Biallelic Mutations in p16INK4a Confer Resistance to Ras- and Ets-Induced Senescence in Human Diploid Fibroblasts
Open Access
- 1 December 2002
- journal article
- Published by Taylor & Francis in Molecular and Cellular Biology
- Vol. 22 (23) , 8135-8143
- https://doi.org/10.1128/mcb.22.23.8135-8143.2002
Abstract
The INK4a/ARF tumor suppressor locus is implicated in the senescence-like growth arrest provoked by oncogenic Ras in primary cells. INK4a and ARF are distinct proteins encoded by transcripts in which a shared exon is decoded in alternative reading frames. Here we analyze dermal fibroblasts (designated Q34) from an individual carrying independent missense mutations in each copy of the common exon. Both mutations alter the amino acid sequence of INK4a and functionally impair the protein, although they do so to different degrees. Only one of the mutations affects the sequence of ARF, causing an apparently innocuous change near its carboxy terminus. Unlike normal human fibroblasts, Q34 cells are not permanently arrested by Ras or its downstream effectors Ets1 and Ets2. Moreover, ectopic Ras enables the cells to grow as anchorage-independent colonies, and in relatively young Q34 cells anchorage independence can be achieved without addition of telomerase or perturbation of the p53 pathway. Whereas ARF plays the principal role in Ras-induced arrest of mouse fibroblasts, our data imply that INK4a assumes this role in human fibroblasts.Keywords
This publication has 58 references indexed in Scilit:
- Role of p14ARF in Replicative and Induced Senescence of Human FibroblastsMolecular and Cellular Biology, 2001
- The INK4a/ARF network in tumour suppressionNature Reviews Molecular Cell Biology, 2001
- A melanoma-associated germline mutation in exon 1β inactivates p14ARFOncogene, 2001
- An N-terminal p14ARF peptide blocks Mdm2-dependent ubiquitination in vitro and can activate p53 in vivoOncogene, 2000
- Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group [published erratum appears in Hum Mol Genet 1998 May;7(5):941]Human Molecular Genetics, 1998
- Regulation of p53 stability by Mdm2Nature, 1997
- Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4aCell, 1997
- Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindredsNature Genetics, 1995
- Genetic heterogeneity in familial malignant melanomaHuman Molecular Genetics, 1994
- A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4Nature, 1993