Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 56

The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.

Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells

Yasaei, H, Gilham, E, Pickles, J C, Roberts, T P, O'Donovan, M, Newbold, R F·2013·Oncogene
DOI 10.1038/onc.2012.45
Open this paper in CoChat — free account

Abstract

Immortalization (senescence bypass) is a critical rate-limiting step in the malignant transformation of mammalian somatic cells. Human cells must breach at least two distinct senescence barriers to permit unfettered clonal evolution during cancer development: (1) stress- or oncogene-induced premature senescence (SIPS/OIS), mediated via the p16-Rb and/or ARF-p53-p21 tumour-suppressive pathways, and (2) replicative senescence triggered by telomere shortening. In contrast, because their telomerase is constitutively active, cells from small rodents possess only the SIPS/OIS barrier, and are therefore useful for studying SIPS/OIS bypass in isolation. Dermal fibroblasts from the Syrian hamster (SHD cells) are exceptionally resistant to spontaneous SIPS bypass, but it can be readily induced following exposure to a wide range of chemical and physical carcinogens. Here we show that a spectrum of carcinogen-specific mutational and epigenetic alterations involving the INK4A (p16), p53 and INK4B (p15) genes are associated with induced SIPS bypass. With ionizing radiation, immortalization is invariably accompanied by efficient biallelic deletion of the complete INK4/CDKN2 locus. In comparison, SHD cells immortalized by the powerful polycyclic hydrocarbon carcinogen benzo(a)pyrene display transversion point mutations in the DNA-binding domain of p53 coupled with INK4 alterations such as loss of expression of p15. Epimutational silencing of p16 is the primary event associated with immortali…

