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

Abstract

SummaryIn 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.

Down-Regulation of miR-3928 Promoted Osteosarcoma Growth

“…The reason may be that CDK6 was targeted by miR-3928. Interestingly, recent study showed that CDK6 linked the cell cycle to tumor angiogenesis [35]. Angiogenesis is a key step of tumor growth.…”

microRNA-365-targeted nuclear factor I/B transcriptionally represses cyclin-dependent kinase 6 and 4 to inhibit the progression of cutaneous squamous cell carcinoma

“…This repression affected downstream cancer-related effectors, including CDK6 (Zhou et al, 2014). Although the role of CDK6 in the initiation and development of tumors has been well-characterized (Kollmann et al, 2013), the underlying mechanism(s) responsible for the regulation of CDK6 by NFIB remain unclear. Interactions between CDK6 and CDK4 have been described as well (Kollmann et al, 2013).…”

“…Although the role of CDK6 in the initiation and development of tumors has been well-characterized (Kollmann et al, 2013), the underlying mechanism(s) responsible for the regulation of CDK6 by NFIB remain unclear. Interactions between CDK6 and CDK4 have been described as well (Kollmann et al, 2013). Thus, an important question is whether CDK4 is also regulated by NFIB.…”

Cyclin-Dependent Kinases as Coregulators of Inflammatory Gene Expression

“…By contrast, binding of CDK6 to the p16 INK4A promoter crucially depends on the presence of STAT3 [39], showing that CDK6 can utilize different transcription factor complexes to mediate its association with distinct chromatin regions. In agreement with the dynamic association of CDK6 with different transcription factor complexes, a previous study revealed the testosterone-inducible interaction of CDK6 with the androgen receptor, a nuclear hormone receptor that regulates transcription of the prostate-specific antigen (PSA) gene [40].…”

“…Besides NF-kB p65, a further candidate transcription factor is PAX4 (paired box 4), whose consensus DNA-binding motif is associated with a fraction of CDK6 peaks. However, CDK6 does not only associate with p65 because in BCR-ABL (breakpoint cluster region-Abelson oncogene homolog)-transformed B-acute lymphoid leukemia cells the kinase interacts also with STAT3 and the AP-1 transcription factor subunit JUN (Jun protooncogene) [39], as summarized in Figure 2B.…”