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Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma.
- Source :
-
Oncogene [Oncogene] 1997 Feb 06; Vol. 14 (5), pp. 603-9. - Publication Year :
- 1997
-
Abstract
- Deletions of chromosomal region 9p21 are among the most common genetic alterations observed during the clonal evolution of high grade malignant gliomas. Structural and functional evidence has suggested that homozygous deletion involving CDKN2A (the genetic locus encoding the cyclin-dependent kinase inhibitor p16(NK4a)) is a mechanism of inactivation of this gene and that it can be a growth suppressor in human gliomas. However, the presence of other potential suppressor genes in the 9p21 region and the relatively large sizes of the deletions has made it difficult to be certain that the CDKN2A gene is their actual target. Here, we tested this hypothesis by determining the growth suppressive effects, cell cycle inhibitions, and the activities of seven naturally occurring glioma-derived CDKN2A alleles carrying point mutations and found that two of them were functionally compromised. To resolve discrepancies among the different existing functional assays, we developed an assay for p16(INK4a) function that allowed us to demonstrate that the expression of wild-type CDKN2A, but not alleles with inactivating mutations, prevents pRB phosphorylation in vivo in human glioma cells. These data suggest that CDKN2A is a critical target for mutational inactivation in human malignant gliomas.
- Subjects :
- Alleles
Carrier Proteins genetics
Cell Cycle
Cyclin-Dependent Kinase Inhibitor p16
Enzyme Inhibitors metabolism
Genes, Tumor Suppressor
Glioma pathology
Humans
Phosphorylation
Protein Biosynthesis
Protein Kinase Inhibitors
Recombinant Proteins biosynthesis
Recombinant Proteins metabolism
Retinoblastoma Protein metabolism
Transcription, Genetic
Transfection
Carrier Proteins metabolism
Chromosome Deletion
Chromosomes, Human, Pair 9
Glioma enzymology
Glioma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0950-9232
- Volume :
- 14
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 9053859
- Full Text :
- https://doi.org/10.1038/sj.onc.1200870