Overview

Integrity signals

Registry

Crossref · 10.1038/onc.2012.45

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Show all 6 references

Research works printed but not linked: 44

  1. Newbold RF . Cellular immortalization and telomerase activation in cancer. In: Knowles M, Selby P (eds) Introduction to the Cellular and Molecular Biology of Cancer 4th edn. Oxford University Press: Oxford 2005. pp 170–185. · DOI
  2. Russo I, Silver A, Cuthbert A, Griffin D, Trott D, Newbold R . A telomere-independent senescence mechanism is the sole barrier to Syrian hamster cell immortalization. Oncogene 1998; 17: 3417–3426. · DOI
  3. Seluanov A, Hine C, Bozzella M, Hall A, Sasahara TH, Ribeiro AA et al. Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan. Aging Cell 2008; 7: 813–823. · DOI
  4. Campisi J . Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 2001; 11: S27–S31. · DOI · Paper page
  5. Trott D, Cuthbert A, Overell R, Russo I, Newbold R . Mechanisms involved in the immortalization of mammalian cells by ionizing radiation and chemical carcinogens. Carcinogenesis 1995; 16: 193–204. · DOI
  6. Newbold R, Overell R, Connell J . Induction of immortality is an early event in malignant transformation of mammalian cells by carcinogens. Nature 1982; 299: 633–635. · DOI
  7. Creton S, Aardema MJ, Carmichael PL, Harvey JS, Martin FL, Newbold RF et al. Cell transformation assays for prediction of carcinogenic potential: state of the science and future research needs. Mutagenesis 2011; 27: 93–101. · DOI
  8. Newbold RF, Wigley CB, Thompson MH, Brookes P . Cell-mediated mutagenesis in cultured Chinese hamster cells by carcinogenic polycyclic hydrocarbons: nature and extent of the associated hydrocarbon-DNA reaction. Mutat Res 1977; 43: 101–116. · DOI
  9. Newbold R, Brookes P . Exceptional mutagenicity of a benzo(a)pyrene diol epoxide in cultured mammalian cells. Nature 1976; 261: 52–54. · DOI
  10. Newbold R, Warren W, Medcalf A, Amos J . Mutagenicity of carcinogenic methylating agents is associated with a specific DNA modification. Nature 1980; 283: 596–599. · DOI · Paper page
  11. Arita A, Costa M . Epigenetics in metal carcinogenesis: nickel, arsenic, chromium and cadmium. Metallomics 2009; 1: 222–228. · DOI
  12. Ruas M, Peters G . The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1998; 1378: F115–F177.
  13. Csepregi A, Ebert MP, Röcken C, Schneider-Stock R, Hoffmann J, Schulz HU et al. Promoter methylation of CDKN2A and lack of p16 expression characterize patients with hepatocellular carcinoma. BMC Cancer 2010; 10: 317. · DOI
  14. Goh AM, Coffill CR, Lane DP . The role of mutant p53 in human cancer. J Pathol 2011; 223: 116–126. · DOI
  15. Whibley C, Odell A, Nedelko T, Balaburski G, Murphy M, Liu Z et al. Wild-type and Hupki (human p53 knock-in) murine embryonic fibroblasts: p53/ARF pathway disruption in spontaneous escape from senescence. J Biol Chem 2010; 285: 11326–11335. · DOI
  16. Odell A, Askham J, Whibley C, Hollstein M . How to become immortal: let MEFs count the ways. Aging (Albany NY) 2010; 2: 160–165. · DOI
  17. Chang K, Laconi S, Mangold K, Hubchak S, Scarpelli D . Multiple genetic alterations in hamster pancreatic ductal adenocarcinomas. Cancer Res 1995; 55: 2560–2568.
  18. Chang K, Mangold K, Hubchak S, Laconi S, Scarpelli D . Genomic p53 mutation in a chemically induced hamster pancreatic ductal adenocarcinoma. Cancer Res 1994; 54: 3878–3883.
  19. Chang K, Lin S, Koos S, Pather K, Solt D . p53 and Ha-ras mutations in chemically induced hamster buccal pouch carcinomas. Carcinogenesis 1996; 17: 595–600. · DOI
  20. Chang K, Sarraj S, Lin S, Tsai P, Solt D . P53 expression, p53 and Ha-ras mutation and telomerase activation during nitrosamine-mediated hamster pouch carcinogenesis. Carcinogenesis 2000; 21: 1441–1451.
  21. Gimenez-Conti I, LaBate M, Liu F, Osterndorff E . p53 alterations in chemically induced hamster cheek-pouch lesions. Mol Carcinog 1996; 16: 197–202. · DOI
  22. Oreffo V, Lin H, Padmanabhan R, Witschi H . K-ras and p53 point mutations in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced hamster lung tumors. Carcinogenesis 1993; 14: 451–455. · DOI
  23. Legros Y, McIntyre P, Soussi T . The cDNA cloning and immunological characterization of hamster p53. Gene 1992; 112: 247–250. · DOI
  24. Popescu N, Zimonjic D, Albor A, Notario V . Localization of the Tp53 gene on Syrian hamster chromosome 9 by fluorescence in situ hybridization. Cytogenet Cell Genet 1995; 68: 71–73. · DOI
  25. Ling H, Sayer JM, Plosky BS, Yagi H, Boudsocq F, Woodgate R et al. Crystal structure of a benzo[a]pyrene diol epoxide adduct in a ternary complex with a DNA polymerase. Proc Natl Acad Sci USA 2004; 101: 2265–2269. · DOI
