Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

Melnikova, Vladislava O.; Pacifico, Alessia; Chimenti, Sergio; Peris, Ketty; Ananthaswamy, Honnavara N.

doi:10.1038/sj.onc.1208863

Cited by 38 publications

(43 citation statements)

References 41 publications

(70 reference statements)

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“…Importantly, the chemopreventive effects of silibinin were lost in p53 +/− mice. We did not check for the loss of heterozygosity of the p53 +/− mice, but based on a previous study we can deduce that most of these mice had loss of heterozygosity by 8 weeks of chronic UVB radiation (32). These findings confirm that p53 plays an important role in the protective effects of silibinin against UVB-induced skin lesions and carcinogenesis.…”

Section: Discussionsupporting

confidence: 63%

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis

Rigby

Roy

Deep

et al. 2016

CARCIN

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Non-melanoma skin cancers (NMSC) are a growing problem given that solar ultraviolet B (UVB) radiation exposure is increasing most likely due to depletion of the atmospheric ozone layer and lack of adequate sun protection. Better preventive methods are urgently required to reduce UV-caused photodamage and NMSC incidence. Earlier, we have reported that silibinin treatment activates p53 and reduces photodamage and NMSC, both in vitro and in vivo; but whether silibinin exerts its protective effects primarily through p53 remains unknown. To address this question, we generated p53 heterozygous (p53 +/− ) and p53 knockout (p53 −/− ) mice on SKH-1 hairless mouse background, and assessed silibinin efficacy in both short-and long-term UVB exposure experiments. In the chronic UVB-exposed skin tumorigenesis study, compared to p53 +/+ mice, p53 +/− mice developed skin tumors earlier and had higher tumor number, multiplicity and volume. Silibinin topical treatment significantly reduced the tumor number, multiplicity and volume in p53 +/+ mice but silibinin' protective efficacy was significantly compromised in p53 +/− mice. Additionally, silibinin treatment failed to inhibit precursor skin cancer lesions in p53 −/− mice but improved the survival of the mice. In short-term studies, silibinin application accelerated the removal of UVB-induced DNA damage in p53 +/+ mice while its efficacy was partially compromised in p53 −/− mice. Interestingly, silibinin treatment also inhibited the UVB-induced inflammatory markers in skin tissue. These results further confirmed that absence of the p53 allele predisposes mice to photodamage and photocarcinogenesis, and established that silibinin mediates its protection against UVB-induced photodamage, inflammation and photocarcinogenesis partly through p53 activation.

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Section: Discussionsupporting

confidence: 63%

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis

Rigby

Roy

Deep

et al. 2016

CARCIN

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“…5 To identify the early events that may contribute to the tumor development promoted by reduction of IKK␣ expression, we examined UVB-induced p53 V154A/R155C , p53 R270C , and p53 R275C signature mutations in the skin of mice irradiated for 2 weeks using PCR with mutation-specific primers. 8,29 The result showed that these p53 mutations occurred more frequently in Ikk␣ ϩ/Ϫ than in Ikk␣ ϩ/ϩ skin specimens (Figure 2A). However, most of the skin tumors, regardless of the genotype, were positive for these p53 mutations ( Figure 2B).…”

Section: Early Genetic Alteration: More Uvb-induced Signature P53 Mutmentioning

confidence: 88%

“…5,[27][28][29] The PCR primers used included the codons 154/155: 5Ј-CCTCCAGCTGG-GAGCCGTGCTT-3Ј (with mutant-specific sequences) and 5Ј-GAGGGCTTACCATCACCATC-3Ј; C to T mutations at codons 270 and 275: the forward mutant-specific sequences 5Ј-GGACGGGACAGCTTTGAGGTTT-3Ј and 5Ј-GTGTTTGTGCCTGCCT-3Ј, respectively, and the reverse sequences 5Ј-GCCTGCGTACCTCTCTTTGC-3Ј. The PCR primers for exon 5 of the p53 gene were 5Ј-TCTCTTCCAGTACTCTCCTC-3Ј and 5Ј-GAGGGCTTAC-CATCACCATC-3Ј.…”

