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A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis
Open accessAbstract
In contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185BCR-ABL+ B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16INK4a and the pro-angiogenic factor VEGF-A. This function is independent of CDK6's kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16INK4a, providing an internal safeguard. However, in the absence of p16INK4a, 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 p16INK4a.
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“On the other hand, CDK6-specific functions include participating as part of a transcription complex that regulates expression of p16INK4a and VEGF-A[5]”
From Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 (2019) · cites this paper as [5]
In the citing paper
“Moreover, ATP-competitive inhibitors cannot disrupt the scaffolding functions of CDK6, which is important for the transcription function of CDK6 [124, 125].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [124]
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Self-citation
Metadata
- Authors
- Kollmann, K., Heller, G., Schneckenleithner, C., Warsch, W., Scheicher, R., Ott, R. G., Schäfer, M., Fajmann, S., Schlederer, M., Schiefer, A.-I., Reichart, U., Mayerhofer, M., Hoeller, C., Zöchbauer-Müller, S., Kerjaschki, D., Bock, C., Kenner, L., Hoefler, G., Freissmuth, M., Green, A. R., Moriggl, R., Busslinger, M., Malumbres, M., & Sexl, V.
- Affiliations
- University of Veterinary Medicine Vienna (AT)
- Comprehensive Cancer Center Vienna (AT)
- Research Institute of Molecular Pathology (AT)
- Medical University of Vienna (AT)
- Austrian Academy of Sciences (AT)
- Ludwig Boltzmann Institute for Cancer Research (AT)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Sexl, Veronika
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 24
- Issue
- 2
- Pages
- 167-181
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5637299
- OpenAlex
- W2152600133
- Cited by
- 313
- References
- 81
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 27 · 2023: 23 · 2022: 35 · 2021: 33 · 2020: 42 · 2019: 25 · 2018: 20 · 2017: 20 · 2016: 17 · 2015: 19 · 2014: 10 · 2013: 4
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-08-08)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (079249, 100140)
- Medizinische Universität Wien
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- CDK6, CDK4, p16INK4a, VEGF-A, tumor angiogenesis, B-cell acute lymphoblastic leukemia, BCR-ABL, transcriptional regulation, cell cycle, kinase-independent function, lymphoid malignancies, cell proliferation, hematologic malignancies
- MeSH terms
- Animals, Cell Cycle, Humans, Mice, Inbred C57BL, Mice, Nude, Mice, Transgenic, Neoplasms, Neovascularization, Pathologic, Leukemia, B-Cell, Lymphoma, B-Cell, Cyclin-Dependent Kinase 6, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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