  26. Li J, Weghorst C, Tsutsumi M, Poi M, Knobloch T, Casto B et al. Frequent p16INK4A/CDKN2A alterations in chemically induced Syrian golden hamster pancreatic tumors. Carcinogenesis 2004; 25: 263–268. · DOI
  27. Li J, Warner B, Casto B, Knobloch T, Weghorst C . Tumor suppressor p16(INK4A)/Cdkn2a alterations in 7, 12-dimethylbenz(a)anthracene (DMBA)-induced hamster cheek pouch tumors. Mol Carcinog 2008; 47: 733–738. · DOI
  28. Muscarella P, Knobloch T, Ulrich A, Casto B, Moniaux N, Wittel U et al. Identification and sequencing of the Syrian Golden hamster (Mesocricetus auratus) p16(INK4a) and p15(INK4b) cDNAs and their homozygous gene deletion in cheek pouch and pancreatic tumor cells. Gene 2001; 278: 235–243. · DOI
  29. Li J, Qin D, Knobloch T, Tsai M, Weghorst C, Melvin W et al. Expression and characterization of Syrian golden hamster p16, a homologue of human tumor suppressor p16 INK4A. Biochem Biophys Res Commun 2003; 304: 241–247. · DOI
  30. Hanaoka M, Shimizu K, Shigemura M, Kato A, Fujii H, Honoki K et al. Cloning of the hamster p16 gene 5′ upstream region and its aberrant methylation patterns in pancreatic cancer. Biochem Biophys Res Commun 2005; 333: 1249–1253. · DOI
  31. Haga K, Ohno S, Yugawa T, Narisawa-Saito M, Fujita M, Sakamoto M et al. Efficient immortalization of primary human cells by p16INK4a-specific short hairpin RNA or Bmi-1, combined with introduction of hTERT. Cancer Sci 2007; 98: 147–154. · DOI
  32. Yaswen P, Stampfer MR . Molecular changes accompanying senescence and immortalization of cultured human mammary epithelial cells. Int J Biochem Cell Biol 2002; 34: 1382–1394. · DOI
  33. Camacho CV, Mukherjee B, McEllin B, Ding LH, Hu B, Habib AA et al. Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks. Carcinogenesis 2010; 31: 1889–1896. · DOI
  34. Florl AR, Schulz WA . Peculiar structure and location of 9p21 homozygous deletion breakpoints in human cancer cells. Genes Chromosomes Cancer 2003; 37: 141–148. · DOI
  35. Grafström E, Egyházi S, Ringborg U, Hansson J, Platz A . Biallelic deletions in INK4 in cutaneous melanoma are common and associated with decreased survival. Clin Cancer Res 2005; 11: 2991–2997. · DOI
  36. Raschke S, Balz V, Efferth T, Schulz WA, Florl AR . Homozygous deletions of CDKN2A caused by alternative mechanisms in various human cancer cell lines. Genes Chromosomes Cancer 2005; 42: 58–67. · DOI
  37. Windhofer F, Krause S, Hader C, Schulz WA, Florl AR . Distinctive differences in DNA double-strand break repair between normal urothelial and urothelial carcinoma cells. Mutat Res 2008; 638: 56–65. · DOI
  38. Garbe JC, Bhattacharya S, Merchant B, Bassett E, Swisshelm K, Feiler HS et al. Molecular distinctions between stasis and telomere attrition senescence barriers shown by long-term culture of normal human mammary epithelial cells. Cancer Res 2009; 69: 7557–7568. · DOI
  39. Liu Z, Muehlbauer KR, Schmeiser HH, Hergenhahn M, Belharazem D, Hollstein MC . p53 mutations in benzo(a)pyrene-exposed human p53 knock-in murine fibroblasts correlate with p53 mutations in human lung tumors. Cancer Res 2005; 65: 2583–2587. · DOI
  40. Krimpenfort P, Ijpenberg A, Song JY, van der Valk M, Nawijn M, Zevenhoven J et al. p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a. Nature 2007; 448: 943–946. · DOI · Paper page
  41. Peters G . An INKlination for epigenetic control of senescence. Nat Struct Mol Biol 2008; 15: 1133–1134. · DOI
  42. He J, Kallin EM, Tsukada Y, Zhang Y . The H3K36 demethylase Jhdm1b/Kdm2b regulates cell proliferation and senescence through p15(Ink4b). Nat Struct Mol Biol 2008; 15: 1169–1175. · DOI
  43. Lam T, Ruczinski I, Helzlsouer K, Shugart Y, Li K, Clipp S et al. Copy number variants of GSTM1 and GSTT1 in relation to lung cancer risk in a prospective cohort study. Ann Epidemiol 2009; 19: 546–552. · DOI
  44. Li LC, Dahiya R . MethPrimer: designing primers for methylation PCRs. Bioinformatics 2002; 18: 1427–1431. · DOI

Cited by

See all 56

Metadata

Authors
Yasaei, H., Gilham, E., Pickles, J. C., Roberts, T. P., O'Donovan, M., & Newbold, R. F.
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2012-03-12
Volume
32
Issue
2
Pages
171-179
ISSN
  • 0950-9232
  • 1476-5594
DOI
10.1038/onc.2012.45
Cited by
56
References
6
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells. https://app.cochat.ai/papers/10.1038/onc.2012.45
The paper
Yasaei, H., Gilham, E., Pickles, J. C., Roberts, T. P., O'Donovan, M., & Newbold, R. F. (2013). Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells. Oncogene. https://doi.org/10.1038/onc.2012.45