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Tshooj 2: Krϋppel-zoo li Factor 15 Tshem Tawm Lub Raum Glomerular Mesangial Cell Proliferation Via Enhancing P53 SUMO1 Conjugation

May 12, 2022

Yog xav paub ntxiv. tiv taujtina.xiang@wecistanche.com

3 TSEEM CEEB

3.1|Kev tshuaj ntsuam xyuas ntawm KLF15- khi cov noob los ntawm ChiP-Seq hauv thawj lub raum glomerular MCs

Txhawm rau txheeb xyuas tus khub sib txuas ncaj qha ntawm KLF15, peb tau soj ntsuam ChlP-Seq thiab thaum kawg kuaj 2478 cov noob. GO tsom xam ntawm cov noob no los ntawm cov cuab yeej ntawm lub vev xaib www.uniprot.org (Daim duab 1A, B) nthuav tawm cov ntsiab lus ua haujlwm molecular cuam tshuam nrog 1941 cov noob, cov ntsiab lus ntawm cov khoom siv ntawm tes muaj feem xyuam rau 1662 cov noob thiab cov txheej txheem lom neeg muaj feem xyuam rau 1766 noob. Txij li thaum peb lub hom phiaj yog kom paub seb KLF15 cuam tshuam li cas rau MCs, peb tau tsom mus rau cov txheej txheem ntawm cov noob caj noob ces. Ntawm 1315 cov txheej txheem ntawm cov noob caj ces, 74 cov noob tau pom los koom nrog cov txheej txheem ntawm tes; tshwj xeeb, cov noob no tau koom nrog hauv lub voj voog ntawm tes mitotic, lub sijhawm hloov pauv ntawm tes thiab lwm yam txheej txheem (Daim duab 1C, D). Tsis tas li ntawd, peb tau soj ntsuam cov noob muaj feem cuam tshuam nrog kev loj hlob thiab pom tias lawv muaj feem cuam tshuam rau kev loj hlob, kev loj hlob ntawm tes thiab lwm yam kev loj hlob (Daim duab 1E).

FIGURE 1 Annotation of KLF15 ChIP-Seq data in HRMCs. A-B, GO analysis of the 2,478 screened genes. C, GO analysis of 1,315 cell process-related genes. D, Cell cycle process-related gene analysis results. E, Growth process-related gene analysis results

3.2|Kev tshuaj ntsuam xyuas cov noob sib txawv hauv KLF15- nthuav tawm lub raum glomerular MCs siv SILAC thiab LC/MS

SILAC thiab LC/MS tsom xam ntawm HRMCs overexpressing KLF15 piv rau niam txiv hlwb coj mus rau kev txheeb xyuas ntawm 1357 proteins. Peb tau siv DAVID thiab IPA kom tau txais GO domains thiab en-riched txoj hauv kev ntawm cov protein ntau uas txheeb xyuas los ntawm SILAC. Interestingly, ntau cov proteins 'kev ua haujlwm lom neeg ntsig txog cov ntsiab lus yog nyob rau sab saum toj 30 qhov tseem ceeb ntawm GO cov ntsiab lus, suav nrog kev tswj hwm ntawm cellular amino acid txheej txheem metabolic, proteasome complex, protein khi, thiab cov lus sau thiab txhais lus, tag nrho cov uas muaj feem xyuam nrog. ubiquitination (Daim duab 2A). Daim duab 2B qhia txog sab saum toj 30 cov ntsiab lus tseem ceeb ntawm txoj kev. Ntau cov txheej txheem lom neeg, suav nrog cov ntsiab lus ntawm cov kab mob proteasome thiab neurodegenerative, kuj muaj feem xyuam rau ubiquitination.

