Nature Cell Biology2, 148 - 155 (2000)
Published online: 8 February 2000; | doi:10.1038/35004020
p16INK4A and p19ARF act in overlapping
pathways in cellular immortalization
Amancio Carnero1, 2, James D. Hudson1, Cathy M. Price1
& David H. Beach1, 2
1
Institute of Child Health, 30 Guilford
Street, London WC1 1EH, UK
Correspondence should be addressed to David H. Beach dbeach@ucl.ac.uk
2
Present address: Institute of Child Health, UCL, Cruciform
Building, Gower Street, London WC1E
6BT, UK
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.
