5.2 Identifizierung neuer Interaktionspartner von PRMTs
5.2.1 Reinigung endogener PRMT1- und PRMT4-haltiger Komplexe
5.2.1.4 Die weitere Reinigung
Für eine weitere Reinigung sollten Alternativen zu Ionentauschern, wie z. B.
Heparin-Fractogel verwendet werden. Im Batch-Verfahren konnte bereits eine Bindung von PRMT4 an dieses Material festgestellt werden (Daten nicht gezeigt).
Für PRMT4 bietet sich als einer der letzten Schritte ebenfalls die Verwendung einer MiniQ, eines noch höher auflösenderen Anionentauschers als der MonoQ an, da PRMT4 relativ konzentriert von der MonoQ eluierte. Für PRMT1 wurde dieses Material bereits getestet. Da eine Verteilung von PRMT1 über den gesamten Elutionsgradienten zu beobachten war, ist eine MiniQ Säule hier nicht zu empfehlen (Daten nicht gezeigt). Weitere Alternativen stellen z. B. die hydrophobe Interaktions-Chromatographie (HIC) dar, die Proteine nach ihrer Hydrophobizität trennt oder eine Affinitätschromatographie. In jedem Fall muss die Menge an Ausgangsmaterial deutlich erhöht werden, so dass eine der PRMT1 oder 4 entsprechende Bande in einem Silber gefärbten SDS-Gel detektiert und identifiziert
werden kann. Nur so ist gewährleistet, dass Proteine die in stöchiometrischen Verhältnissen im Komplex vorliegen ebenfalls identifizierbar sind.
6 Zusammenfassung
Die Modifikation der N-Termini von Histonen trägt zur Regulierung der Expression von Genen bei. Einzelmodifikationen oder Kombinationen regulieren den Verpackungsstatus des Chromatins. So Methylieren z. B. die Protein Arginin Methyltransferasen (PRMT) 1, 4 und 5 Arginine der Histone H2A, H3 und H4. Ziel der vorliegenden Arbeit war es, mehr über die von PRMT1 katalysierte asymmetrische Dimethylierung des Arginins 3 am Histon H4 und deren Funktion bei der Transkriptionskontrolle zu erfahren. Weiterhin sollten endogene PRMT1- und PRMT4-haltige Proteinkomplexe aus Zellextrakten chromatographisch gereinigt werden.
Mit Hilfe von Bindungsstudien mit unmodifizierten bzw. asymmetrisch an Arginin 3 dimethylierten Histon H4 Peptiden (As 1 – 15) konnten differentiell bindende Proteine aus Kernextrakten isoliert und mittels MALDI TOF analysiert werden.
Dabei wurde TAF-Iβ identifiziert, ein Bestandteil des INHAT-Komplexes, der Histonacetylierung inhibiert. TAF-Iβ, das selektiv mit dem unmodifizierten Peptid interagiert, bindet an den uninduzierten, PRMT1 abhängigen pS2 Promotor und verlässt diesen nach der Induktion des Gens durch Estradiol. Die Arginin 3 Methylierung scheint in vivo jedoch nicht allein entscheidend für das Ablösen von TAF-Iβ nach der Induktion zu sein. Die erfolgreiche Reduktion der TAF-Iβ Proteinmenge durch siRNA zeigte, dass das Fehlen von TAF-Iβ zu einer verfrühten Hyperacetylierung des pS2 Promotors führte. Dadurch wurden die Arginin 3 Methylierung und wahrscheinlich nachfolgende Ereignisse am Promotor verhindert, was negative Auswirkungen auf die Transkription des pS2 Gens hat. Die Untersuchung weiterer Estrogen induzierbarer Gene ergab, dass eine verfrühte Hyperacetylierung des ebenfalls PRMT1 abhängigen Lactoferrin Gens auch eine ineffiziente Transkription des Gens zur Folge hatte. Die Expression dieses Gens war jedoch unabhängig von TAF-Iβ, woraus geschlossen werden kann, dass die Inhibition einer verfrühten Acetylierung auch durch andere Proteine erfolgt. Im Gegensatz dazu wurden PRMT1 unabhängige Zielgene des Estrogenrezeptors bereits
ohne Hormoninduktion allein durch eine Hyperacetylierung aktiviert.
Zusammenfassend wurde in dieser Arbeit in vivo die Voraussetzung für eine effiziente Rekrutierung von PRMT1 und die nachfolgende Arginin 3 Methylierung an Estrogenrezeptor Zielgenen bestimmt. Die benötigte Hypoacetylierung der Promotoren wird durch Proteine wie TAF-Iβ vermittelt.