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3.3|Bioinformatics tsom xam ntawm KLF15-binding genes uas muaj feem cuam tshuam nrog rau lub raum glomerular MC proliferation

Tshawb nrhiav KLF15-binding genes uas muaj feem cuam tshuam nroglub raum glomerularMC proliferation, peb tau ua ib qho kev ntsuam xyuas bioinformatics ntawm cov ntaub ntawv Chip-Seq thiab cov ntaub ntawv SILAC-LC/MS. Tsib caug-ob noob tau raug tshuaj xyuas (Table 2 thiab daim duab 2C), thiab tsib ntawm cov noob no, suav nrog SUMO1, macrophage migration inhibitory factor (MIF), eukaryotic initiation factor (EIF), insulin-zoo li kev loj hlob zoo (IGF) thiab reticulocalbin (RCN). ), tau ze ze raucell proliferation. Txij li thaum GO thiab txoj kev ntsuam xyuas ntawm cov protein sib txawv qhia tau hais tias cov noob tshuaj ntsuam xyuas muaj feem cuam tshuam rau cov txheej txheem ubiquitination, peb tau txiav txim siab tias SUMO1, tus tswv cuab ntawm tsev neeg ubiquitin-zoo li (UBL) cov protein, koom nrog kev hloov pauv tom qab kev hloov pauv zoo ib yam li. ubiquitination raws li lub hom phiaj noob ntawm KLF15.

Ntau cov pov thawj tau qhia tias HG yog ib qho tseem ceeb ua rau muaj kev txhim kho ntshav qab zib nephropathy, thiab nws txhawb nqa MC proliferation thiab nce matrix synthesis hauv vitro.25A txoj kev tshawb fawb yav dhau los tau qhia tias PDGF-BB yog qhov tseem ceeb rau MC proliferation ua ntej txoj kev loj hlob. ntawm glomerulosclerosis hauv kev sim glomerulonephritis.26 Tom qab lees paub tias MCs tau txhawb nqa los ntawm HG lossis PDGF-BB hauv vitro, peb tau kuaj pom cov kev hloov pauv ntawm KLF15 thiab SUMO1 ntawm RNA thiab cov protein.

qib thiab pom tias cov molecules muaj qhov sib xws (Daim duab 2D-l). Thaum kawg, peb txiav txim siab SUMO1 los ua lub hom phiaj ntawm KLF15.

FIGURE 2 Bioinformatics analysis of KLF15-binding genes. A, DAVID analysis and IPA were performed to acquire the GO domains of the 1,357 SILAC-LC/MS-screened proteins. B, Top 30 signalling pathways identified by IPA of the SILAC-LC/MS data. C, Fifty-two genes identified by bioinformatics analysis of ChIP-Seq data and SILAC-LC/MS data. D, KLF15 and SUMO1 mRNA expression in HG-treated HRMCs. E, KLF15 and SUMO1 mRNA expression in PDGF-BB-treated HRMCs. F-G, KLF15 and SUMO1 protein expression in HG-treated HRMCs. H-I, KLF15 and SUMO1 protein expression in PDGF-BB-treated HRMCs. *P < .05, ***P < .01, n = 3

3.4|KLF15 up-regulates SUMO-1 noob qhia los ntawm kev khi rau 16 bp CACCCA-SUMO-1 txhawb nqa cheeb tsam thiab C ntxiv rau A-nplua nuj motif

Peb siv MEME suite (http://meme-suite.org/tools/meme) los ua tus yam ntxwv ntawm KLF15-binding motifs ntawm 52 cov noob tshuaj ntsuam xyuas los ntawm KLF15 ChlP-Seq cov ntaub ntawv thiab txheeb xyuas KLF-binding motif (Daim duab 3A). Tsis tas li ntawd, peb tau soj ntsuam ntau dua ib txhiab lub hauv paus ntawm SUMO1 tus txhawb nqa thiab pom tias KLF15 tuaj yeem lees paub thiab khi rau 16 bp ib ntus (nucleotides -205~-199) suav nrog - CACCCA-(Daim duab 3B).ChIP-PCR tau lees paub tias KLF15 raug khi rau SUMO1 tus txhawb nqa, thiab cov txiaj ntsig tau pom muaj kev qhia ntau dua ntawm SUMO1 hauv pawg tshuaj tiv thaiv-KLF15 ntau dua li hauv pawg tswj hwm keeb kwm yav dhau (Daim duab 3C).

