Cdk6-cyclin D3 activity in murine ES cells is resistant to inhibition by p16(INK4a).
Through a screen aimed at identifying genes that are specifically upregulated in embryomic stem (ES) cells but not primitive ectoderm, we identified cyclin D3. This was surprising since cyclin D activity is generally believed to be inactive in ES cells even though retinoblastoma tumor suppressor protein (pRb) accumulates in a predominantly hyperphosphorylated state. Cdk6 is the major catalytic partner for cyclin D3 in ES cells and exhibits robust pRb kinase activity that is downregulated during the early stages of ES embryoid body differentiation. To investigate the basis underlying the insensitivity of ES cells to ectopic p16 expression, we show that Cdk6-cyclin D3 complexes are not subject to inhibition by p16, similar to Cdk-viral cyclin complexes. These observations show that specificity exists between Cdk4/6-cyclin D complexes and their ability to be targeted by p16. Our data suggest that Cdk6-cyclin D3 activity in other cell types, including tumors, may also be refractory to p16-mediated growth inhibition and raises the possibility of additional specificity within the INK4 family.
Faast
Renate
R
Department of Molecular Biosciences, BresaGen Cell Therapy Program, Center for Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia, Australia.
White
Josephine
J
Cartwright
Peter
P
Crocker
Lesley
L
Sarcevic
Boris
B
Dalton
Stephen
S
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D056741:Cyclin D; D056743:Cyclin D3; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D017403:In Situ Hybridization; D046911:Macromolecular Substances; D051379:Mice; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
C534697:Ccnd3 protein, mouse; D056741:Cyclin D; D056743:Cyclin D3; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D046911:Macromolecular Substances; D012333:RNA, Messenger; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases