A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis

Kollmann, Karoline; Heller, Gerwin; Schneckenleithner, Christine; Warsch, Wolfgang; Scheicher, Ruth; Ott, Rene G.; Rg, Ott; Schäfer, Markus; Fajmann, Sabine; Schlederer, Michaela; Schiefer, Ana-Iris; Ai, Schiefer; Reichart, Ursula; Mayerhofer, Matthias; Hoeller, Christoph; Zöchbauer-Müller, Sabine; Kerjaschki, Dontscho; Bock, Christoph; Kenner, Lukas; Hoefler, Gerald; Freissmuth, Michael; Green, Anthony R.; Moriggl, Richard; Busslinger, Meinrad; Malumbres, Marcos; Sexl, Veronika

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Cell Press, Cancer Cell, 2(24), p. 167-181, 2013

DOI: 10.1016/j.ccr.2013.07.012

Cell Press, Cancer Cell, 2(30), p. 359-360, 2016

DOI: 10.1016/j.ccell.2016.07.003

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A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis

Journal article published in 2013 by Karoline Kollmann, Gerwin Heller, Christine Schneckenleithner, Wolfgang Warsch, Ruth Scheicher, Rene G. Ott, Ott Rg, Markus Schäfer, Sabine Fajmann, Michaela Schlederer, Ana-Iris Schiefer, Schiefer Ai, Ursula Reichart, Matthias Mayerhofer, Christoph Hoeller and other authors.

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Abstract

In contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185(BCR-ABL+) B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16(INK4a) and the pro-angiogenic factor VEGF-A. This function is independent of CDK6's kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16(INK4a), providing an internal safeguard. However, in the absence of p16(INK4a), CDK6 can exert its full tumor-promoting function by enhancing proliferation and stimulating angiogenesis. The finding that CDK6 connects cell-cycle progression to angiogenesis confirms CDK6's central role in hematopoietic malignancies and could underlie the selection pressure to upregulate CDK6 and silence p16(INK4a).