Tsis tas li ntawd, peb tau ua qhov kev ntsuam xyuas dual-luciferase tus neeg sau xov xwm kom paub meej txog kev sib raug zoo ntawm SUMO1 thiab KLF15. Cov tsiaj qus-hom SUMO1 pab pawg txhawb nqa tau pom cov kev ua si luciferase ntau dua li cov pGL3 vector thiab mutant pawg hauv HRMCs, thiab cov haujlwm tau nce ntxiv los ntawm kev nthuav tawm ntau dhau ntawm KLF15. Qhov kev txhim kho hauv kev ua luciferase tau thim rov qab los ntawm kev hloov pauv nrog lub plasmid nthuav qhia thaj tsam mutant txhawb nqa (Daim duab 3D). Ua ke, cov ntaub ntawv no qhia tias SUMO1 yog lub hom phiaj ncaj qha ntawm KLF15.

 52 genes of bioinformatics analysis of ChIP-Seq data and SILAC-LC/MS data

 52 genes of bioinformatics analysis of ChIP-Seq data and SILAC-LC/MS data

 Motif analysis and validation of KLF15-binding sites. A, Consensus KLF15-binding motif identified by WebLogo in the KLF15 ChIP-Seq data using the MEME program. B, Target region of the SUMO1 promoter to which KLF15 binds. C, ChIP-PCR results for SUMO1, n = 5. D, Dual-luciferase reporter assay results, n = 5. ***P < .01

3.5|Kev tshuaj xyuas ntawm P53 raws li SUMOylation substrate ntawm SUMO1

SUMO kev hloov kho tau nthuav dav nthuav dav tom qab kev hloov pauv hloov hauv eukaryotes. Reversible conjugation ntawm cov kev hloov kho rau substrate proteins kuj hu ua SUMOylation, uas plays lub luag hauj lwm tseem ceeb nyob rau hauv kev tswj lub luag hauj lwm ntawm lub hom phiaj proteins thiab ntxiv koom nyob rau hauv ntau yam kab mob lom, xws li nucleocytoplasmic thauj, transcriptional regulation, apoptosis, protein stabilization, kev nyuaj siab teb thiab cell cycle progression.27 Txhawm rau tshawb xyuas cov kab hluav taws xob qis qis ncaj qha sib txuas los ntawm SUMO1, peb tau ua qhov kev txheeb xyuas network ntawm SUMO1 siv IPA database, thiab cov ntaub ntawv qhia tias SUMO1 tuaj yeem ncaj qha con-jugate rau P53, APP, JUN thiab AKT, ntawm lwm yam. proteins (Daim duab 4A-C). Peb pib xaiv P53 raws li ib tug downstream molecule ntawm SUMO1 vim hais tias nws yog ib tug zoo-paub protein uas yog ze ze rau lub cell proliferation.28.29 Tsis tas li ntawd, peb siv SUMOsp software los kwv yees qhov ua tau SUMOylation sequences ntawm P53invariousspecies thiab pom tias P53 muaj cov SUMOylation ib ntus ( Daim duab 4D). Txhawm rau txiav txim siab seb P53 yog qhov tseeb hloov kho los ntawm SUMOylation, peb tau hloov pauv HRMCs nrog SUMO1 overexpression plasmid lossis SUMO1 siRNA.Ob lub IP thiab Western blot cov txiaj ntsig tau nthuav tawm cov kev hloov pauv hauv kev qhia hloov pauv ntawm SUMO1-P53 thiab P53 uas tau ua raws li cov kev hloov pauv. hauv SUMO1 (Daim duab 4E-J). Cov ntaub ntawv no qhia tias P53 yog SUMOylation substrate ntawm SUMO1.

