This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rebel, H. Articles by de Gruijl, F. R. Search for Related Content PubMed PubMed Citation Articles by Rebel, H. Articles by de Gruijl, F. R.

Early p53-positive Foci as Indicators of Tumor Risk in Ultraviolet-exposed Hairless Mice: Kinetics of Induction, Effects of DNA Repair Deficiency, and p53 Heterozygosity¹

Department of Dermatology, University Medical Center Utrecht, 3508 GA Utrecht [H. R., L. O. M., R. J. W. B., F. R. d. G.], and Laboratory for Health Effects Research, National Institute for Public Health and the Environment, 3721 MA Bilthoven [A. W-d. V., H. v. S., H. J. v. K.], the Netherlands

p53 mutations appear to be early events in skin carcinogenesis induced by chronic UVB irradiation. Clusters of epidermal cells that express p53 in mutant conformation ("p53 positive foci") are easily detected by immunohistochemical staining long before the appearance of skin carcinomas or their precursor lesions. In a hairless mouse model, we determined the dose-time dependency of the induction of these p53+ foci and investigated the relationship with the induction of skin carcinomas. The density of p53+ foci may be a good direct indicator of tumor risk.

Hairless SKH1 mice were exposed to either of two regimens of daily UVB (500 or 250 J/m² broadband UV from Philips TL12 lamps; 54% UVB 280–315 nm). With the high-dose regimen, the average number of p53+ foci in a dorsal skin area (7.2 cm²) increased rapidly from 9.0 ± 2.1 (SE) at 15 days to 470 ± 80 (SE) at 40 days. At half that daily dose, the induction of p53+ foci was slower by a factor of 1.49 ± 0.15, very similar to a previously observed slower induction of squamous cell carcinomas by a factor of 1.54 ± 0.02. In a double-log plot of the average number of p53+ foci versus time, the curves for the two exposure regimens ran parallel (slope, 3.7 ± 0.7), similar to the curves for the number of tumors versus time (slope, 6.9 ± 0.8). The difference in slopes (3.7 versus 6.9) is in line with the contention that more rate-limiting steps are needed to develop a tumor than a p53+ focus. By the time the first tumors appear (around 7–8 weeks with the high daily dose), the dorsal skin contains >100 p53+ foci/cm².

To further validate the density of p53+ foci as a direct measure of tumor risk, we carried out experiments with transgenic mice with an enhanced susceptibility to UV carcinogenesis, homozygous Xpa knockout mice (deficient in nucleotide excision repair) and heterozygous p53 knockout mice (i.a. partially deficient in apoptosis). In both of these cancer-prone strains, the p53+ foci were induced at markedly increased rates, corresponding to increased rates of carcinoma formation. Therefore, the frequency of p53+ foci appears to correlate well with UVB-induced tumor risk.

This article has been cited by other articles:

				D. L. Chao, J. T. Eck, D. E. Brash, C. C. Maley, and E. G. Luebeck Preneoplastic lesion growth driven by the death of adjacent normal stem cells PNAS, September 30, 2008; 105(39): 15034 - 15039. [Abstract] [Full Text] [PDF]

				D. M. Wiktor-Brown, H.-S. Kwon, Y. S. Nam, P. T. C. So, and B. P. Engelward Integrated one- and two-photon imaging platform reveals clonal expansion as a major driver of mutation load PNAS, July 29, 2008; 105(30): 10314 - 10319. [Abstract] [Full Text] [PDF]

				Z. Walaszek, M. Hanausek, and T. J. Slaga The Role of Skin Painting in Predicting Lung Cancer International Journal of Toxicology, July 1, 2007; 26(4): 345 - 351. [Abstract] [Full Text] [PDF]

				J. G.W. Nijhof, C. van Pelt, A. A. Mulder, D. L. Mitchell, L. H.F. Mullenders, and F. R. de Gruijl Epidermal stem and progenitor cells in murine epidermis accumulate UV damage despite NER proficiency Carcinogenesis, April 1, 2007; 28(4): 792 - 800. [Abstract] [Full Text] [PDF]

				J. C. van der Pols, C. Xu, G. M. Boyle, P. G. Parsons, D. C. Whiteman, and A. C. Green Expression of p53 Tumor Suppressor Protein in Sun-exposed Skin and Associations with Sunscreen Use and Time Spent Outdoors: A Community-based Study Am. J. Epidemiol., June 1, 2006; 163(11): 982 - 988. [Abstract] [Full Text] [PDF]

