Antigen-specific immunity does not mediate acute regression of UVB-induced p53-mutant clones

Abstract

Chronic irradiation of human or murine epidermis with ultraviolet B (UVB) induces clones of p53-mutant keratinocytes. Clones precede and parallel the induction of carcinomas, suggesting that they are an early stage of UVB carcinogenesis. In the absence of UVB, these clones rapidly regress. For UVB-induced murine skin tumors and papillomas, regression is known to involve antigen-specific immunity. To determine whether antigen-specific immunity influences the creation, expansion, or regression of p53-mutant clones, we studied Rag1 knockout mice deficient in the recombination activating gene 1 required for development of B, abT, cdT, and natural killer T cells. Since tissue homeostasis could affect proliferation or persistence of clones, we also examined the effect of Rag1 on UVB-induced hyperplasia and apoptosis. Mice were irradiated with UVB daily for 7-11 weeks to create p53-mutant clones, and then retained in the absence of UV. After UV ended, epidermal thickness decreased and p53-mutant clones observed in the epidermal sheets regressed, with no significant differences between Rag1 À/À and wild type. During the initial chronic UVB irradiation, increasing irradiation time increased both the number and size of p53-mutant clones, with no significant difference between genotypes. We conclude that antigen-specific immunity is not involved in the initiation, expansion, or acute regression of p53-mutant clones.

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

“…However, in both UV regimens, p53-positive clones were still detectable for as long as 8 weeks after the last UV radiation exposure (Berg et al, 1996). Similarly, Remenyik et al (2003) found that approximately 50% of p53-positive keratinocyte clones in C57Bl/6 mouse skin disappeared within 2 weeks after discontinuation of UV treatment (37 or 47 kJ/m 2 total UV). In our experiments, there was a slight decrease in the incidence of p53 R270C mutations at 22 weeks after UV radiation discontinuation, but it was not statistically significant.…”

“…In hairless mouse skin, UV-induced p53 mutations could be detected by AS-PCR as early as 1 week after the first UV radiation exposure, with 80-90% of animals incurring p53 mutations after 8 weeks of UV treatment (Ouhtit et al, 2000a). Clones of keratinocytes carrying mutant p53 have also been detected in mouse skin within 2-3 weeks after UV treatment (Berg et al, 1996;Rebel et al, 2001;Remenyik et al, 2003). In this study, we investigated the fate of p53 mutations and the development of skin cancer after discontinuation of UV treatment.…”

“…Remenyik et al (2003) demonstrated that regression of precancerous p53-positive clones occurs owing to mechanisms other than antigen-specific immunity, since it proceeds with similar kinetics in the skin of immunedeficient Rag1 À/À mice and their wild-type counterparts. In addition, they found that precancerous p53-positive cells have normal morphology and that patches of these cells are not infiltrated with lymphocytes or any other immune cells (Remenyik et al, 2003). Two other possible mechanisms for elimination of initiated keratinocytes are apoptotic death and normal cell turnover.…”

“…shown that the number and size of p53-positive cell clones in mouse epidermis decrease within 2 weeks after the discontinuation of chronic UV treatment (Berg et al, 1996;Remenyik et al, 2003). This acute regression phase may be followed by a significantly slower second phase (Berg et al, 1996).…”

“…While evidence supports the role of mutant p53 in enabling apoptosis resistance in keratinocytes (Ziegler et al, 1994;Tron et al, 1998;Zhang et al, 2001;Mudgil et al, 2003), the possibility that mutant p53 provides keratinocyte progenitors with proliferative advantages remains largely unexplored, even though two phenotypes may be related to the same underlying molecular changes (Kuhn et al, 1999;van Hogerlinden et al, 1999;Peus et al, 2000;Marconi et al, 2003). Nevertheless, discontinuation of UV irradiation has been shown to result in the fast spontaneous regression of some mutant p53 clones in mouse skin, although the mechanisms involved in this process are unclear (Berg et al, 1996;Rebel et al, 2001;Remenyik et al, 2003).…”