Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma

Wadih Arap, Erik S. Knudsen, Jean Y J Wang, Webster K. Cavenee, H. J Su Huang

Research output: Contribution to journalArticle

31 Citations (Scopus)

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(INK4a)) 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.

Original languageEnglish (US)
Pages (from-to)603-609
Number of pages7
JournalOncogene
Volume14
Issue number5
StatePublished - 1997

Fingerprint

Point Mutation
Glioma
Alleles
Cyclin-Dependent Kinase Inhibitor p16
Clonal Evolution
Suppressor Genes
p16 Genes
Genetic Loci
Gene Silencing
Growth
Cell Cycle
Phosphorylation
In Vitro Techniques
Mutation

Keywords

  • CDKN2A
  • Glioma
  • Mutation
  • p16(INK4a)
  • RB
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Arap, W., Knudsen, E. S., Wang, J. Y. J., Cavenee, W. K., & Huang, H. J. S. (1997). Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma. Oncogene, 14(5), 603-609.

Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma. / Arap, Wadih; Knudsen, Erik S.; Wang, Jean Y J; Cavenee, Webster K.; Huang, H. J Su.

In: Oncogene, Vol. 14, No. 5, 1997, p. 603-609.

Research output: Contribution to journalArticle

Arap, W, Knudsen, ES, Wang, JYJ, Cavenee, WK & Huang, HJS 1997, 'Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma', Oncogene, vol. 14, no. 5, pp. 603-609.
Arap W, Knudsen ES, Wang JYJ, Cavenee WK, Huang HJS. Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma. Oncogene. 1997;14(5):603-609.
Arap, Wadih ; Knudsen, Erik S. ; Wang, Jean Y J ; Cavenee, Webster K. ; Huang, H. J Su. / Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma. In: Oncogene. 1997 ; Vol. 14, No. 5. pp. 603-609.
@article{32bd84679fd4470d90e771ed161c2710,
title = "Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma",
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(INK4a)) 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.",
keywords = "CDKN2A, Glioma, Mutation, p16(INK4a), RB, Tumor suppressor gene",
author = "Wadih Arap and Knudsen, {Erik S.} and Wang, {Jean Y J} and Cavenee, {Webster K.} and Huang, {H. J Su}",
year = "1997",
language = "English (US)",
volume = "14",
pages = "603--609",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma

AU - Arap, Wadih

AU - Knudsen, Erik S.

AU - Wang, Jean Y J

AU - Cavenee, Webster K.

AU - Huang, H. J Su

PY - 1997

Y1 - 1997

N2 - 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(INK4a)) 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.

AB - 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(INK4a)) 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.

KW - CDKN2A

KW - Glioma

KW - Mutation

KW - p16(INK4a)

KW - RB

KW - Tumor suppressor gene

UR - http://www.scopus.com/inward/record.url?scp=0031047550&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031047550&partnerID=8YFLogxK

M3 - Article

C2 - 9053859

AN - SCOPUS:0031047550

VL - 14

SP - 603

EP - 609

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 5

ER -