 IPA of downstream signalling molecules of SUMO1 and validation. A-C, IPA network associated with SUMO1. D, Alignment of various P53 sequences from different species (indicated). The SUMOylation consensus sites are shown in red. E-J, SUMO1-P53, KLF15 and SUMO1 expression in SUMO1-overexpressing or SUMO1-depleted HRMCs. *P < .05, **P < .01, n = 3

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3.6|KLF15 inhibits MC proliferation los ntawm kev txhawb nqa SUMO1 qhia thiab P53 SUMOylation

Txhawm rau tsim cov kev cai ntawm P53 SUMOylation thiab MC proliferation los ntawm KLF15 thiab SUMO1, peb tau cuam tshuam nrog KLF15 lossis SUMO1 qhia hauv HRMCs thiab kho HRMCs nrog PDGF-BB. Ntawm PDGF-BB-kho HRMCs, hlwb hloov nrog KLF15 overexpression plasmid nthuav qhia ntau dua ntawm SUMO1-P53, P53, KLF15 thiab SUMO1 dua li cov hlwb hloov nrog KLF15 tswj plasmid. Tib qhov kev hloov pauv hauv SUMO1-P53, P53 thiab SUMO1 tau pom nyob rau hauv SUMO1 overexpression plasmid-transfected hlwb, thaum KLF15 qhia tsis hloov hauv cov hlwb (Daim duab 5A-F). PDGF-BB yog ib qho ntawm cov kev loj hlob zoo tshaj plaws ntawm MCs tau piav qhia txog tam sim no, thiab cov lus teb nthuav dav ntawm HRMCs rau PDGF-BB tau pom. Raws li pom nyob rau hauv daim duab 5G, H, feem pua ​​​​ntawm EdU-zoo hlwb tau nce ntxiv los ntawm kev tswj hwm ntawm recombinant PDGF-BB. Cov txiaj ntsig EdU staining tau qhia tias KLF15 thiab SUMO1 overexpression inhibited PDGF-BB-induced cell proliferation (Daim duab 5G, H).

FIGURE 5 Both KLF15 overexpression and SUMO1 overexpression inhibit PDGF-BB-induced cell proliferation. A-C, HRMCs were transfected with a control plasmid (VECTOR) or a KLF15 overexpression plasmid (KLF15) and incubated with PDGF-BB. A, The expression of SUMO1-P53 and input (P53) was assessed by IP analysis. B, The expression of KLF15 and SUMO1 was assessed by Western blot analysis. C, Quantitative data. D-F, HRMCs were transfected with an empty vector (VECTOR) or a SUMO1 overexpression plasmid (SUMO1) and incubated with PDGF-BB. D, The expression of SUMO1-P53 and input (P53) was assessed by IP analysis. E, The expression of KLF15 and SUMO1 was assessed by Western blot analysis. F, Quantitative data. G-H, Cell proliferation assay results. KLF15 or SUMO1 overexpression inhibited PDGF-BB-induced cell proliferation. *P < .05, n = 3

Txhawm rau kom nkag siab ntxiv rau lub luag haujlwm ntawm KLF15 thiab SUMO1 hauv kev nthuav dav HRMCs, peb tau hloov cov hlwb nrog tsuas yog SUMO1 siRNA lossis cotransfected lawv nrog SUMO1 siRNA thiab KLF15 overexpression plasmid. Kev tswj hwm qis ntawm SUMO1 tsis cuam tshuam rau qhov kev qhia ntawm KLF15, tab sis cov lus qhia theem ntawm SUMO1-P53 thiab P53 tau pom tseeb txo qis tom qab SUMO1 siRNA transfection (Figure6A-C). Tsis tas li ntawd, thaum qhov kev qhia ntawm SUMO1 raug txwv, SUMO1-P53 thiab P53 qhia qib kuj raug txwv txawm tias hauv cov hlwb overexpressing KLF15 (Daim duab 6D-F). Tom qab ntawd, MC kev loj hlob tau raug soj ntsuam los ntawm kev siv EdU staining assay. SUMO1 RNAi txhim kho cov nyhuv proliferative ntawm PDGF-BBon HRMCs, thiab pab pawg neeg cotransfected nrog KLF15 overexpression plasmid thiab SUMO1 siRNA muaj ntau EdU-zoo hlwb tshaj li pab pawg neeg cotransfected nrog lub overexpression plasmid thiab hybrid sib lawv liag tswj siRNA(Fi) . Peb, yog li ntawd, xaus lus tias KLF15 suppresses MC proliferation los ntawm kev txhim kho P53 SUMOylation.

