TY - JOUR
T1 - Functional analysis of mild-type and malignant glioma derived CDKN2Aβ alleles
T2 - Evidence for an RB-independent growth suppressive pathway
AU - Arap, Wadih
AU - Knudsen, Erik
AU - Sewell, Duane A.
AU - Sidransky, David
AU - Wang, Jean Y J
AU - Huang, H. J Su
AU - Cavenee, Webster K.
PY - 1997
Y1 - 1997
N2 - 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).
AB - 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).
KW - CDKN2A
KW - Malignant glioma
KW - P16(INK4a.)
KW - RB
KW - Tumor suppressor gene
KW - p16β
UR - http://www.scopus.com/inward/record.url?scp=0030613650&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030613650&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1201389
DO - 10.1038/sj.onc.1201389
M3 - Article
C2 - 9366518
AN - SCOPUS:0030613650
SN - 0950-9232
VL - 15
SP - 2013
EP - 2020
JO - Oncogene
JF - Oncogene
IS - 17
ER -