Im Verlauf dieser Arbeit wurde die Etablierung der chromatographischen Reinigung endogener PRMT1- und PRMT4-haltiger Komplexe über Ionenaustausch-Chromatographie im analytischen Maßstab begonnen. Die Bestimmung der Größe der PRMT1- und PRMT4-haltigen Fraktionen mittels Gelfiltration lässt auf Multiproteinkomplexe schließen. Eine nachfolgende Analyse der Proteinkomplexe soll Aufschluss über weitere Funktionen von PRMT1 und PRMT4 und deren Rekrutierung an Zielpromotoren geben.
7 Abkürzungen
α anti
°C Grad Celsius
µg Mikrogramm µl Mikroliter µM Mikromol A Adenin A Alanin a. b. Aqua bidest
AA Acrylamid
Abb. Abbildung
AF-1,2 „Activation function 1,2“
AIB1 „Amplified in breastcancer 1“
Amp. Ampicillin
APS Ammoniumpersulfat Arg Arginin
ATP Adenosintriphosphat BA Bisacrylamid Bp Basenpaar
Brg1 „Brahma-related gene 1“
BSA Rinderserumalbumin (“Bovine Serum Albumin”) BTG1 „B cell translocation gene 1”
bzw. beziehungsweise C Cytosin C Cystein
C3 Complement 3
cAMP „Cyclic AMP”
CAN „Cancer intron on nine“
CARM1 „Coactivator associated arginine methyltransferase 1“
CatD Cathepsin D
CBP „CREB binding protein“
cDNA „copy” DNA
CERC „Cyclin E1 repressor complex“
Ci Curie cm Zentimeter CoCoA „Coiled coil coactivator“
COX7RP „Cytochrome c oxidase subunit VIIa related protein”
CREB „cAMP response element binding protein”
DAL4/4.1B „differentially expressed in adenocarcinoma of the lung”
DBD DNA bindende Domäne
DEAE Diethylaminoethan DMEM „Dulbeccos modified Eagels” Medium
DNA Deoxyribonukleinsäure („acid”)
DNase Desoxyribonuklease
dNTP Desoxynukleosidtriphosphat DRBP76 „Double stranded RNA binding protein 76”
DTT Dithiothreitol E. coli Eschericia coli
E1B-AP5 „Adenovirus E1B associated protein 5“
EB1 „E. coli binding protein“
EBAG9 „ER-binding fragment-associated antigen 9“
EBNA-2 Ebstein-Barr virus nuclear antigen 2
ECL „Enhance Chemolumineszenz”
EDF EMD-DEAE Fractogel 650 (S)
EDTA Ethylendiamintetraacetat EFP Estrogen responsive finger protein
EGTA 1,2-Bis-(2-aminoethoxyethan)-N,N,N,´,N´-tetraacetat ER Estrogenrezeptor
ERE „Estrogen response element“
et al. und andere („et aliter”) EtOH Ethanol
EWS „Ewing sarcoma“
FCP1 „TFIIF-associating CTP phosphatase 1“
FCS Fötales Kälberserum („fetal calf serum”)
FCS-DCC FCS „Dextran Charcoal“ (Dextran Aktivkohle behandelt) FGF-2 „Fibroblast growth factor 2“
FKBP12 „FK506 binding protein 12“
FoxO3a „Forkhead box class O 3a”
FPLC „Fast Performance Liquid Chromatography“
FXII Faktor XII
G Guanin G Glycin
GADD45 „Growth arrest and DNA-damage inducible”
GAR Glyzin Arginin reich GFP „Green fluorescent protein”
GRIP1 „Glucocorticoidreceptor interacting protein 1“
GRP33 „Artemia saline gycine rich protein”
H3,4, 2A, 2B Histon 3, 4, 2A, 2B
HA Hämagglutinin
HAT Histone Acetyltransferase
hBrm humanes Brahma
HCl Salzsäure
HDAC Histone Deacetylase
HEK „human embryonic kidney”
HeLa Henrietta Lacks
HepC NS3 „Hepatitis C virus nonstructural protein 3“
Hepes N-(2-Hydroxyethyl)piperazin-N´-(2-ethansulfonsäure) HIC „Hydrophobic interaction chromatography“
HIV-1 TAT „Human immunodeficiency virus type 1 transactivator protein”
HMGA1a „High mobility group A1 protein a1”
hnRNA heterogene nukleäre RNA
hnRNP Heteronukleäres Ribonukleoprotein HPLC „High Perfomance Liquid Chromatography“
HuR Mitglied R der Hu Proteinfamilie IFN Interferon
IgG Immunglobulin G
ILF3 „Interleukin enhancer binding factor 3“
INHAT „Inhibitor of acetylation“
JAK Janus kinase
