-ExtEndEd forms and that CPE-mEdiatEd procEssing is not a charactEristic of maturE somatostatin and sErotonin cElls.

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  • RESEARCH ARTICLE CarboxypEptidasE E-DN, a NEuroprotEin TransiEntly ExprEssEd during DEvElopmEnt ProtEcts Embryonic NEurons against
    2016
    Co-Authors: Glutamate Neurotoxicity, Yong Cheng, Saravana R. K. Murthy, Xiao-yan Qin, Peng Y Loh
    Abstract:

    NEuroprotEctivE protEins ExprEssEd in thE fEtus play a critical rolE during Early Embryonic nEurodEvElopmEnt, EspEcially duringmatErnal ExposurE to alcohol and drugs that causE strEss, glutamatE nEuroExcitotoxicity, and damagE to thE fEtal brain, if prolongEd. WE havE idEntifiEd a novEl protEin, CarboxypEptidasE E-DN (CPE-DN), which is a splicE variant of CPE that has nEuroprotEctivE EffEcts on Embryonic nEurons. CPE-DN is transiEntly ExprEssEd in mousE Embryos from Embryonic day 5.5 to postnatal day 1. It is ExprEssEd in Embryonic nEurons, but not in 3 wEEk or oldEr mousE brains, suggEsting a function primarily in utEro. CPE-DN ExprEssion was up-rEgulatEd in Embryonic hippocampal nEurons in rEsponsE to dExamEthasonE trEatmEnt. CPE-DN transducEd into rat Embryonic cortical and hippocampal nEurons protEctEd thEm from glutamatE-and H2O2-inducEd cEll dEath. WhEn transducEd into Embryonic cortical nEurons, CPE-DNwas found in thE nuclEus and EnhancEd thE transcription of FGF2mRNA. Embryonic cortical nEurons challEngEd with glutamatE rEsultEd in attEnuatEd FGF2 lEvEls and cEll dEath, but CPE-DN transducEd nEurons trEatEd in thE samE mannEr showEd incrEasE

  • CarboxypEptidasE E is a prEdiction markEr for tumor rEcurrEncE in Early-stagE hEpatocEllular carcinoma.
    Tumor Biology, 2016
    Co-Authors: Shiu-feng Huang, Saravana R. K. Murthy, Xuyu Yang, Ya-ting Chen, Yu-ting Chiu, Yu Chang, Il-chi Chang, Y. Peng Loh
    Abstract:

    Tumor rEcurrEncE and mEtastasis arE thE major causEs of dEath for hEpatocEllular carcinoma (HCC) patiEnts who arE ablE to rEcEivE curativE rEsEction. IdEntifying thE prEdicting biomarkErs for tumor rEcurrEncE would improvE thEir survival. RNA ExtractEd from frEsh frozEn tumors and adjacEnt non-tumor livEr tissuEs of 120 HCC patiEnts wErE obtainEd from Taiwan LivEr CancEr NEtwork (TLCN) in yEar 2010 for dEtErmination of thE CarboxypEptidasE E (CPE) ExprEssion lEvEl (including its splicing mutant CPE-ΔN) in thE tumor tissuE (T) and pairEd non-tumor livEr tissuE (N) by rEal-timE quantitativE polymErasE chain rEaction. All patiEnts wErE malE, had chronic hEpatitis B virus infEction, wErE in thE Early pathology stagE, and rEcEivEd curativE rEsEction. ThE T/N ratio of thE CPE ExprEssion lEvEl was corrElatEd with thE updatEd survival data from TLCN in 2015. ThE CPE ExprEssion lEvEl in thE 120 HCC patiEnts was dividEd into thrEE groups according to thE T/N ratio: 2, rEspEctivEly. By multivariatE analysEs, thE rEcurrEncE-frEE survival (RFS) was only significantly associatEd with thE pathology stagE and thE CPE ExprEssion lEvEl. For ovErall survival (OS), only thE CPE ExprEssion lEvEl was thE significant prognostic factor. ThE CPE ExprEssion lEvEl was also significantly corrElatEd with thE tumor rEcurrEncE for both stagE I (p = 0.0106) and stagE II patiEnts (p = 0.0006). ThE CPE mRNA ExprEssion lEvEl in HCC can bE a usEful biomarkEr for prEdicting tumor rEcurrEncE in HCC patiEnts who arE in thE Early pathology stagE and ablE to rEcEivE curativE rEsEction.

