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Statements

Subject Item
n2:RIV%2F61989592%3A15310%2F12%3A33142894%21RIV13-MSM-15310___
rdf:type
n12:Vysledek skos:Concept
rdfs:seeAlso
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0030128
dcterms:description
Neutrophils are the most abundant leukocyte and play a central role in the immune defense against rapidly dividing bacteria. However, they are also the shortest lived cell in the blood with a lifespan in the circulation of 5.4 days. The mechanisms underlying their short lifespan and spontaneous entry into apoptosis are poorly understood. Recently, the broad range cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to increase neutrophil apoptosis, implicating CDKs in the regulation of neutrophil lifespan. To determine which CDKs were involved in regulating neutrophil lifespan we first examined CDK expression in human neutrophils and found that only three CDKs: CDK5, CDK7 and CDK9 were expressed in these cells. The use of CDK inhibitors with differing selectivity towards the various CDKs suggested that CDK9 activity regulates neutrophil lifespan. Furthermore CDK9 activity and the expression of its activating partner cyclin T1 both declined as neutrophils aged and entered apoptosis spontaneously. CDK9 is a component of the P-TEFb complex involved in transcriptional regulation and its inhibition will preferentially affect proteins with short half-lives. Treatment of neutrophils with flavopiridol, a potent CDK9 inhibitor, increased apoptosis and caused a rapid decline in the level of the anti-apoptotic protein Mcl-1, whilst Bcl2A was unaffected. We propose that CDK9 activity is a key regulator of neutrophil lifespan, preventing apoptosis by maintaining levels of short lived anti-apoptotic proteins such as Mcl-1. Furthermore, as inappropriate inhibition of neutrophil apoptosis contributes to chronic inflammatory diseases such as Rheumatoid Arthritis, CDK9 represents a novel therapeutic target in such diseases. Neutrophils are the most abundant leukocyte and play a central role in the immune defense against rapidly dividing bacteria. However, they are also the shortest lived cell in the blood with a lifespan in the circulation of 5.4 days. The mechanisms underlying their short lifespan and spontaneous entry into apoptosis are poorly understood. Recently, the broad range cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to increase neutrophil apoptosis, implicating CDKs in the regulation of neutrophil lifespan. To determine which CDKs were involved in regulating neutrophil lifespan we first examined CDK expression in human neutrophils and found that only three CDKs: CDK5, CDK7 and CDK9 were expressed in these cells. The use of CDK inhibitors with differing selectivity towards the various CDKs suggested that CDK9 activity regulates neutrophil lifespan. Furthermore CDK9 activity and the expression of its activating partner cyclin T1 both declined as neutrophils aged and entered apoptosis spontaneously. CDK9 is a component of the P-TEFb complex involved in transcriptional regulation and its inhibition will preferentially affect proteins with short half-lives. Treatment of neutrophils with flavopiridol, a potent CDK9 inhibitor, increased apoptosis and caused a rapid decline in the level of the anti-apoptotic protein Mcl-1, whilst Bcl2A was unaffected. We propose that CDK9 activity is a key regulator of neutrophil lifespan, preventing apoptosis by maintaining levels of short lived anti-apoptotic proteins such as Mcl-1. Furthermore, as inappropriate inhibition of neutrophil apoptosis contributes to chronic inflammatory diseases such as Rheumatoid Arthritis, CDK9 represents a novel therapeutic target in such diseases.
dcterms:title
Cyclin-Dependent Kinase 9 Activity Regulates Neutrophil Spontaneous Apoptosis Cyclin-Dependent Kinase 9 Activity Regulates Neutrophil Spontaneous Apoptosis
skos:prefLabel
Cyclin-Dependent Kinase 9 Activity Regulates Neutrophil Spontaneous Apoptosis Cyclin-Dependent Kinase 9 Activity Regulates Neutrophil Spontaneous Apoptosis
skos:notation
RIV/61989592:15310/12:33142894!RIV13-MSM-15310___
n12:predkladatel
n17:orjk%3A15310
n3:aktivita
n7:Z n7:P
n3:aktivity
P(GA204/08/0511), P(GA301/08/1649), Z(AV0Z50380511), Z(MSM6198959216)
n3:cisloPeriodika
1
n3:dodaniDat
n5:2013
n3:domaciTvurceVysledku
n10:9961216 n10:4712048
n3:druhVysledku
n14:J
n3:duvernostUdaju
n6:S
n3:entitaPredkladatele
n22:predkladatel
n3:idSjednocenehoVysledku
129351
n3:idVysledku
RIV/61989592:15310/12:33142894
n3:jazykVysledku
n18:eng
n3:klicovaSlova
inflammation; inhibition; in-vivo; life-span; MCL-1 expression; leukocyte apoptosis; rheumatoid-arthritis; down-regulation; programmed cell-death; colony-stimulating factor
n3:klicoveSlovo
n4:inflammation n4:inhibition n4:down-regulation n4:in-vivo n4:rheumatoid-arthritis n4:leukocyte%20apoptosis n4:programmed%20cell-death n4:MCL-1%20expression n4:colony-stimulating%20factor n4:life-span
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[CC07CBE83FCD]
n3:nazevZdroje
PLoS One
n3:obor
n21:EB
n3:pocetDomacichTvurcuVysledku
2
n3:pocetTvurcuVysledku
7
n3:projekt
n8:GA301%2F08%2F1649 n8:GA204%2F08%2F0511
n3:rokUplatneniVysledku
n5:2012
n3:svazekPeriodika
7
n3:tvurceVysledku
Lord, Janet M Wang, Keqing Hazeldine, Jon Hampson, Peter Kryštof, Vladimír Strnad, Miroslav Pechan, Paul
n3:wos
000301457200034
n3:zamer
n15:MSM6198959216 n15:AV0Z50380511
s:issn
1932-6203
s:numberOfPages
6
n19:doi
10.1371/journal.pone.0030128
n11:organizacniJednotka
15310