FIGURE 6 KLF15 suppresses MC proliferation byenhancing p53 SUMO1 conjugation. A-C, HRMCs were transfected with negative control siRNA (SI CON) or SUMO1 siRNA (SI SUMO1) and incubated with PDGF-BB. A, The expression of SUMO1-P53 and input (P53) was assessed by IP analysis. B, The expression of KLF15 and SUMO1 was assessed by Western blot analysis. C, Quantitative data. D-F, HRMCs were transfected with a control plasmid and negative control siRNA (VECTOR + SI CON) or SUMO1 siRNA (VECTOR + SI SUMO1), and KLF15 overexpression plasmid and negative control siRNA (KLF15 + SI CON) or SUMO1 siRNA (KLF15 + SI SUMO1) and incubated with PDGF-BB. D, The expression of SUMO1-P53 and input (P53) was assessed by IP analysis. E, The expression of KLF15 and SUMO1 was assessed by Western blot analysis. F, Quantitative data. G-H, Cell proliferation assay results. *P < .05, n = 3

3.7| Ntiaj teb no SUMO1 thiab P53 qhia nyob rau hauv glomerular MCs yog tsis zoo correlated nrog MC proliferation nyob rau hauv nas Koj-1 nephritis

Anti-Thy1 nephritis yog ib qho qauv ntawm tus kheej txwv tsis pub mesangial proliferative glomerulonephritis nrog rau theem proliferative thiab theem rov qab. Peb txhaj tshuaj tiv thaiv Thy1 rau hauv Wistar nas los tsim cov qauv no. Ob leeg urea nitrogen thiab creatinine tsis muaj kev hloov pauv tseem ceeb ntawm cov nas tswj thiab cov qauv nas (Daim duab S1). Cov cim mesangial proliferation thiab ECM tsub zuj zuj tau pom thaum lub sij hawm proliferative theem (hnub 5 thiab 7) nyob rau hauv cov qauv nas, thiab tus naj npawb ntawm MCs poob thaum lub sij hawm rov qab mus rau hnub 10 (Daim duab 7A). Peb kuj tau kuaj pom cov kev hloov pauv ntawm cov cell proliferation marker PCNA los ntawm IHC (Daim duab 7A, B).PCNA qib tau nce rau hnub 5, nce siab rau hnub 7 thiab poob rau hnub 10 (Daim duab 7F). Western blot tsom xam pom tias cov protein qhia ntawm P53, SUMO1 thiab KLF15 nyob rau hauv cais glomeruli yog qis dua nyob rau hauv cov qauv pab pawg tshaj li nyob rau hauv pawg tswj (Daim duab 7C, D), raws li zoo raws li cov immunohistochemical tau (Daim duab 7E, F). Cov txiaj ntsig no qhia tau hais tias qhov txawv txav ntawm MCs hauv cov qauv nas anti-Thy1 muaj feem cuam tshuam nrog kev qhia qis ntawm KLF15 thiab SUMO1. Kev cuam tshuam nrog kev qhia ntawm cov molecules yuav tsum tau txo qis cov kab mob pathological hauv nas.

