Abstract
p53 is a protein that causes cell cycle arrest, apoptosis or senescence, being crucial in the process of tumor suppression in several cell types. Different in vitro and animal models have been designed for the study of p53 role in skin cancer. These models have revealed opposing results, as in some experimental settings it appears that p53 protects against skin cancer, but in others, the opposite conclusion emerges. We have generated cohorts of mice with efficient p53 deletion restricted to stratified epithelia and control littermates expressing wild type p53 and studied their sensitivity to both chemically-induced and spontaneous tumoral transformation, as well as the tumor types originated in each experimental group. Our results indicate that the absence of p53 in stratified epithelia leads to the appearance, in two-stage skin carcinogenesis experiments, of a higher number of tumors that grow faster and become malignant more frequently than tumors arisen in mice with wild type p53 genotype. In addition, the histological diversity of the tumor type is greater in mice with epidermal p53 loss, indicating the tumor suppressive role of p53 in different epidermal cell types. Aging mice with p53 inactivation in stratified epithelia developed spontaneous carcinomas in skin and other epithelia. Overall, these results highlight the truly protective nature of p53 functions in the development of cancer in skin and in other stratified epithelia.
Highlights
The cancer preventive activity of p53 could be mediated by other pathways; for example, it has been shown that rapamycin, a known inhibitor of mTOR pathway, decreases the number of tumors originated in p53-/- or p53+/- mice [5, 6], www.impactjournals.com/oncotarget suggesting a causative role of mTOR inhibition in tumor prevention
Two-stage skin carcinogenesis experiments show that p53 null mice develop fewer and smaller skin tumors than p53 wild type mice [31, 32], indicating that the presence of p53 in skin cells provokes the emergence of more tumors, at difference with the results found in epithelial cells of the intestine [33] and other cell types
It is expected that the expression of Cre recombinase from a K14-Cre transgene will lead to the recombination of floxed alleles in the cells of stratified epithelia, including epidermis, many of these cells stop expressing K14 as they proceed through the differentiation process
Summary
The gene coding for cellular tumor protein p53, TP53, is the most frequently mutated gene in human cancers, being altered in approximately 50% of malignancies (for a review, see [1]). p53 is a transcriptional factor able to interact both with DNA, regulating the expression of a myriad of target genes, and with numerous proteins, mutually modifying their activity. p53 is usually found at very low levels in the cells, but it accumulates in case of genetic damage. p53 promotes multiple cell functions associated to tumor suppression, as cell cycle arrest, apoptosis and cellular senescence, being fundamental in the prevention of the division of cells that have suffered DNA damage; for all these functions, p53 has been nicknamed as “guardian of the genome” [2]. p53 precludes tumor formation by regulating additional mechanisms, as genetically modified mice expressing a mutant form of p53 unable to direct cell cycle arrest, apoptosis and senescence do not suffer from early onset tumor formation [3]. In a different cancer model (i.e., mouse keratinocytes grafted onto nude mice), aimed to study the cooperation of p53 loss and v-rasHa-mediated initiation, the tumor originated showed increased growth and malignancy in the absence of one or two p53 alleles [30]. These results seem to demonstrate a protective role of p53 in skin carcinogenesis and malignization. We conclude that p53 in epidermal keratinocytes truly protects against tumor promotion, progression and malignancy in skin, both in chemically-induced and in spontaneous carcinogenesis, acting as a bona fide tumor suppressor gene, in accordance to the generally admitted role of p53 in other cell types
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