A pathway in quiescent cells that controls p27Kip1 stability, subcellular localization, and tumor suppression.
We have created two knock-in mouse models to study the mechanisms that regulate p27 in normal cells and cause misregulation of p27 in tumors: p27(S10A), in which Ser10 is mutated to Ala; and p27(CK-), in which point mutations abrogate the ability of p27 to bind cyclins and CDKs. These two mutant alleles identify steps in a pathway that controls the proteasomal degradation of p27 uniquely in quiescent cells: Dephosphorylation of p27 on Ser10 inhibits p27 nuclear export and promotes its assembly into cyclin-CDK complexes, which is, in turn, necessary for p27 turnover. We further show that Ras-dependent lung tumorigenesis is associated with increased phosphorylation on Ser10 and cytoplasmic mislocalization of p27. Indeed, we find that p27(S10A) is refractory to Ras-induced cytoplasmic translocation and that p27(S10A) mice are tumor resistant. Thus, phosphorylation of p27 on Ser10 is an important event in the regulation of the tumor suppressor function of p27.
Besson
Arnaud
A
Howard Hughes Medical Institute, Division of Basic Sciences, Seattle, Washington 98109, USA.
Gurian-West
Mark
M
Chen
Xueyan
X
Kelly-Spratt
Karen S
KS
Kemp
Christopher J
CJ
Roberts
James M
JM
D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D017354:Point Mutation; D021381:Protein Transport; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014520:Urethane; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism
D016213:Cyclins; D020703:ras GTPase-Activating Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014520:Urethane; D012694:Serine; D018844:Cyclin-Dependent Kinases