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Cyclin-dependent kinase inhibitor indirubin-3′-oxime selectively inhibits human papillomavirus type 16 E7-induced numerical centrosome anomalies

Abstract

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.

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Abbreviations

AhR:

aryl hydrocarbon receptor

ATP:

adenosine 5′-triphosphate

CDK:

cyclin-dependent kinase

DTT:

dithiothreitol

GSK-3β:

glycogen synthase kinase-3β

HPV:

human papillomavirus

IO:

indirubin-3′-oxime

MeIO:

1-methyl-indirubin-3′-oxime

PMSF:

phenylmethylsulfonyl fluoride

pRB:

retinoblastoma tumor suppressor protein

siRNA:

small interfering RNA

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Acknowledgements

We are grateful to Michel Bornens, Philip W Hinds, and Robert A Weinberg for sharing reagents. We thank Philip W Hinds for critical reading of the manuscript and helpful comments. This work was supported by PHS Grant CA66980 to KM and a postdoctoral fellowship by the Deutsche Forschungsgemeinschaft (SD). SD's laboratory at the University of Pittsburgh Cancer Institute is supported by a Special Innovation Award from the PNC Foundation and a UPCI Pilot Project Developmental Grant. LM's work on AhR/CDK modulation by indirubins was supported by a grant from the ‘Association pour la Recherche sur le Cancer’ (ARC-3362).

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Correspondence to Stefan Duensing or Karl Münger.

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Duensing, S., Duensing, A., Lee, D. et al. Cyclin-dependent kinase inhibitor indirubin-3′-oxime selectively inhibits human papillomavirus type 16 E7-induced numerical centrosome anomalies. Oncogene 23, 8206–8215 (2004). https://doi.org/10.1038/sj.onc.1208012

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