p53-regulated apoptosis is differentiation dependent in ultraviolet B-irradiated mouse keratinocytes
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Previous studies from our laboratory, using p53 transgenic mice, have suggested that ultraviolet (UV) light-induced keratinocyte apoptosis in the skin is not affected by overexpression of mutant p53 protein. To further elucidate a possible role for p53 in UV-induced keratinocyte cell death, we now examine apoptosis in skin and isolated keratinocytes from p53 null (-/-) mice and assess the influence of cell differentiation on this process. In vivo, using this knockout model, epidermal keratinocytes in p53-/- mice exhibited only a 5.2-fold increase in apoptosis after 2000 J/m2 UVB irradiation compared with a 26.3-fold increase in normal control animals. If this p53-dependent apoptosis is important in elimination of precancerous, UV-damaged keratinocytes, then it should be active in the undifferentiated cells of the epidermal basal layer. To test this hypothesis, we examined the effect of differentiation on UV-induced apoptosis in primary cultures of murine and human keratinocytes. Apoptosis was p53-independent in undifferentiated murine keratinocytes, which exhibited relative resistance to UVB-induced killing with only a 1.5-fold increase in apoptosis in p53+/+ cells and a 1.4-fold increase in p53-/- cells. Differentiated keratinocytes, in contrast, showed a 9.4-fold UVB induction of apoptosis in p53+/+ cells, almost three times the induction observed in p53-/- cells. This UV-induced difference in apoptosis was observed when keratinocytes were cultured on type IV collagen substrate, but not on plastic alone. Western blotting of UV-irradiated, differentiated keratinocytes did not support a role for either Bax or Bcl-2 in this process. In support of these findings in mice, cell death in human cultured keratinocytes also occurred in a differentiation-associated fashion. We conclude that p53-induced apoptosis eliminates damaged keratinocytes in the differentiated cell compartment, but this mechanism is not active in the basal, undifferentiated cells and is therefore of questionable significance in protection against skin cancer induction.
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Compared with wild-type mice, knockout mice lacking the p53 protein show a reduction of sunburn cells in the epidermis following UVB irradiation.
“Compared with the wild-type mice, knockout mice lacking the p53 protein show a reduction of sunburn cells in the epidermis following UVB irradiation [32].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [32]
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Kastan, M. B., Zhan, Q., El-Deiry, W. S., Carrier, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B., & Fornace, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90593-2 · Cited by 3,047 · see citing works
p53 is required for radiation-induced apoptosis in mouse thymocytes
Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A., & Jacks, T. (1993) · Nature · doi:10.1038/362847a0 · Cited by 2,864 · see citing works
p53-Dependent apoptosis suppresses tumor growth and progression in vivo
Symonds, H., Krall, L., Remington, L., Saenz-Robles, M., Lowe, S., Jacks, T., & Van Dyke, T. (1994) · Cell · doi:10.1016/0092-8674(94)90534-7 · Cited by 880 · see citing works
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Research works printed but not linked: 35
- Murphy GF: Histology of the skin, in Histopathology of the skin, Elder D (Ed). Philadelphia, Lippincott-Raven, 1997, pp 5-11
- Gilchrest BA, Soter NA, Stoff JS, Mihm MC Jr: The human sunburn reaction: histologic and biochemical studies. J Am Acad Dermatol 1981, 5:411-422
- Daniels F: Acute cutaneous effects of light. Photomedicine. Edited by E Ben-Hur, I Rosenthal. Boca Raton, FL, CRC Press, Inc., 1990, pp 45-61
- Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 1991, 253:49 -53
- Kastan MB, Onyine O, Sidransky D, Vogelstein B, Craig RW: Partici- pation of p53 protein in the cellular response to DNA damage. Cancer Res 1991, 51:6304 -6311
- Midgley CA, Owens B, Briscoe CV, Thomas DB, Lane DP, Hall PA: Coupling between ␥ irradiation, p53 induction and the apoptotic response depends upon cell type in vivo. J Cell Science 1995, 108:1843-1848
- Li G, Mitchell DL, Ho VC, Reed JC, Tron VA: Decreased DNA repair but normal apoptosis in ultraviolet-irradiated skin of p53-transgenic mice. Am J Pathol 1996, 148:1113-1123
- Smith ML, Chen IT, Zhan Q, O'Connor PM, Fornace AJ Jr: Involve- ment of the p53 tumor suppressor in repair of u.v.-type DNA damage. Oncogene 1995, 10:1053-1059
- Ford JM, Hanawalt PC: Li-Fraumeni syndrome fibroblasts homozy- gous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair, and enhanced UV resistance. Proc Natl Acad Sci USA 1995, 92:8876 -8880
- Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ, Ponte ´n JA: A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA 1991, 88:10124 -10128
- Burns JE, Baird MC, Clark LJ, Burns PA, Edington K, Chapman C, Mitchell R, Robertson G, Soutar D, Parkinson EK: Gene mutations and increased levels of p53 protein in human squamous cell carcinomas and their cell lines. Br J Cancer 1993, 67:1274 -1284
- Coulter LK, Wolber R, Tron VA: Site-specific comparison of p53 immunostaining in squamous cell carcinomas. Hum Pathol 1995, 26:531-533
- Dumaz N, Drougard C, Sarasin A, Daya-Grosjean L: Specific UV- induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. Proc Natl Acad Sci USA 1993, 90:10529 -10533