FIGURE 7 Expression of SUMO1 and P53 in anti-Thy1 rat glomeruli. A, Periodic acid-Schiff (PAS) staining results and PCNA immunohistochemical staining results. B, Statistic results of the proportion of PCNA-positive cells in the glomerulus. C-D, P53, KLF15 and SUMO1 expression in glomerular protein extracts. E-F, Expression of KLF15 and SUMO1 in the glomerulus as assessed by immunohistochemical staining. *P < .05, ▲P < .01, #P < .01, n = 5

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4 Kev sib tham

Covglomeruliyog cov filtration unitsraum. Kev cuam tshuam ntawm glomerular muaj nuj nqi tuaj yeem tshwm sim los ntawm thawj glomerular pathology lossis tuaj yeem ua rau cov kab mob hauv lub cev. Kev hloov pauv mesangial tau pom tom qab raug mob glomerular nrog rau hyperproliferation ntawm MCs ua raws li kev tsim tawm ntau dhau ntawm ECM (mesangial expansion) thiab tsim cov tshuaj chemoattractant rau inflammatory cells. Yog li ntawd, kev hloov kho ntawm MC cov lus teb, tshwj xeeb tshaj yog qhov txawv txav, yog ib txoj hauv kev kho tshiab. KLF15 yog cov protein uas ua lub luag haujlwm tswj hwm raws li qhov hloov pauv los ntawm kev khi rau cov kab ke DNA tshwj xeeb. Ntau qhov kev tshawb fawb tau tshaj tawm tias KLF15 tau koom nrog hauv kev tswj hwm ntawm cov cell proliferation. Piv txwv li, nws tau pom tias KLF15 koom nrog inhibition ntawm MC proliferation-related signaling pathways, 15,30tab sis nws cov hom phiaj ncaj qha tsis tau tshaj tawm hauv cov ntaub ntawv. Yog li, txoj kev tshawb fawb no koom nrog kev sib koom ua ke ntawm kev sib sau thiab kev txhais lus los txheeb xyuas cov hom phiaj ncaj qha ntawm KLF15.

KLF15 tswj cov noob sib txawv hauv ntau hom thiab hauv cov ntaub so ntswg thiab cov kabmob sib txawv. Nyob rau hauv cov txheej txheem ntawm kev tswj cov kev loj hlob ntawm MCs, KLF15 cuam tshuam rau kev nthuav qhia ntawm ntau cov noob thiab koom nrog ntau txoj hauv kev.131,32 Txhawm rau tshawb xyuas cov noob ncaj qha ntawm KLF15, peb siv Chip-Seg.Klein RH thiab nws cov npoj yaig siv ChlP-seq. thev naus laus zis los kawm txog kev tswj hwm ntawm KLF7 ntawm kev sib txawv ntawm cov pob txha ntawm pob txha epithelial hlwb.33 Ying M thiab al siv cov txheej txheem no los kawm txog cov nyhuv inhibitory ntawm KLF9 ntawm pluripotency ntawm glioblastoma.34Piv nrog ChlP-chip, Chip-Seq ua kom muaj tseeb tag nrho-genome tsom xam. nrog kev daws teeb meem siab dua, kev tshawb pom ntau dua thiab qis dua cov qauv xav tau.35 Peb siv ChP kom tau txais cov DNA tawg ncaj qha los ntawm KLF15, thiab tom qab kev sib piv thiab kev tshuaj xyuas nrog GenBank, peb tau tshuaj xyuas 2478 cov hom phiaj ua tau. Los ntawm GO thiab kev txheeb xyuas txoj hauv kev, peb tau txheeb xyuas ntau lub hom phiaj cov noob koom nrog hauv lub voj voog ntawm tes thiab cov txheej txheem proliferation.

