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.
Highlights
Phosphorylation of Tyr in the 310 helix of p27 reduces its inhibitory activity on cyclin-cyclin-dependent kinase (CDK) complexes
A number of possible tumor-promoting mechanisms ranging from proliferation driven by Kip-dependent cyclin D1-CDK4 nuclear localization [25, 39, 41] to an effect on migration and metastasis associated with Kip-dependent interactions with RhoA signaling molecules [36, 38, 40] have been proposed
Leveraging the ability to complement genetic deficiencies in tumor cells with different alleles of a gene has allowed us to use the RCAS-PDGF-HA/nestin-TvA model to begin to address the importance of particular modifications and protein interactions in the development of proneural glioma
Summary
Phosphorylation of Tyr in the 310 helix of p27 reduces its inhibitory activity on cyclin-CDK complexes. It had been suggested that phosphorylation of this site could switch the tumor-suppressive CDK inhibitory activity to an oncogenic activity 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 310 helix. Tyrosine Phosphorylation of the CDK Inhibitor p21 tor contributes to its conversion from a growth suppressor to a tumor promoter affecting cyclin-CDK inhibitory activity
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