Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

Inhibition of post-transcriptional RNA processing by CDK inhibitors and its implication in anti-viral therapy

J. Holcakova, P. Muller, P. Tomasec, R. Hrstka, M. Nekulova, V. Krystof, M. Strnad, GW. Wilkinson, B. Vojtesek,

. 2014 ; 9 (2) : e89228.

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc15014487

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and RNA polymerase II mediated transcription. Several pharmacological CDK inhibitors are currently in clinical trials as potential cancer therapeutics and some of them also exhibit antiviral effects. Olomoucine II and roscovitine, purine-based inhibitors of CDKs, were described as effective antiviral agents that inhibit replication of a broad range of wild type human viruses. Olomoucine II and roscovitine show high selectivity for CDK7 and CDK9, with important functions in the regulation of RNA polymerase II transcription. RNA polymerase II is necessary for viral transcription and following replication in cells. We analyzed the effect of inhibition of CDKs by olomoucine II on gene expression from viral promoters and compared its effect to widely-used roscovitine. We found that both roscovitine and olomoucine II blocked the phosphorylation of RNA polymerase II C-terminal domain. However the repression of genes regulated by viral promoters was strongly dependent on gene localization. Both roscovitine and olomoucine II inhibited expression only when the viral promoter was not integrated into chromosomal DNA. In contrast, treatment of cells with genome-integrated viral promoters increased their expression even though there was decreased phosphorylation of the C-terminal domain of RNA polymerase II. To define the mechanism responsible for decreased gene expression after pharmacological CDK inhibitor treatment, the level of mRNA transcription from extrachromosomal DNA was determined. Interestingly, our results showed that inhibition of RNA polymerase II C-terminal domain phosphorylation increased the number of transcribed mRNAs. However, some of these mRNAs were truncated and lacked polyadenylation, which resulted in decreased translation. These results suggest that phosphorylation of RNA polymerase II C-terminal domain is critical for linking transcription and posttrancriptional processing of mRNA expressed from extrachromosomal DNA.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc15014487
003      
CZ-PrNML
005      
20150421092204.0
007      
ta
008      
150420s2014 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1371/journal.pone.0089228 $2 doi
035    __
$a (PubMed)24586613
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Holcakova, Jitka $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
245    10
$a Inhibition of post-transcriptional RNA processing by CDK inhibitors and its implication in anti-viral therapy / $c J. Holcakova, P. Muller, P. Tomasec, R. Hrstka, M. Nekulova, V. Krystof, M. Strnad, GW. Wilkinson, B. Vojtesek,
520    9_
$a Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and RNA polymerase II mediated transcription. Several pharmacological CDK inhibitors are currently in clinical trials as potential cancer therapeutics and some of them also exhibit antiviral effects. Olomoucine II and roscovitine, purine-based inhibitors of CDKs, were described as effective antiviral agents that inhibit replication of a broad range of wild type human viruses. Olomoucine II and roscovitine show high selectivity for CDK7 and CDK9, with important functions in the regulation of RNA polymerase II transcription. RNA polymerase II is necessary for viral transcription and following replication in cells. We analyzed the effect of inhibition of CDKs by olomoucine II on gene expression from viral promoters and compared its effect to widely-used roscovitine. We found that both roscovitine and olomoucine II blocked the phosphorylation of RNA polymerase II C-terminal domain. However the repression of genes regulated by viral promoters was strongly dependent on gene localization. Both roscovitine and olomoucine II inhibited expression only when the viral promoter was not integrated into chromosomal DNA. In contrast, treatment of cells with genome-integrated viral promoters increased their expression even though there was decreased phosphorylation of the C-terminal domain of RNA polymerase II. To define the mechanism responsible for decreased gene expression after pharmacological CDK inhibitor treatment, the level of mRNA transcription from extrachromosomal DNA was determined. Interestingly, our results showed that inhibition of RNA polymerase II C-terminal domain phosphorylation increased the number of transcribed mRNAs. However, some of these mRNAs were truncated and lacked polyadenylation, which resulted in decreased translation. These results suggest that phosphorylation of RNA polymerase II C-terminal domain is critical for linking transcription and posttrancriptional processing of mRNA expressed from extrachromosomal DNA.
650    _2
$a zvířata $7 D000818
650    _2
$a buněčný cyklus $x účinky léků $7 D002453
650    _2
$a buněčné linie $7 D002460
650    _2
$a Cercopithecus aethiops $7 D002522
650    _2
$a cyklin-dependentní kinasy $x antagonisté a inhibitory $7 D018844
650    _2
$a DNA virů $7 D004279
650    _2
$a lidé $7 D006801
650    _2
$a ledviny $x účinky léků $x metabolismus $7 D007668
650    _2
$a fosforylace $x účinky léků $7 D010766
650    _2
$a promotorové oblasti (genetika) $x účinky léků $7 D011401
650    _2
$a inhibitory proteinkinas $x farmakologie $7 D047428
650    _2
$a puriny $x farmakologie $7 D011687
650    _2
$a RNA-polymerasa II $x genetika $x metabolismus $7 D012319
650    _2
$a posttranskripční úpravy RNA $x účinky léků $7 D012323
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Muller, Petr $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
700    1_
$a Tomasec, Peter $u School of Medicine, Cardiff University, Cardiff, United Kingdom.
700    1_
$a Hrstka, Roman $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
700    1_
$a Nekulova, Marta $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
700    1_
$a Krystof, Vladimir $u Laboratory of Growth Regulators, Faculty of Science, Palacky University, Olomouc, Czech Republic ; Institute of Experimental Botany AS CR, Olomouc, Czech Republic.
700    1_
$a Strnad, Miroslav $u Laboratory of Growth Regulators, Faculty of Science, Palacky University, Olomouc, Czech Republic ; Institute of Experimental Botany AS CR, Olomouc, Czech Republic.
700    1_
$a Wilkinson, Gavin W G $u School of Medicine, Cardiff University, Cardiff, United Kingdom.
700    1_
$a Vojtesek, Borivoj $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
773    0_
$w MED00180950 $t PloS one $x 1932-6203 $g Roč. 9, č. 2 (2014), s. e89228
856    41
$u https://pubmed.ncbi.nlm.nih.gov/24586613 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20150420 $b ABA008
991    __
$a 20150421092502 $b ABA008
999    __
$a ok $b bmc $g 1072068 $s 897365
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2014 $b 9 $c 2 $d e89228 $i 1932-6203 $m PLoS One $n PLoS One $x MED00180950
LZP    __
$a Pubmed-20150420

Najít záznam

Citační ukazatele

Možnosti archivace