ChlP-Seq thwmsim xav tau PCR rau kev nthuav dav ntawm cov teeb liab kuaj pom, thiab qee qhov kev tsis ncaj ncees thaum lub sijhawm ua kom nthuav dav yog qhov tsis muaj tseeb. Tsis tas li ntawd, ChiP-Seq tau txais cov noob nkaus xwb uas KLF15 tuaj yeem khi thiab tsis qhia txog cov kev hloov pauv uas tshwm sim hauv kev qhia ntawm cov noob no thaum qhia txog KLF15 hloov. Peb siv SILAC-LC/MS proteomics tsom xam los them rau cov kev tsis txaus no. Cov txheej txheem no muab cov ntaub ntawv ntawm tag nrho cov proteins uas nws cov lus hloov pauv raws li kev tswj hwm los ntawm KLF15, suav nrog cov proteins ncaj qha tswj hwm los ntawm KLF15 thiab cov proteins uas raug tswj tsis ncaj lossis tom qab hloov pauv. HRMCs tau coj los siv SILAC, thiab KLF15 tau tshaj tawm hauv cov hlwb los ntawm kev hloov pauv plasmid. Cov proteins tau sau rau LC / MS nrhiav pom, thiab 1357 cov protein sib txawv tau txais. GO thiab kev txheeb xyuas txoj hauv kev tau qhia tias qee qhov sib txawv ntawm cov protein tau koom nrog hauv ubiquitination. Cov ntaub ntawv gene thiab protein tau sib cuam tshuam. Cov noob tsis cuam tshuam nrog lub hom phiaj tshawb fawb thiab cov noob tsis ncaj qha tswj hwm los ntawm KLF15 raug tshem tawm; Thaum kawg, 52 cov noob tau tshuaj xyuas. Ntawm cov no, tsib lub noob nrog qhov pom tseeb tshaj plaws qhia qhov sib txawv uas yog qhov cuam tshuam zoo tshaj plaws rau kev loj hlob tau raug xaiv. Muab cov txiaj ntsig sib xyaw ua ke ntawm txoj kev tsom xam, SUMO1 thiab KLF15 qhia kev tsom xam hauv kev nthuav dav HRMCs, ChlP-PCR thiab dual-luciferase reporter assays, protein SUMO1 raug xaiv los ua lub hom phiaj ntawm KLF15.

Ntxiv rau ubiquitin, nce tus lej ntawm UBLproteins, 3637 suav nrog SUMO, 38 neural precursor cell-expressed, kev loj hlob qis- tswj 8 (NEDD8) 3940 thiab interferon-stimulated gene 15 (ISG15), 41 raug txheeb xyuas. Cov kev hloov pauv cov protein no muaj zog tswj ntau yam txheej txheem lom neeg. Qhov sib ntxiv ntawm SUMO rau substrates, hu ua SUMOylation, yog ib qho kev hloov pauv tom qab kev txhais lus koom nrog hauv cov txheej txheem ntawm tes, suav nrog kev thauj mus los ntawm nuclear-cytosolic, kev tswj hwm kev hloov pauv, apoptosis, tswj kev ruaj ntseg protein, kev ntxhov siab thiab lub voj voog ntawm tes.27SUMO feem ntau yog txuas mus rau txais lysine residues ntawm cov protein substrates harboring ib tug kev pom zoo ib theem zuj zus thiab pab rau cov kev cai ntawm protein-protein kev sib tshuam nrog rau cov subcellular compartmentalization thiab protein stability.2 sUMO1, raws li ib tug tswv cuab ntawm tsev neeg SUMOS, muaj peev xwm cuam tshuam lub cell proliferation los ntawm kev hloov substrate. thiab stabilizing cell cycle regulatory proteins.43 Yog li ntawd, ua ke nrog cov ntaub ntawv qhia thiab cov kev ntsuam xyuas thiab tsom xam, peb tsom mus rau yuav ua li cas KLF15 tswj cov nyhuv ntawm SUMO1 ntawm mesangial cell proliferation.

