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HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway

Histone deacetylase (HDAC) inhibitors induce an intrinsic type of apoptosis in human papillomavirus (HPV)-positive cells by disrupting the mitochondrial transmembrane potential (ΔΨm). Loss of ΔΨm was only detected in E7, but not in E6 oncogene-expressing cells. HDAC inhibition led to a time-dependen...

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Hauptverfasser: Finzer, Patrick (VerfasserIn) , Krammer, Peter H. (VerfasserIn) , Rösl, Frank (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 12 April 2004
In: Oncogene
Year: 2004, Jahrgang: 23, Heft: 28, Pages: 4807-4817
ISSN:1476-5594
DOI:10.1038/sj.onc.1207620
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/sj.onc.1207620
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/1207620
Volltext
Verfasserangaben:Patrick Finzer, Andreas Krueger, Michael Stöhr, Dirk Brenner, Ubaldo Soto, Christian Kuntzen, Peter H. Krammer and Frank Rösl
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Zusammenfassung:Histone deacetylase (HDAC) inhibitors induce an intrinsic type of apoptosis in human papillomavirus (HPV)-positive cells by disrupting the mitochondrial transmembrane potential (ΔΨm). Loss of ΔΨm was only detected in E7, but not in E6 oncogene-expressing cells. HDAC inhibition led to a time-dependent degradation of the pocket proteins pRb, p107 and p130, releasing ‘free’ E2F-1 following initial G1 arrest. Inhibition of proteasomal proteolysis, but not of caspase activity rescued pRb from degradation and functionally restored its inhibitory effect on the cyclin E gene, known to be suppressed by pRb-E2F-1 in conjunction with HDAC1. Using siRNA targeted against p53, E2F-1 still triggered apoptosis by inducing the E2F-responsive proapoptotic α- and β-isoforms of p73. These data may determine future therapeutic strategies in which HDAC inhibitors can effectively eliminate HPV-positive cells by an apoptotic route that does not rely on the reactivation of the ‘classical’ p53 pathway through a preceding shut-off of viral gene expression.
Beschreibung:Gesehen am 06.04.2021
Beschreibung:Online Resource
ISSN:1476-5594
DOI:10.1038/sj.onc.1207620

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