Sci. Signal., 3 September 2013
Cancer Branching Out
Leslie K. Ferrarelli
Science Signaling, AAAS, Washington, DC 20005, USA
The cell cycle is often deregulated in cancer because of mutations or increased activity of cyclins and cyclin-dependent kinases (CDKs) (see Otto and Sicinski). The abundance of CDK6 is frequently increased in lymphoma and leukemia. Kollmann et al. found that CDK6 activated distinct transcriptional pathways that regulated B and T cell proliferation and angiogenesis independently of its kinase function. In CDK6-deficient or wild-type p185BCR-ABL-transformed pro-B cells or NPM-ALK+ (which encodes a fusion product of nucleophosmin and anaplastic lymphoma kinase) anaplastic large-cell lymphoma (ALCL) cells, the overexpression of CDK6 or a catalytically inactive mutant (CDK6-K43M) inhibited cell proliferation and delayed the onset of subcutaneous xenograft tumors in nude mice. In addition, overexpression of wild-type or catalytically inactive CDK6 correlated with increased mRNA and protein abundance of its inhibitor p16INK4a, an effect that required cyclins and STAT3 (signal transducer and activator of transcription 3). Deletion of p16INK4A in cells prevented the antiproliferative effects of CDK6 overexpression. Furthermore, in tissue arrays of human B and T cell malignancies that were deficient for p16INK4a, the abundance of CDK6 was increased compared with those with abundant p16INK4a, and several ALCL-derived cell lines showed increased p16INK4a promoter methylation, suggesting that p16INK4a is a negative feedback target of CDK6 but is often silenced in lymphomas. In cells overexpressing a form of CDK6 that could not bind p16INK4a (CDK6-R31C), p16INK4a expression was induced but proliferation was not altered, indicating that CDK6 and p16INK4a interact at both the gene and protein levels to repress cell proliferation. As well as binding to the promoter of p16INK4a, CDK6 bound to that of VEGFA, which encodes vascular endothelial growth factor A. In human ALCL tissue, CDK6 abundance correlated with increased blood vessel density. Mouse xenograft tumors from CDK6-deficient ALCL or B cells overexpressing CDK6, CDK6-K43M, or CDK6-R31C had increased angiogenesis and abundance and secretion of VEGF-A, an effect that required the transcription factor c-Jun, but not STAT3 or cyclins. Together, the findings indicate that CDK6 promotes different transcriptional pathways that are either antiproliferative or proangiogenic.
K. Kollmann, G. Heller, C. Schneckenleithner, W. Warsch, R. Scheicher, R. G. Ott, M. Schäfer, S. Fajmann, M. Schlederer, A.-I. Schiefer, U. Reichart, M. Mayerhofer, C. Hoeller, S. Zöchbauer-Müller, D. Kerjaschki, C. Bock, L. Kenner, G. Hoefler, M. Freissmuth, A. R. Green, R. Moriggl, M. Busslinger, M. Malumbres, V. Sexl, A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer Cell 24, 167–181 (2013). [PubMed]
T. Otto, P. Sicinski, The kinase-independent, second life of CDK6 in transcription. Cancer Cell 24, 141–143 (2013). [PubMed]
Citation: L. K. Ferrarelli, Branching Out. Sci. Signal. 6, ec207 (2013).
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