cdk6 can shorten G(1) phase dependent upon the N-terminal INK4 interaction domain.
Deregulated activity of cdk4 or cdk6 can lead to inappropriate cellular proliferation and tumorigenesis accompanied by unchecked inactivation of the retinoblastoma tumor suppressor protein. Certain tumor types preferentially activate either cdk4 or cdk6, suggesting that these kinases may not be equivalently oncogenic in all cell types. Although it is clear that cdk4 can act as an oncogene at least in part by evading inhibition by p16(INK4a), the role of cdk6 in tumorigenesis is less well understood. To investigate the consequences of aberrant expression of cdk6, the requirements for proliferation caused by cdk6 overexpression were studied. cdk6-transfected U2OS cells displayed an accelerated progression through G(1) phase that was dependent on kinase activity and that did not correlate with p27 binding. Furthermore, a mutation that prevents cdk6 interaction with INK4 proteins (cdk6R31C) was found to inactivate the proliferative effect of cdk6 and increase cytoplasmic localization, despite the fact that this mutant could phosphorylate the retinoblastoma protein in vitro. Together, these data suggest a role for the cdk6 INK4 interaction domain in the generation of functional, nuclear cdk6 complexes and demonstrate the importance of elevated cdk6 kinase activity in G(1) acceleration.
Grossel
M J
MJ
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Baker
G L
GL
Hinds
P W
PW
D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases; D005434:Flow Cytometry; D016193:G1 Phase / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases