Tyrosine phosphorylation of the p21 cyclin-dependent kinase inhibitor facilitates the development of proneural glioma Journal Article
| Authors: | Hukkelhoven, E.; Liu, Y.; Yeh, N.; Ciznadija, D.; Blain, S. W.; Koff, A. |
| Article 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 cyclinD1-CDK4and 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.Mutationof this residue to phenylalanine reduced thetumorpromoting 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. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | mutation; nonhuman; glioma; cell proliferation; mouse; animals; mice; amino acid substitution; animal experiment; animal model; in vivo study; in vitro study; enzyme activity; tyrosine; phosphorylation; central nervous system neoplasms; carcinogenesis; gene expression regulation, neoplastic; enzyme phosphorylation; amino acid sequence; molecular sequence data; tumors; glioblastoma; cyclin-dependent kinase inhibitor p27; cyclin-dependent kinase inhibitors; tumor promotion; cyclin-dependent kinase inhibitor p21; amino acids; mouse models; disease models, animal; cyclin d1; cyclin-dependent kinase; cyclin dependent kinase 4; cyclin-dependent kinase 4; tumor cells; hydrogen bonds; cdk inhibitors; hek293 cells; cyclin dependent kinase inhibitor 1; alanine substitution; tyrosine phosphorylation; cyclind1; tumor formation; van der waals forces; tumor development; inhibitory activity; oncogenic activities; van der waals |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 287 |
| Issue: | 46 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2012-11-09 |
| Start Page: | 38523 |
| End Page: | 38530 |
| Language: | English |
| DOI: | 10.1074/jbc.M112.366542 |
| PROVIDER: | scopus |
| PMCID: | PMC3493897 |
| PUBMED: | 23007395 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 December 2012" - "CODEN: JBCHA" - "Source: Scopus" |
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