- Li G, Ho VC, Berean K, Tron VA: Ultraviolet radiation induction of squamous cell carcinomas in p53 transgenic mice. Cancer Res 1995, 55:2070 -2074
- Ziegler A, Jonason AS, Leffell DJ, Simon JA, Sharma HW, Kimmelman J, Remington L, Jacks T, Brash DE: Sunburn and p53 in the onset of skin cancer. Nature 1994, 372:773-776
- Ren ZP, Hedrum A, Ponte ´n F, Niste ´r M, Ahmadian A, Lundberg J, Uhle ´n M, Ponte ´n J: Human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-neoplastic keratinocytes. Oncogene 1996, 12:765-773
- Morris RJ, Fischer SM, Slaga TJ: Evidence that a slowly cycling subpopulation of adult murine epidermal cells retains carcinogen. Cancer Res 1986, 46:3061-3066
- Morris RJ, Coulter K, Tryson K, Steinberg SR: Evidence that cutane- ous carcinogen-initiated epithelial cells from mice are quiescent rather than actively cycling. Cancer Res 1997, 57:3436 -3443
- Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A: Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 1992, 356: 215-221
- Weinberg WC, Azzoli CG, Chapman K, Levine AJ, Yuspa SH: p53- mediated transcriptional activity increases in differentiating epider- mal keratinocytes in association with decreased p53 protein. Onco- gene 1995, 10:2271-2279
- Wijsman JH, Jonker RR, Keijzer R, Van De Velde CJH, Cornelisse CJ, Van Dierendonck JH: A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA. J Histochem Cyto- chem 1993, 41:7-12
- Krajewski S, Krajewska M, Shabaik A, Miyashita T, Wang HG, Reed JC: Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol 1994, 145:1323-1336
- Gniadecki R, Hansen M, Wulf HC: Two pathways for induction of apoptosis by ultraviolet radiation in cultured human keratinocytes. J Invest Dermatol 1997, 109:163-169
- Miyashita T, Reed JC: Tumor suppressor p53 is a direct transcrip- tional activator of the human bax gene. Cell 1995, 80:293-299
- Li G, Ho VC, Mitchell DL, Trotter MJ, Tron VA: Differentiation-depen- dent p53 regulation of nucleotide excision repair in keratinocytes. Am J Pathol 1997, 150:1457-1464
- Wolf D, Harris N, Goldfinger N, Rotter V: Isolation of full-length mouse cDNA clone coding for an immunologically distinct p53 molecule. Mol Cell Biol 1985, 5:127-132
- Bayle JH, Elenbaas B, Levine AJ: The carboxy-terminal domain of the p53 protein regulates sequence-specific DNA binding through its nonspecific nucleic acid-binding activity. Proc Natl Acad Sci USA 1995, 92:5729 -5733
- Kulesz-Martin MF, Lisafeld B, Huang H, Kisiel ND, Lee L: Endoge- nous p53 protein generated form wild-type alternatively spliced p53 in mouse epidermal cells. Mol Cell Biol 1994, 14:1698 -1708
- Rehberger PA, Richter KH, Schwartz D, Goldfinger N, Oskato R, Almog N, Marks F, Rotter V: Differential expression of the regularly spliced wild-type p53 and its COOH-terminal alternatively spliced form during epidermal differentiation. Cell Growth Differ 1997, 8:851- 860
- Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC: Hepatitis B virus X protein inhibits p53 sequence-specific DNA bind- ing, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA 1994, 91:2230 -2234
- Wang XW, Yeh H, Schaeffer L, Roy R, Moncollin V, Egly JM, Wang Z, Freidberg EC, Evans MK, Taffe BG, Bohr VA, Weeda G, Hoeijmakers JHJ, Forrester Keratinocytes, Harris CC: p53 modulation of TFIIH- associated nucleotide excision repair activity. Nat Genet 1995, 10: 188 -195
- Wu L, Bayle JH, Elenbaas B, Pavletich NP Levine AJ: Alternatively spliced forms in the carboxy-terminal domain of the p53 protein regulate its ability of promote annealing of complementary single strands of nucleic acids. Mol Cell Biol 1995, 15:497-504
- Wu Y, Huang H, Miner Z, Kulesz-Martin M: Activities and response to DNA damage of latent and active sequence-specific DNA binding forms of mouse p53. Proc Natl Acad Sci USA 1997, 94:8982-8987
- Zhan O, Fan S, Bae I, Guillouf C, Liebermann DA, O'Connor PM, Fornace AJ Jr: Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. Oncogene 1994, 9:3743-3751
- Gillardon F, Eschenfelder C, Uhlmann E, Hartschuh W, Zimmerman M: Differential regulation of c-fos, fosB, c-jun, junB, bcl-2 and bax expression in rat skin following single or chronic ultraviolet irradiation and in vivo modulation by antisense oligonucleotide superfusion. Oncogene 1994, 9:3219 -3225
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- Authors
- Tron, V. A., Trotter, M. J., Tang, L., Krajewska, M., Reed, J. C., Ho, V. C., & Li, G.
- Affiliations
- University of British Columbia (CA)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Tron, Victor A.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 1998-08
- Volume
- 153
- Issue
- 2
- Pages
- 579-585
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1852971
- OpenAlex
- W2018042307
- Cited by
- 97
- References
- 3
- Citations by year
- 2024: 1 · 2023: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2016: 1 · 2015: 1 · 2014: 6 · 2013: 3
- FWCI
- 11.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- p53, apoptosis, UVB irradiation, keratinocytes, keratinocyte differentiation, p53 knockout mice, epidermis, skin cancer prevention, Bax, Bcl-2
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Collagen, Humans, Immunohistochemistry, Proto-Oncogene Proteins, Ultraviolet Rays, Keratinocytes, Genes, p53, Apoptosis, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, bcl-2-Associated X Protein, Mice
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