Txhawm rau txheeb xyuas cov substrates ntawm SUMO1, peb tau ua qhov kev txheeb xyuas network ntawm SUMO1 siv IPA database thiab SUMOsp software. Ua ke nrog kev tshawb fawb luam tawm ntawm P53, peb cov ntaub ntawv soj ntsuam thawj zaug tau qhia P53 raws li cov dej ntws qis ntawm SUMO1 nrog SUMOylation ib ntu YKxD/E. Cov kev tshawb fawb yav dhau los tau qhia tias P53 yog ib qho substrate ntawm SUMOylation, 45 thiab txhim kho P53 SUMO1 conjugation txhawb kev ruaj ntseg thiab kev ua haujlwm ntawm P53 thiab induced se-nescence.46 Hauv peb txoj kev tshawb fawb, cuam tshuam nrog kev qhia ntawm SUMO1 hauv HRMCs ua tib yam kev hloov pauv hauv SUMO1-P53 thiab P53, qhia tias P53 yog SUMOylation substrate ntawm SUMO1.

Cov ntaub ntawv pov thawj tshiab tau qhia tias SUMOylation thiab de-SUMOylation ua lub luag haujlwm hauv ntau yam kab mob nephropathic, xws li lub raum dysgenesis, raum mob cancer, kab mob glomerular, podocyte apoptosis, thiab lub raum medulla hypertonicity, mob raum raug mob thiab nephrolithiasis. 7-51 Kom paub meej cov Kev sib raug zoo ntawm KLF15, SUMO1, P53 SUMOylation thiab MC proliferation, peb tau ua ntau txoj kev kho mob ntawm cov hlwb uas tau dhau los ntawm PDGF-BB-induced proliferation. Overexpression ntawm KLF15 nce-tswj cov lus qhia ntawm SUMO1, thaum overexpression ntawm SUMO1 tsis cuam tshuam rau kev qhia ntawm KLF15. KLF15 los yog SUMO1 overexpression nce SUMOylation ntawm P53 thiab antagonized lub cell proliferation induced los ntawm PDGF-BB. Thaum qhov kev qhia ntawm SUMO1 raug txwv, SUMOylation ntawm P53 kuj tau inhibited, thiab KLF15 poob nws cov antagonistic nyhuv ntawm cell proliferation. Hauv vivo. Kev loj hlob ntawm MCs maj mam nce nrog kev ua rau mesangial proliferative nephritis, thaum qhov kev qhia ntawm KLF15, SUMO1 thiab P53 poob qis. Xav txog cov kev soj ntsuam sib xyaw ua ke hauv cov hlwb thiab cov ntaub so ntswg, peb ua ntej xaus tias KLF15 tswj cov SUMOylation ntawm P53 txog SUMO1, yog li inhibiting MC proliferation.

effects of cistanche nedir：treat adrenal cortical insufficiency2

5 Cov lus xaus

Qee qhov kev tshawb fawb tau qhia tias KLF15 ua lub luag haujlwm tseem ceeb hauv kev tswj hwm kev loj hlob ntawm MCs. Hauv kev ua haujlwm no, peb tau tshawb xyuas cov txheej txheem ntawm MC proliferation suppression mediated by this transcription factor. Peb tau txheeb xyuas SUMO1 yog lub hom phiaj tseem ceeb ntawm KLF15 hauv MCs ntawm bioinformatics tsom xam nrog rau Chip-Seq thiab SILAC-LC/MS. Tsis tas li ntawd, nrog kev pab ntawm IPA database thiab SUMOsp software, peb txiav txim siab tias P53 yog ib qho ncaj qha substrate ntawm SUMO1. Kev sim hauv vitro thiab hauv vivo tau lees paub tias KLF15 tuaj yeem txhawb kev qhia ntawm SUMO1 thiab SUMOylation ntawm P53 tom qab ntawd inhibit qhov kev loj hlob ntawm MCs (Daim duab S2). Cov txiaj ntsig no ua rau muaj kev nkag siab txog kev tswj hwm lub luag haujlwm ntawm KLF15 hauv MC proliferation thiab muab lub hauv paus rau kev nrhiav kev kho tshiab rau MC proliferation-related mob raum.



Koj Tseem Yuav Zoo Li