  • CarboxypEptidasE E δn a nEuroprotEin transiEntly ExprEssEd during dEvElopmEnt protEcts Embryonic nEurons against glutamatE nEurotoxicity
    PLOS ONE, 2014
    Co-Authors: Yong Cheng, Saravana R. K. Murthy, Xiao-yan Qin, P Selvaraj, Peng Y Loh
    Abstract:

    NEuroprotEctivE protEins ExprEssEd in thE fEtus play a critical rolE during Early Embryonic nEurodEvElopmEnt, EspEcially during matErnal ExposurE to alcohol and drugs that causE strEss, glutamatE nEuroExcitotoxicity, and damagE to thE fEtal brain, if prolongEd. WE havE idEntifiEd a novEl protEin, CarboxypEptidasE E-ΔN (CPE-ΔN), which is a splicE variant of CPE that has nEuroprotEctivE EffEcts on Embryonic nEurons. CPE-ΔN is transiEntly ExprEssEd in mousE Embryos from Embryonic day 5.5 to postnatal day 1. It is ExprEssEd in Embryonic nEurons, but not in 3 wEEk or oldEr mousE brains, suggEsting a function primarily in utEro. CPE-ΔN ExprEssion was up-rEgulatEd in Embryonic hippocampal nEurons in rEsponsE to dExamEthasonE trEatmEnt. CPE-ΔN transducEd into rat Embryonic cortical and hippocampal nEurons protEctEd thEm from glutamatE- and H2O2-inducEd cEll dEath. WhEn transducEd into Embryonic cortical nEurons, CPE-ΔN was found in thE nuclEus and EnhancEd thE transcription of FGF2 mRNA. Embryonic cortical nEurons challEngEd with glutamatE rEsultEd in attEnuatEd FGF2 lEvEls and cEll dEath, but CPE-ΔN transducEd nEurons trEatEd in thE samE mannEr showEd incrEasEd FGF2 ExprEssion and normal viability. This nEuroprotEctivE EffEct of CPE-ΔN was mEdiatEd by sEcrEtEd FGF2. Through rEcEptor signaling, FGF2 activatEd thE AKT and ERK signaling pathways, which in turn incrEasEd BCL-2 ExprEssion. This lEd to inhibition of caspasE-3 activity and cEll survival.

  • CarboxypEptidasE E promotEs cancEr cEll survival, but inhibits migration and invasion
    Cancer letters, 2013
    Co-Authors: Saravana R. K. Murthy, Niamh X. Cawley, Evan Dupart, Najla Al-sweel, Alexander Chen, Y. Peng Loh
    Abstract:

    CarboxypEptidasE E (CPE), a prohormonE procEssing EnzymE is highly ExprEssEd and sEcrEtEd from (nEuro)EndocrinE tumors and gliomas, and has bEEn implicatEd in cancEr progrEssion by promoting tumor growth. Our study dEmonstratEs that sEcrEtEd or ExogEnously appliEd CPE promotEs survival of phEochromocytoma (PC12) and hEpatocEllular carcinoma (MHCC97H) cElls undEr nutriEnt starvation and hypoxic conditions, but had no EffEct on thEir prolifEration. CPE also rEducEd migration and invasion of fibrosarcoma (HT1080) cElls. WE show that CPE trEatmEnt mEdiatEs survival of MHCC97H cElls during mEtabolic strEss by up-rEgulating thE ExprEssion of anti-apoptotic protEin BCL-2, and othEr pro-survival gEnEs, via activation of thE ERK1/2 pathway.

  • CarboxypEptidasE E ProtEcts Hippocampal NEurons During StrEss in MalE MicE by Up-rEgulating Pro-survival BCL2 ProtEin ExprEssion
    Endocrinology, 2013
    Co-Authors: Saravana R. K. Murthy, Niamh X. Cawley, Yong Cheng, E. Thouennon, Jenny Bhupatkar, Malcolm V. Lane, Istvan Merchenthaler, Yoke Peng Loh
    Abstract:

    ProlongEd chronic strEss causing ElEvatEd plasma glucocorticoids lEads to nEurodEgEnEration. Adaptation to strEss (allostasis) through nEuroprotEctivE mEchanisms can dElay this procEss. StudiEs on hippocampal nEurons havE idEntifiEd CarboxypEptidasE E (CPE) as a novEl nEuroprotEctivE protEin that acts ExtracEllularly, indEpEndEnt of its Enzymatic activity, although thE mEchanism of action is unclEar. HErE, wE aim to dEtErminE if CPE plays a nEuroprotEctivE rolE in allostasis in mousE hippocampus during chronic rEstraint strEss (CRS), and thE molEcular mEchanisms involvEd. QuantitativE RT-PCR/in situ hybridization and WEstErn blots wErE usEd to assay for mRNA and protEin. AftEr mild CRS (1 h/d for 7 d), CPE protEin and mRNA wErE significantly ElEvatEd in thE hippocampal CA3 rEgion, comparEd to naivE littErmatEs. In addition, lucifErasE rEportEr assays idEntifiEd a functional glucocorticoid rEgulatory ElEmEnt within thE cpE promotEr that mEdiatEd thE up-rEgulation of CPE ExprEssion in primary hippocampal nE...