title: Tyrosine phosphorylation of the p21 cyclin-dependent kinase inhibitor facilitates the development of proneural glioma.
abstract: Phosphorylation of Tyr-88/Tyr-89 in the 3(10) helix of p27 reduces its cyclin-dependent kinase (CDK) inhibitory activity. This modification does not affect the interaction of p27 with cyclin-CDK complexes but does interfere with van der Waals and hydrogen bond contacts between p27 and amino acids in the catalytic cleft of the CDK. Thus, it had been suggested that phosphorylation of this site could switch the tumor-suppressive CDK inhibitory activity to an oncogenic activity. Here, we examined this hypothesis in the RCAS-PDGF-HA/nestin-TvA proneural glioma mouse model, in which p21 facilitates accumulation of nuclear cyclin D1-CDK4 and promotes tumor development. In these tumor cells, approximately one-third of the p21 is phosphorylated at Tyr-76 in the 3(10) helix. Mutation of this residue to glutamate reduced inhibitory activity in vitro. Mutation of this residue to phenylalanine reduced the tumor-promoting activity of p21 in the animal model, whereas glutamate or alanine substitution allowed tumor formation. Consequently, we conclude that tyrosine phosphorylation contributes to the conversion of CDK inhibitors from tumor-suppressive roles to oncogenic roles.
authors.affiliation: Gerstner School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hukkelhoven
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Liu
authors.forename: Nancy
authors.initials: N
authors.lastname: Yeh
authors.forename: Daniel
authors.initials: D
authors.lastname: Ciznadija
authors.forename: Stacy W
authors.initials: SW
authors.lastname: Blain
authors.forename: Andrew
authors.initials: A
authors.lastname: Koff
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D016543:Central Nervous System Neoplasms / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism; D005910:Glioma / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D014443:Tyrosine; D051358:Cyclin-Dependent Kinase 4