A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis.
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.
Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
Karoline
K
Kollmann
Gerwin
G
Heller
Christine
C
Schneckenleithner
Wolfgang
W
Warsch
Ruth
R
Scheicher
Rene G
RG
Ott
Markus
M
Schäfer
Sabine
S
Fajmann
Michaela
M
Schlederer
Ana-Iris
AI
Schiefer
Ursula
U
Reichart
Matthias
M
Mayerhofer
Christoph
C
Hoeller
Sabine
S
Zöchbauer-Müller
Dontscho
D
Kerjaschki
Christoph
C
Bock
Lukas
L
Kenner
Gerald
G
Hoefler
Michael
M
Freissmuth
Anthony R
AR
Green
Richard
R
Moriggl
Meinrad
M
Busslinger
Marcos
M
Malumbres
Veronika
V
Sexl
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015448:Leukemia, B-Cell / Q000201:enzymology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology
D051361:Cyclin-Dependent Kinase 6