Alternative splicing of the p15 cdk inhibitor in glioblastoma multiforme.
Thirty-four to fifty-six percent of malignant gliomas harbor homozygous co-deletions of the INK4a(p16-p14ARF) and INK4b(p15) tumor suppressor genes. Recently, an alternatively spliced form of p15 has been cloned and termed p10 based on the presumed molecular weight of the protein. In this study, we have investigated the role of p10 expression in human glioblastomas. Both, wild-type p15 and p10 were detected in three of nine glioblastoma cell lines. Sixteen of twenty-nine (55%) glioblastoma tumor samples contained INK4b transcripts, but only nine (31%) tumors expressed p15 protein. Three p15 protein-negative tumors expressed only p10 mRNA. Preferential expression of p10 was not due to splice site mutations. Strong suppression of tumorigenicity was seen in four glioblastoma cell lines after transfection with p15 but not with p10. Loss of p15 protein expression was almost always accompanied by loss of p16 expression. p1 6/p15-negative tumors commonly lacked p14ARF expression. These results suggest that differential splicing of the INK4b gene may result in the expression of p10 at the expense of p15, which would lead to loss of p15-mediated growth suppression. This novel mechanism of loss of p15 might complement alterations of the INK4a tumor suppressor gene in some glioblastomas, resulting in combined loss of p16, p15 and p14ARF.
Simon
M
M
Neurochirurgische Klinik, Universitätskliniken Bonn, Germany. Matthias.Simon@ukb.uni-bonn.de
Köster
G
G
Ludwig
M
M
Mahlberg
R
R
Rho
S
S
Watzka
M
M
Schramm
J
J
D017398:Alternative Splicing / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins