HOMOZYGOUS CODELETION AND DIFFERENTIAL DECREASED EXPRESSION OF P15(INK4B) P16(INK4A)-ALPHA AND P16(INK4A)-BETA IN MOUSE LUNG-TUMOR CELLS

Citation
Cr. Herzog et al., HOMOZYGOUS CODELETION AND DIFFERENTIAL DECREASED EXPRESSION OF P15(INK4B) P16(INK4A)-ALPHA AND P16(INK4A)-BETA IN MOUSE LUNG-TUMOR CELLS, Oncogene, 13(9), 1996, pp. 1885-1891
Citations number
40
Categorie Soggetti
Oncology,Biology,"Cell Biology
Journal title
ISSN journal
09509232
Volume
13
Issue
9
Year of publication
1996
Pages
1885 - 1891
Database
ISI
SICI code
0950-9232(1996)13:9<1885:HCADDE>2.0.ZU;2-W
Abstract
The genes of murine cyclin D-dependent kinase inhibitors, p15(INK4b) a nd p16(INK4a), are located in a region of chromosome 4 where overlappi ng deletions were found in lung adenocarcinomas, The p16(INK4a) gene u niquely consists of alternative first exons (E1 alpha and E1 beta), wh ich are spliced to exon 2 in alternative reading frames to either enco de p16(INK4a) (alpha form) or another potential tumor suppressor, p19( ARF) (beta form), We examined 99 lung adenocarcinomas of C3H/HeJ x A/J F-1(C3AF(1)) and A/J x C3H/HeJ F-1(AC3F(1)) mouse hybrids and 18 (13 metastatic, 5 nonmetastatic) tumorigenic mouse lung epithelial cell li nes for p15(INK4b) and p16(INK4a) gene inactivation, Homozygous codele tion occurred in eight of the 13 (62%) metastatic, four of the five (8 0%) nonmetastatic cell lines, but in only six of 99 (6%) adenocarcinom as. Neither p15(INK4b) nor p16(INK4a) gene was individually deleted in any of the tumors or cell lines, and all deletions of the p16(INK4a) gene extended into exon 2, which would be expected to disrupt the func tions of both p16(INK4a) and p19(ARF). We also detected no intragenic mutations of either gene in 44 tumors that displayed loss of heterozyg osity at the p16(INK4a) locus or in any of the cell lines, Transcript levels of p16(INK4a)-alpha, p16(INK4a)-beta and p15(INK4b) also were e xamined in each of the cell lines that retained copies of these genes, Whereas an immortal mouse lung epithelial cell line (E10) and two met astatic tumor cell lines (LM1 and E9) expressed p16(INK4a)-beta and p1 5(INK4b) mRNA, the a transcript of p16(INK4a) was detected in only the LM1 cell line. These results suggest that both p15(INK4b) and p16(INK 4a) (alpha and beta) are targets of inactivation in mouse lung tumorig enesis.