p16INK4a, but not constitutively active pRb, can impose a sustained G1 arrest: molecular mechanisms and implications for oncogenesis (original) (raw)

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• Published: 14 July 1999

Oncogene volume 18, pages 3930–3935 (1999)Cite this article

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Abstract

p16ink4a and pRb, two components of a key G1/S regulatory pathway, and tumor suppressors commonly targeted in oncogenesis, are among the candidates for gene therapy of cancer. Wild-type p16 and a constitutively active pRbΔcdk mutant both blocked G1 in short-term experiments, but only p16 imposed a sustained G1 arrest. Unexpectedly, cells conditionally exposed to pRbΔcdk entered S phase after 2 days, followed by endoreduplication between days 4 – 6. The distinct phenotypes evoked by p16 vs pRbΔcdk appear mediated by cyclin E/CDK2 which, while active in the pRbΔcdk-expressing cells, became rapidly inhibited through restructuring diverse cyclin/CDK/p21 complexes by p16. These results provide novel insights into the roles of p16, pRb and cyclin E in G1/S control and multistep oncogenesis, with implications for gene therapy strategies.

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Acknowledgements

We thank C Lindeneg for technical assistance, and A Fattaey, P Hamel, K Helin, SS Jensen, M Pagano, SI Reed and M Seto for some of the reagents. This work was supported by grants from the Danish Cancer Society, The Danish Medical Research Council (#9600821), a DFG postdoctoral fellowship (So 385/1-1) to C Lukas, and the Human Frontier Science Programme (RG-299/97). J Lukas and CS Sørensen contributed equally to this work.

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Authors and Affiliations

1. Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, DK-2100, Denmark
   Jiri Lukas, Claus S Sørensen, Claudia Lukas, Eric Santoni-Rugiu & Jiri Bartek

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1. Jiri Lukas
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2. Claus S Sørensen
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3. Claudia Lukas
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4. Eric Santoni-Rugiu
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5. Jiri Bartek
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Lukas, J., Sørensen, C., Lukas, C. et al. p16INK4a, but not constitutively active pRb, can impose a sustained G1 arrest: molecular mechanisms and implications for oncogenesis.Oncogene 18, 3930–3935 (1999). https://doi.org/10.1038/sj.onc.1202777

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• Received: 23 December 1998
• Revised: 04 February 1999
• Accepted: 26 February 1999
• Published: 14 July 1999
• Issue Date: 08 July 1999
• DOI: https://doi.org/10.1038/sj.onc.1202777

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