| First Author | Herzog CR | Year | 1999 |
| Journal | Mol Carcinog | Volume | 25 |
| Issue | 2 | Pages | 92-8 |
| PubMed ID | 10365910 | Mgi Jnum | J:55837 |
| Mgi Id | MGI:1339456 | Doi | 10.1002/(sici)1098-2744(199906)25:2<92::aid-mc3>3.0.co;2-2 |
| Citation | Herzog CR, et al. (1999) Cdkn2a encodes functional variation of p16INK4a but not p19ARF, which confers selection in mouse lung tumorigenesis. Mol Carcinog 25(2):92-8 |
| abstractText | The cyclin-dependent kinase inhibitor Za (Cdkn2a) locus encodes two distinct tumor suppressors, p16(INK4a) and p19(ARF), whose functions interrelate in the regulation of cell proliferation as key components of the retinoblastoma and p53 pathways, respectively. In many types of cancer, alterations of Cdkn2a abrogate the functions of both suppressors, implying that both are integral to the genesis of certain cancer types. While this has been observed in mouse lung adenocarcinogenesis, recent observations also suggested that naturally occurring variation at the Cdkn2a locus is probably operative in the development of these tumors. Firstly, two common haplotypes of mouse Cdkn2a have been identified, each of which encodes cosegregating variants of p16(INK4a) and p19(ARF). The p16(INK4a) variants differ at amino acids 18 (histidine or proline) and 51 (valine or isoleucine), whereas the p19(ARF) variants differ only at amino acid 72 (histidine or arginine). Secondly, genetic resistance to lung tumor formation appears to segregate with one particular haplotype, which also is deleted preferentially in lung adenocarcinomas of Cdkn2a heterozygous mice. Here we attempt to explain these observations and to characterize further the roles of p16(INK4a) and p19(ARF) in mouse lung tumorigenesis by examining the function and expression of each of the variants of Cdkn2a. Functional analysis showed that the proline 18/isoleucine 51 p16(INK4a) variant was diminished in cdk6 binding, cdk6 inhibition and NIH/3T3 fibroblast growth suppression compared with the histidine 18/valine 51 variant, whereas both of the p19(ARF) variants suppressed growth with similar potencies. Also, the different alleles for p16(INK4a) and p19(ARF) were transcribed equally in the normal lungs of Cdkn2a heterozygotes, as determined by comparative reverse transcription-polymerase chain reaction-single-stranded conformation polymorphism analysis. These results indicate that strain-specific variation in p16(INK4a) function is exploited in mouse lung tumorigenesis and strongly implicate a role for p16(INK4a) in lung cancer predisposition and development. (C) 1999 Wiley-Liss, Inc. |
