Regulation of promyelocytic leukemia protein expression

Abstract

4. CONCLUSIONS Major resultsof this PhD thesiscanbe summarizedas follows: |. For full tÍanscTiptionalactivationof ISG @ML' Sp100'IRFI) by inteďeronor'the deaceýlationof unknownfactor(s)is necessary.IFNer.inducedexpressionof PML at mRNA andproteinlevel and zubsequentincreaseof PML NBs are suppressedby all tested HDACIs independentlyon cellular origin. Importantly,baml (i.e. IFNc- nonstimulated)expressionof PML is not influencedby ÍIDACIs. The classical Jak. STAT pathwaymediatingtransitionof IFNo signalremainsunaffectedby HDACIs and the targetof HDACIs lies downstreamof ISGF3 binding to PML promoter. AdverseaffectsofHDACIs usedin clinical praxisarepredicted. 2. Human mesenchymalstem cells (gfowing, confluent or terminally differentiated) expressPML protein,form PML nuclearboďes and respondto IFNcr teaEnent by dramaticelevationof PML mRNA andproteinlevels and mďerate increaseof PML NBs. Numberof PML NBs per cell nucleusis depende,nton thecultureproliferative age. ln normal diploid but not in immorbl cells PML forms various nucleoli- associatedshuctuÍes.The localization of PML into nucleoli is teestablishedin senescentcells. The importanc€ of PML association with nucleoli for its fumor suppressoractivitiesis hypothesized. 3. Drug-induced senescencein several human cell lines leads to increased PML...

4. CONCLUSIONS Major resultsof this PhD thesiscanbe summarizedas follows: |. For full tÍanscTiptionalactivationof ISG @ML' Sp100'IRFI) by inteďeronor'the deaceýlationof unknownfactor(s)is necessary.IFNer.inducedexpressionof PML at mRNA andproteinlevel and zubsequentincreaseof PML NBs are suppressedby all tested HDACIs independentlyon cellular origin. Importantly,baml (i.e. IFNc- nonstimulated)expressionof PML is not influencedby ÍIDACIs. The classical Jak. STAT pathwaymediatingtransitionof IFNo signalremainsunaffectedby HDACIs and the targetof HDACIs lies downstreamof ISGF3 binding to PML promoter. AdverseaffectsofHDACIs usedin clinical praxisarepredicted. 2. Human mesenchymalstem cells (gfowing, confluent or terminally differentiated) expressPML protein,form PML nuclearboďes and respondto IFNcr teaEnent by dramaticelevationof PML mRNA andproteinlevels and mďerate increaseof PML NBs. Numberof PML NBs per cell nucleusis depende,nton thecultureproliferative age. ln normal diploid but not in immorbl cells PML forms various nucleoli- associatedshuctuÍes.The localization of PML into nucleoli is teestablishedin senescentcells. The importanc€ of PML association with nucleoli for its fumor suppressoractivitiesis hypothesized. 3. Drug-induced senescencein several human cell lines leads to increased PML...