Cyclin-dependent kinase inhibitor indirubin-3'-oxime selectively inhibits human papillomavirus type 16 E7-induced numerical centrosome anomalies.
Dysregulation of the centrosome duplication cycle has been implicated in tumorigenesis. Our previous work has shown that the human papillomavirus type 16 (HPV-16) E7 oncoprotein rapidly induces aberrant centrosome and centriole duplication in normal human cells. We report here that HPV E7-induced abnormal centriole duplication is specifically abrogated by a small molecule CDK inhibitor, indirubin-3'-oxime (IO), but not a kinase-inactive derivative. Importantly, normal centriole duplication was not markedly affected by IO, and the inhibitory effects were observed at concentrations that did not affect the G1/S transition of the cell division cycle. Depletion of CDK2 by siRNA similarly abrogated HPV E7-induced abnormal centrosome duplication and ectopic expression of CDK2 in combination with cyclin E or cyclin A could rescue the inhibitory effect of IO. IO treatment also reduced the steady-state level of aneuploid cells in HPV-16 E7-expressing cell populations. Our results suggest that cyclin/CDK2 activity is critically involved in abnormal centrosome duplication induced by HPV-16 E7 oncoprotein expression, but may be dispensable for normal centrosome duplication and cell cycle progression.
Duensing
Stefan
S
Molecular Virology Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
Duensing
Anette
A
Lee
David C
DC
Edwards
Kirsten M
KM
Piboonniyom
Siribang-On
SO
Manuel
Edwin
E
Skaltsounis
Leandros
L
Meijer
Laurent
L
Münger
Karl
K
D001483:Base Sequence; D045744:Cell Line, Tumor; D018385:Centrosome; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009856:Oncogene Proteins, Viral / Q000037:antagonists & inhibitors* / Q000502:physiology; D010091:Oximes / Q000494:pharmacology*; D050725:Papillomavirus E7 Proteins; D012313:RNA; D016196:S Phase
D004791:Enzyme Inhibitors; D007211:Indoles; D009856:Oncogene Proteins, Viral; D010091:Oximes; D050725:Papillomavirus E7 Proteins; C474021:indirubin-3'-monoxime; C059731:oncogene protein E7, Human papillomavirus type 16; D012313:RNA; D018844:Cyclin-Dependent Kinases