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  • The EMBO Journal: 21 (12)

Article

INK4a‐deficient human diploid fibroblasts are resistant to RAS‐induced senescence

Sharon Brookes, Janice Rowe, Margarida Ruas, Susana Llanos, Paula A. Clark, Martine Lomax, Marion C. James, Radost Vatcheva, Stewart Bates, Karen H. Vousden, David Parry, Nelleke Gruis, Nico Smit, Wilma Bergman, Gordon Peters
DOI 10.1093/emboj/cdf289 | Published online 17.06.2002
The EMBO Journal (2002) 21, 2936-2945
Sharon Brookes
Molecular Oncology, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
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Janice Rowe
Molecular Oncology, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
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Margarida Ruas
Molecular Oncology, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
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Susana Llanos
Molecular Oncology, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
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Paula A. Clark
Molecular Oncology, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
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Martine Lomax
Molecular Oncology, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
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Marion C. James
Molecular Oncology, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
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Radost Vatcheva
Human Cytogenetics Laboratories, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
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Stewart Bates
NCI‐FCRDC, Frederick, MD, 21702‐1201, USA
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Karen H. Vousden
NCI‐FCRDC, Frederick, MD, 21702‐1201, USA
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David Parry
DNAX Research Institute, Palo Alto, CA, 94304‐1104, USA
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Nelleke Gruis
Department of Dermatology, Leiden University Medical Centre, 2333, AL Leiden, The Netherlands
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Nico Smit
Department of Dermatology, Leiden University Medical Centre, 2333, AL Leiden, The Netherlands
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Wilma Bergman
Department of Dermatology, Leiden University Medical Centre, 2333, AL Leiden, The Netherlands
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Gordon Peters
Molecular Oncology, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
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Author Affiliations

  1. Sharon Brookes1,
  2. Janice Rowe1,
  3. Margarida Ruas1,
  4. Susana Llanos1,
  5. Paula A. Clark1,
  6. Martine Lomax1,
  7. Marion C. James1,
  8. Radost Vatcheva2,
  9. Stewart Bates3,
  10. Karen H. Vousden3,
  11. David Parry4,
  12. Nelleke Gruis5,
  13. Nico Smit5,
  14. Wilma Bergman5 and
  15. Gordon Peters*,1
  1. 1 Molecular Oncology, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
  2. 2 Human Cytogenetics Laboratories, Cancer Research UK London Research Institute, Lincolns Inn Fields, London, WC2A 3PX, UK
  3. 3 NCI‐FCRDC, Frederick, MD, 21702‐1201, USA
  4. 4 DNAX Research Institute, Palo Alto, CA, 94304‐1104, USA
  5. 5 Department of Dermatology, Leiden University Medical Centre, 2333, AL Leiden, The Netherlands
  1. ↵*Corresponding author. E‐mail: g.peters{at}cancer.org.uk
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Abstract

The CDKN2A tumour suppressor locus encodes two distinct proteins, p16INK4a and p14ARF, both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by aberrant proliferative signals or by cumulative population doublings in culture. Here we describe primary fibroblasts from a member of a melanoma‐prone family who is homozygous for an intragenic deletion in CDKN2A. Analyses of the resultant gene products imply that the cells are p16INK4a deficient but express physiologically relevant levels of a frameshift protein that retains the known functions of p14ARF. Although they have a finite lifespan, the cells are resistant to arrest by oncogenic RAS. Indeed, ectopic expression of RAS and telomerase (hTERT) results in outgrowth of anchorage‐independent colonies that have essentially diploid karyotypes and functional p53. We find that in human fibroblasts, ARF is not induced demonstrably by RAS, pointing to significant differences between the proliferative barriers implemented by the CDKN2A locus in different cell types or species.

  • anchorage independence
  • p14ARF
  • p16INK4a
  • Ras
  • senescence
  • Received January 2, 2002.
  • Revision received April 8, 2002.
  • Accepted April 18, 2002.
  • Copyright © 2002 European Molecular Biology Organization
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Volume 21, Issue 12
17 June 2002
The EMBO Journal: 21 (12)
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