Utjecaj izoformi gena p73 na metiliranja DNA u stanicama raka

doctoral thesis

• Title (english): The role of p73 isoforms on DNA methylation in cancer cells
• Author: Neven Tučkar
• Mentor: Neda Slade (mentor)
• Committee member: Kristian Vlahoviček (član povjerenstva)
• Committee member: Neda Slade (član povjerenstva)
• Committee member: Damir Eljuga (član povjerenstva); MBZ: 87925
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2012, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology
• Universal decimal classification (UDC): 575 - General genetics. General cytogenetics

Abstract

Uloga gena p73 u tumorigenezi nije u potpunosti razjašnjena. Korištenjem promotora P1 nastaju izoforme sa cjelovitim transaktivacijskim područjem (TAp73), odnosno korištenjem promotora P2 izoforme bez te regije (ΔNp73). Najčešća promjena u tumorima je povećana ekspresija izoforme ΔNp73, koja djeluje kao transdominantni inhibitor TAp73 i p53. Metiliranost DNA je oblik reverzibilne epigenetičke regulacije, kojim se nakon replikacije dodaju metilne skupine na citozinske ostatke DNA, mijenjajući aktivnost staničnih gena. Hipermetiliranost otoka CpG u promotorskim regijama pojedinih gena inhibira transkripciju utištavajući gene. Koristeći inducibilni sustav tet-on ispitali smo utjecaj pojačane ekspresije TAp73α i ΔNp73α na globalnu metiliranost DNA, no nismo pronašli statistički značajnu promjenu metiliranosti uzoraka s aktiviranim izoformama p73 u odnosu na njihove kontrole. Rezultate smo usporedili s rezultatima genske ekspresije nakon aktivacije ΔNp73α i TAp73α iz literature. Za gene koji pokazuju pojačanu ekspresiju našli smo, premda statistički ne značajno, smanjenje metiliranosti promotorskih CpG otoka, što potvrđuje činjenicu da metiliranje može utjecati na regulaciju aktivnosti gena.

Abstract (english)

The role of p73 in tumorigenesis is not fully understood. Using P1 promoter transactivating (TAp73) isoforms are generated and P2 promoter the isoforms without this region (ΔNp73). The most common change in tumors is increased expression of ΔNp73, which acts as transdominant inhibitor of TAp73 and p53. DNA methylation is a form of epigenetic regulation, which adds methyl groups to cytosine residues, regulating gene activity. Hypermethylation of CpG islands in promoter regions inhibits transcription of genes silencing its expression. Using inducible tet-on system, we examined the impact of increased expression of TAp73α and ΔNp73α on global DNA methylation. However statistically significant change was not found upon induced expression of p73 isoforms. The results were compared with gene expression data obtained after induction of TAp73α or ΔNp73α from literature. For genes with increased expression we found, although not statistically significant, reduction of methylated CpG sites in promoter regions, which confirms the fact that methylation could affect the regulation of gene activity.

• Keywords: TP73; izoforme p73; TAp73α; ΔNp73α; metiliranje
• Keywords (english): TP73; p73 isoforms; TAp73α; ΔNp73α; methylation
• Language: croatian
• URN:NBN: urn:nbn:hr:217:650490
• Study programme: Title: Biology; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija (doktor/doktorica znanosti, područje prirodnih znanosti, polje biologija)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2019-06-08
• Created on: 2017-06-08 10:22:24