p63heterozygous mutant mice are not prone to spontaneous or chemically induced tumors

Abstract

Homology between p63 and p53 has suggested that these proteins might function similarly. However, the majority of data from human tumors have not supported a similar role for p63 in tumor suppression. To investigate this issue, we studied spontaneous tumorigenesis in p63؉͞؊ mice in both WT and p53-compromised backgrounds. We found that p63؉͞؊ mice were not tumor prone and mice heterozygous for both p63 and p53 had fewer tumors than p53؉͞؊ mice. The rare tumors that developed in mice with compromised p63 were also distinct from those of p53؉͞؊ mice. Furthermore, p63؉͞؊ mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. These findings demonstrate that, in agreement with data from human tumors, p63 plays a markedly different biological role in cancer than p53.mouse model ͉ p53 ͉ tumor suppressor ͉ cancer T he p63 protein is a member of the p53 family that includes p53, p63, and p73, which share extensive homology within the core DNA binding domain (DBD) (reviewed in ref. 1). A well established feature of p53 is that it is frequently lost or inactivated in a variety of human cancers (2). Although some evidence suggests that p63 may perform biological roles analogous to those of p53 (3, 4), p63 is rarely mutated, and p63 expression is often retained in human tumors (reviewed in ref. 5). Although mutations in human p63 have been identified, these mutations cause severe birth anomalies, and tumor susceptibility is not a typical feature of these syndromes (1). In contrast to p53's ubiquitous pattern of expression, p63 is most readily detectable in proliferating cells of stratified squamous epithelia such as the skin, the precursor cell type for the majority of human cancers. Interactions between p63 and p53 and subsequent degradation of p63 can occur when p53 contains tumorderived missense mutations, suggesting that p63 could affect the tumor-suppressive capabilities of p53 (6). Thus, p63's role in modulating tumor-suppressive mechanisms in vivo has not been fully evaluated.To investigate whether p63 functions as a tumor suppressor in the intact organism, we evaluated spontaneous and chemically induced tumorigenesis in mice with decreased levels of p63. In addition, spontaneous tumors were monitored in mice that had reduced levels of p63 in combination with compromised levels of p53 to assess whether combined p63 and p53 deficiency affects tumorigenesis in vivo.Results p63؉͞؊ Mice Are Not Predisposed to Spontaneous Tumors. p53Ϫ͞Ϫ and p53ϩ͞Ϫ mice are highly tumor-prone with the majority of mice developing spontaneous tumors by 10 months and 2 years, respectively (7,8). To determine the impact of compromised p63 on tumorigenesis, we performed a spontaneous tumor study of 153 p63ϩ͞Ϫ mice and sibling controls for Ͼ2 years. Mice lacking p63 die shortly after birth (9, 10), and therefore the effect of germ-line deficiency of p63 in cancer could not be evaluated in p63Ϫ͞Ϫ mice. We had previously disrupted the endogenous p63 locus and generated two distinct p63 null alleles...

Impaired repair of cyclobutane pyrimidine dimers in human keratinocytes deficient in p53 and p63

“…Although p63 was originally anticipated to function as a tumor suppressor similarly to p53, there is also evidence that p63 functions as an oncogene (27,45). Recently, disparate reports have emerged regarding the tumor predisposition of mice heterozygous for p63 and p63/p53 (25,26,46).…”

“…While p63 has been reported to be absent or reduced in some human cancers, including basal cell carcinomas (18), it has more frequently been reported to be overexpressed in various tumors (19,20), including non-melanoma skin cancers (21)(22)(23)(24). Similarly, conflicting data from mice heterozygous for p63 have not resolved whether p63 is a tumor suppressor or oncogene (25)(26)(27).…”

“…XPA, XPC, DDB2, glyceraldehyde-3-phosphate dehydrogenase and peptidyl prolyl isomerase messenger RNA (mRNA) levels were assayed by quantitative real-time reverse transcription-polymerase chain reaction, as described previously (26). TAp63, ΔNp63, TAp73 and ΔNp73 mRNA levels were determined similarly, using the following primers (Oligos Etc., Wilsonville, OR) with location in the mRNA sequence denoted by position of the 5′ end relative to the translation start site: 5′-GACCTGAGTGACCCCATGTG-3′ (TAp63 forward, position 187), 5′-TGCCCAGACTCAATTTAGTGAG-3′ (ΔNp63 forward, position 21), 5′-AGAGAGAGCATCGAAGGTGGAG-3′ (common p63 reverse, ΔN position 198, TA position 363), 5′-CCACCTGGAGGGCATGAC-TA-3′(TAp73 forward, position 156), 5′-ATGCTGTACGTCGGTGACCC-3′ (ΔNp73 forward, position 1) and 5′-TTGTGCGTAGGGCGAGTGG-3′ (common p73 reverse, ΔN position 156, TA position 303 TA).…”

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

“…7,8 In contrast to TP53, which plays critical roles in regulating multiple cellular pathways and is mutated in many human cancers (reviewed in references 9-11), TP63 is rarely mutated, 12,13 and its role in cancer is not yet clarified. Data from mouse models are also inconclusive: although some studies show that p63 ϩ/Ϫ mice are not tumor prone, 14 other groups reported that p63 ϩ/Ϫ mice developed spontaneous tumors, including squamous cell carcinoma and sarcomas. 15 Despite the structural and partly functional identity among the TP53 family members, studies in knockout mice demonstrate significant functional differences among them.…”

A new mutation in TP63 is associated with age-related pathology

“…TP63 has two transcription initiation sites and is subject to extensive alternative splicing, giving rise to at least six isotypes having various and opposing activities (Figure 1). 12,14 One class of p63 isoforms contains the N-terminal transactivation domain (TA a, b, g), homologous to that of p53, whereas the other class of p63 isoforms lacks this domain (DN a, b, g) but is still transcriptionally active. 15 The balance between these two groups influences proper epidermal morphogenesis and the role of p63 in stem cell maintenance and differentiation seems to be the basis for most of the defects.…”