JBP1 JAK bindendes Protein 1 K Lysin Kac Kaliumacetat kBp Kilobasenpaare KCl Kaliumchlorid kDa Kilodalton
KLF „Kruppel-like factor“
L Leucin LB Medium Luria Bertoni Medium
LBD Ligand bindende Domäne
LiCl Lithiumchlorid Lsg. Lösung
LSm4 Sm-like protein 4
M Molar mA Milliampere
MALDI TOF „Matrix-assisted laser desorption ionization time-of-flight”
MAP „Mitogen-activated protein“
MBP „Myelin basic protein“
MEF-2C „Myocyte Enhancer Faktor 2C“
MEP50 „Methylosome protein 50“
mg Milligramm MHCII „Major histocompatibility class II“
Min. Minute
ml Milliliter
MOPS Na-Morpholin-Propan-Sulfonsäure Mre11 „Meiotic recombination 11“
mRNA Boten-RNA („messenger RNA“)
NaCl Natriumchlorid NaOH Natriumhydroxid N-CoR „Nuclear receptor corepressor“
NE Nukleärer Extrakt
NFAT „Nuclear factor of activated T cells”
NFκB „Nuclear factor κB“
ng Nanogramm NIP45 „NFAT interacting protein 45 kDa“
NTP Nukleosidtriphosphat Nuc E ERE enthaltendes Nukleosom
Nuc T TATA-Box enthaltendes Nukleosom
NUMAC „Nucleosomal methylation activator complex“
NuRD „Nucleosome remodeling and deacetylase”
OD Optische Dichte
ORF „Open reading frame“
P137GP1 „GPI-anchor protein p137“
PABP1,II „Poly(A)-binding protein 1,II”
PAD Peptidylarginin Deiminase
PAGE Polyacrylamid-Gelelektrophorese
PBS Phosphat-gepufferte Salzlösung („phosphate-buffered-saline“) PC Phosphocellulose
pCAF „p300/CBP-associated factor“
PCI Phenol-Chloroform-Isoamylalkohol PCR Polymerase-Kettenreaktion („polymerase chain reaction“) PCV „packed cell volume“
PEG Polyethylenglykol Pen/Strep Penicillin/Streptomycin PGC-1alpha „PPARγ coactivator 1“
pH Wasserstoffexponent pICln „Chloride conductance regulatory protein“
pmol Pikomolar
PMSF Phenylmethylsulfonylfluorid PPARγ „Peroxisome proliferator activated receptor γ“
PRMT „Protein-Arginine-Methyltransferase”
pS2 Plasmid S2
Puro Puromycin
QKI-5 „Quaking 5“
r rekombinant R Arginin RBP58 „RNA binding protein 58“
RNA Ribonukleinsäure
RNAi RNA „interference”
RNase Ribonuklease
rRNA ribosomale RNA
RT Raumtemperatur S Serin
SAF-A „Scaffold attachment factor A“
SAM S-Adenosyl-Methionin Sam68 „SRC substrate associated in mitosis of 68 kDa“
SAMT1 „Substrate of arginine methyltransferase 1“
SDS Natrium- („sodium“-) Dodecylsulfat
SET „Se translocation“
SET-Domäne „Suvar3 – 9, enhancer of zeste, Trithorax“ - Domäne siRNA „short interfering“ RNA
SLM-1,2 „Sam68 like mammalian protein 1,2“
SMN „Survival motor neuron“
SMRT „Silencing mediator for retinoid an tyhroid hormone receptors“
snRNA „Small nuclear“ RNA
snRNP „Small nuclear ribopnucleoprotein particle“
Sp1 „Specificity protein 1“
SPT5 „Suppressor of Ty 5“
SRC „Steroid receptor coactivator“
T Thymin TAF-I „Template activating factor”-I TAF-II68 TBP assoziierter Faktor II68
TARPP „Thymocyte cyclic AMP-regulated phosphoprotein“
TBE Tris-Borat-EDTA-Puffer
TBP TATA bindendes Protein
TCA Trichloressigsäure TE Tris-EDTA-Puffer TEMED N,N,N´,N´,-Tetramethylethylendiamin TFF1 „Trefoil factor 1“
TGM2 „Tissue transglutaminase type 2“
TIS21 „Tetradecanoyl phorbol acetate-inducible sequence 21“
TLS „Translocated in liposarcoma“
Tris Tris-hydroxy-ethyl-aminomethan Tween Polyoxyethylensorbitanmonolaurat U Unit
u. a. unter anderem
üN über Nacht
UpM Umdrehungen pro Minute
UV Ultraviolett V Volt
v/v Volumen/Volumen („volume per volume”) VEGF „Vascular endothelial growth factor“
Vol. Volumen
VT Volumenteil W Watt
w/v Gewicht/Volumen („weight per volume“)
YY1 Yin Yang 1
z. B. zum Beispiel
ZF5 Zinkfinger 5
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