				A. Maeda, S. W. Schneider, M. Kojima, S. Beissert, T. Schwarz, and A. Schwarz Enhanced photocarcinogenesis in interleukin-12-deficient mice. Cancer Res., March 15, 2006; 66(6): 2962 - 2969. [Abstract] [Full Text] [PDF]

				A. van Schanke, G. M.C.A.L. van Venrooij, M. J. Jongsma, H. A. Banus, L. H.F. Mullenders, H. J. van Kranen, and F. R. de Gruijl Induction of Nevi and Skin Tumors in Ink4a/Arf Xpa Knockout Mice by Neonatal, Intermittent, or Chronic UVB Exposures. Cancer Res., March 1, 2006; 66(5): 2608 - 2615. [Abstract] [Full Text] [PDF]

				H. Rebel, N. Kram, A. Westerman, S. Banus, H. J. van Kranen, and F. R. de Gruijl Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice Carcinogenesis, December 1, 2005; 26(12): 2123 - 2130. [Abstract] [Full Text] [PDF]

				S. Alekseev, H. Kool, H. Rebel, M. Fousteri, J. Moser, C. Backendorf, F. R. de Gruijl, H. Vrieling, and L. H.F. Mullenders Enhanced DDB2 Expression Protects Mice from Carcinogenic Effects of Chronic UV-B Irradiation Cancer Res., November 15, 2005; 65(22): 10298 - 10306. [Abstract] [Full Text] [PDF]

				Y.-P. Lu, Y.-R. Lou, J. Liao, J.-G. Xie, Q.-Y. Peng, C. S. Yang, and A. H. Conney Administration of green tea or caffeine enhances the disappearance of UVB-induced patches of mutant p53 positive epidermal cells in SKH-1 mice Carcinogenesis, August 1, 2005; 26(8): 1465 - 1472. [Abstract] [Full Text] [PDF]

				P. Kramata, Y.-P. Lu, Y.-R. Lou, R. N. Singh, S. M. Kwon, and A. H. Conney Patches of Mutant p53-Immunoreactive Epidermal Cells Induced by Chronic UVB Irradiation Harbor the Same p53 Mutations as Squamous Cell Carcinomas in the Skin of Hairless SKH-1 Mice Cancer Res., May 1, 2005; 65(9): 3577 - 3585. [Abstract] [Full Text] [PDF]

				W. Zhang, A. N. Hanks, K. Boucher, S. R. Florell, S. M. Allen, A. Alexander, D. E. Brash, and D. Grossman UVB-induced apoptosis drives clonal expansion during skin tumor development Carcinogenesis, January 1, 2005; 26(1): 249 - 257. [Abstract] [Full Text] [PDF]

				J. Ramos, J. Villa, A. Ruiz, R. Armstrong, and J. Matta UV Dose Determines Key Characteristics of Nonmelanoma Skin Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2004; 13(12): 2006 - 2011. [Abstract] [Full Text] [PDF]

				Y. Matsumura, A. M. Moodycliffe, D. X. Nghiem, S. E. Ullrich, and H. N. Ananthaswamy Resistance of CD1d-/- Mice to Ultraviolet-Induced Skin Cancer Is Associated with Increased Apoptosis Am. J. Pathol., September 1, 2004; 165(3): 879 - 887. [Abstract] [Full Text] [PDF]

				M.-F. Demierre and L. Nathanson Chemoprevention of Melanoma: An Unexplored Strategy J. Clin. Oncol., January 1, 2003; 21(1): 158 - 165. [Abstract] [Full Text] [PDF]

				W. Zhang, E. Remenyik, D. Zelterman, D. E. Brash, and N. M. Wikonkal Escaping the stem cell compartment: Sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations PNAS, November 9, 2001; (2001) 241353198. [Abstract] [Full Text] [PDF]

				G. Ling, A. Persson, B. Berne, M. Uhlen, J. Lundeberg, and F. Ponten Persistent p53 Mutations in Single Cells from Normal Human Skin Am. J. Pathol., October 1, 2001; 159(4): 1247 - 1253. [Abstract] [Full Text]

				W. Zhang, E. Remenyik, D. Zelterman, D. E. Brash, and N. M. Wikonkal Escaping the stem cell compartment: Sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations PNAS, November 20, 2001; 98(24): 13948 - 13953. [Abstract] [Full Text] [PDF]