Functional analysis of mild-type and malignant glioma derived CDKN2Aβ alleles: Evidence for an RB-independent growth suppressive pathway

Wadih Arap, Erik Knudsen, Duane A. Sewell, David Sidransky, Jean Y J Wang, H. J Su Huang, Webster K. Cavenee

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

The tumor suppressor gene CDKN2A (pl6/MTS1/INK4A), which encodes the cyclin-dependent kinase inhibitor p16(INK4a), is a target of 9p21 deletions during the malignant progression of human gliomas. This gene also encodes a second protein product (human p16β, murine p19(ARF)), which originates from an unrelated exon of CDKN2A (exon 1β) spliced onto exon 2 in an alternate reading frame. Cell cycle arrest by p16β is caused by an as yet unidentified pathway. In order to test the candidacy of p16β as a glioma suppressor, we replaced p16(INK4a), p15(INK4b) and p16β wild-type as well as a series of seven glioma-derived p16β alleles (R87H, A112V, R120H, A121V, G125R, A128A and A128V), into glioma cell lines that had either CDKN2A-/RB+ (U-87MG and U-251MG) or CDKN2A+/RB- (LN-319) endogenous backgrounds and demonstrated that p16β can act as a functional glioma cell growth suppressor. Moreover, p16β, but not p16(INK4a) or p15(INK4b) inhibited the growth of RB-negative LN-319 cells, indicating that p16β likely exerts its effects through an RB-independent pathway. In vitro and in vivo assays of pRB phosphorylation were consistent with this interpretation. Since none of the glioma-derived p16β mutations inactivated their growth suppressive activities, it appears that mutations in CDKN2A exon 2 (which is shared in the coding sequences of p16(INK4a) and p16β) likely exclusively target p16(INK4a).

Original languageEnglish (US)
Pages (from-to)2013-2020
Number of pages8
JournalOncogene
Volume15
Issue number17
DOIs
StatePublished - Jan 1 1997

Keywords

  • CDKN2A
  • Malignant glioma
  • P16(INK4a.)
  • RB
  • Tumor suppressor gene
  • p16β

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Arap, W., Knudsen, E., Sewell, D. A., Sidransky, D., Wang, J. Y. J., Huang, H. J. S., & Cavenee, W. K. (1997). Functional analysis of mild-type and malignant glioma derived CDKN2Aβ alleles: Evidence for an RB-independent growth suppressive pathway. Oncogene, 15(17), 2013-2020. https://doi.org/10.1038/sj.onc.1201389