p16INK4A and p19ARF act in overlapping pathways in cellular immortalization.
The INK4A locus encodes two independent but overlapping genes, p16INK4A and p19ARF, and is frequently inactivated in human cancers. The unusual structure of this locus has lead to ambiguity regarding the biological role of each gene. Here we express, in primary mouse embryonic fibroblasts (MEFs), antisense RNA constructs directed specifically towards either p16INK4A or p19 ARF. Such constructs induce extended lifespan in primary MEFs; this lifespan extension is reversed upon subsequent elimination of the p16INK4A or p19ARF antisense constructs. In immortal derivatives of cell lines expressing antisense p16INK4A or p19ARF RNA, growth arrest induced by recovery of p16INK4A expression is bypassed by compromising the function of the retinoblastoma protein (Rb), whereas growth arrest induced by re-expression of p19ARF is overcome only by simultaneous inactivation of both the Rb and the p53 pathways. Thus, the physically overlapping p16INK4A and p19ARF genes act in partly overlapping pathways.
Carnero
A
A
Institute of Child Health, 30 Guilford Street, London WC1 1EH, UK.
Hudson
J D
JD
Price
C M
CM
Beach
D H
DH
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000096:biosynthesis / Q000494:pharmacology; D016923:Cell Death / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D019426:Integrases / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000494:pharmacology; D050725:Papillomavirus E7 Proteins; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016372:RNA, Antisense / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014764:Viral Proteins
D000957:Antigens, Viral, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016372:RNA, Antisense; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C045073:Cre recombinase; D019426:Integrases