Mutual requirement of CDK4 and Myc in malignant transformation: evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc (original) (raw)

Oncogene volume 15, pages 179–192 (1997)Cite this article

Abstract

We demonstrate in this paper that CDK4 which is a G1 phase specific cell cycle regulator and catalytic subunit of D-type cyclins has oncogenic activity similar to D-type cyclins themselves and is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo fibroblasts. Surprisingly, using two different mutants we show that CDK4's ability to bind to p16INK4a and not its kinase activity is important for its transforming potential. In addition, p16INK4a but not a mutant form that is found in human tumours can completely abrogate focus formation by CDK4 suggesting that CDK4 can malignantly transform cells by sequestering p16INK4a or other CKIs. We demonstrate that both cyclin D1 and CDK4 functionally depend on active Myc to exert their potential as oncogenes and vice versa that the transforming ability of Myc requires functional cyclin D/CDK complexes. Moreover, we find that p16INK4a and the Rb related protein p107 which releases Myc after phosphorylation by cyclin D1/CDK4 efficiently block Myc's activity as a transcriptional transactivator and as an oncogene. We conclude that both p16INK4a and cyclin D/CDK4 complexes are upstream regulators of Myc and directly govern Myc function in transcriptional transactivation and transformation via the pocket protein p107.

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Authors and Affiliations

  1. Institut für Zellbiologie (Tumorforschung), IFZ, Universitätsklinikum Essen, Virchowstrasse 173, D-45122, Essen, Germany
    Kirsten Haas, Christoph Geisen & Tarik Möröy
  2. Zentrum für Molekulare Biologie Heidelberg, ZMBH, Im Neuenheimer Feld 2821, Heidelberg, D-69120, Germany
    Peter Staller & Martin Eilers
  3. Division for Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, DK-2100, Denmark
    Jiri Bartek

Authors

  1. Kirsten Haas
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  2. Peter Staller
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  3. Christoph Geisen
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  4. Jiri Bartek
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  5. Martin Eilers
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  6. Tarik Möröy
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Haas, K., Staller, P., Geisen, C. et al. Mutual requirement of CDK4 and Myc in malignant transformation: evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc.Oncogene 15, 179–192 (1997). https://doi.org/10.1038/sj.onc.1201171

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