Section: P53 Mutation Analysis Using Allele-specific Pcrmentioning

confidence: 99%

Reduction of IKKα Expression Promotes Chronic Ultraviolet B Exposure-Induced Skin Inflammation and Carcinogenesis

Xia

Park

Liu

et al. 2010

The American Journal of Pathology

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Ultraviolet B light (UVB) is a common cause of human skin cancer. UVB irradiation induces mutations in the tumor suppressor p53 gene as well as chronic inflammation, which are both essential for UVB carcinogenesis. Inhibitor of nuclear factor B kinase-␣ (IKK␣) plays an important role in maintaining skin homeostasis, and expression of IKK␣ was found to be down-regulated in human and murine skin squamous cell carcinomas. However, the role of IKK␣ in UVB skin carcinogenesis has not been investigated. Thus, here we performed UVB carcinogenesis experiments on Ikk␣ ؉/؉ and Ikk␣ ؉/؊ mice. Ikk␣ ؉/؊ mice were found to develop a twofold greater number of skin tumors than Ikk␣ ؉/؉ mice after chronic UVB irradiation. In addition, tumor latency was significantly shorter and tumors were bigger in Ikk␣ ؉/؊ than in Ikk␣ ؉/؉ mice. At an early stage of carcinogenesis, an increase in UVB-induced p53 mutations as well as macrophage recruitment and mitogenic activity, and a decrease in UVB-induced apoptosis, were detected in Ikk␣ ؉/؊ compared with those in Ikk␣ ؉/؉ skin. Also, reduction of IKK␣ levels in keratinocytes upregulated the expression of monocyte chemoattractant protein-1 (MCP-1/CCL2), TNF␣, IL-1, and IL-6, and elevated macrophage migration, which might promote macrophage recruitment and inflammation. Therefore, these findings suggest that reduction of IKK␣ expression orchestrates UVB carcinogen, accelerating tumorigenesis.

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“…Studies have shown that UVB radiation produces a variety of adverse effects that includes DNA damage [14,15], mutations in key regulatory genes [16], inflammation [17,18], immuno-suppression [19,20], photo-aging and skin cancer [21,22]. UVB is directly absorbed by cellular DNA leading to the formation of DNA lesions primarily cyclobutane pyrimidine dimers and pyrimidine (6-4)-pyrimidone photoproducts [13,23].…”

Section: Reactive Oxygen Speciesmentioning

confidence: 99%

Oxidative Stress and Skin Cancer: An Overview

Narendhirakannan

Hannah

2012

Ind J Clin Biochem

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Skin is the largest body organ that serves as an important environmental interface providing a protective envelope that is crucial for homeostasis. On the other hand, it is a major target for toxic insult by a broad spectrum of physical and chemical agents that are capable of altering its structure and function. There are a large number of dietary contaminants and drugs can manifest their toxicity in skin. These environmental toxicants or their metabolites are inherent oxidants and/or directly or indirectly drive the production of a variety of reactive oxidants also known as reactive oxygen species. These are short-lived entities that are continuously generated at low levels during the course of normal aerobic metabolism. These are believed to activate proliferative and cell survival signaling that can alter apoptotic pathways that may be involved in the pathogenesis of a number of skin disorders. The skin possesses an array of antioxidant defense mechanisms that interact with toxicants to obviate their deleterious effect. The ''antioxidant power'' of a food is an expression of its capability both to defend the human organism from the action of the free radicals and to prevent degenerative disorders. Plants like olive trees have their own built-in protection against the oxidative damage of the sun, and these built-in protectors function as cell protectors in our own body. Although many antioxidants have shown substantive efficacy in cell culture systems and in animal models of oxidant injury, unequivocal confirmation of their beneficial effects in human populations has proven elusive.

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Fate of UVB-induced p53 mutations in SKH-hr1 mouse skin after discontinuation of irradiation: relationship to skin cancer development

Cited by 38 publications

References 41 publications

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis

Reduction of IKKα Expression Promotes Chronic Ultraviolet B Exposure-Induced Skin Inflammation and Carcinogenesis

Oxidative Stress and Skin Cancer: An Overview

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