p53 is mutated in many human cancers; yet, the role of p63 in tumor suppression remains controversial. In many human tumors, p63 is overexpressed, while in others it is lost indicating that it may be an oncogene and/or a tumor suppressor gene. Many isoforms of p63 exist including a TA isoform that has transactivation activity and a ΔN isoform, which lacks transactivation activity and has dominant negative activities against p53 and TAp63. The lack of antibodies that distinguish between the TA and ΔN isoforms may account for the differences of expression seen in different human tumors, which have been assayed primarily by immunohistochemistry. We have recently shown using mouse models lacking all isoforms of p63 that it is a suppressor of tumorigenesis and metastasis. p53+/-;p63+/- and p63+/-;p73+/- mice exhibited higher tumor burden and metastasis than p53+/- mice. Additionally, using cells from tumors of these mice, we found genes previously shown to play a role in metastasis to be differentially expressed in mice mutant for p63. Finally, using these tumor cells in Boyden chamber assays, cells mutant for p63 exhibited increased motility and invasion compared to p53 mutant cells. While these studies indicate that p63 suppresses tumorigenesis and metastasis, it does not differentiate the individual contributions of the TA and ΔN isoforms of p63 in these processes. We hypothesize that TAp63 is a tumor suppressor gene while ΔNp63 is an oncogene. To test this hypothesis in vivo, we have generated TAp63 conditional knockout mice. Using primary mouse keratinocytes from these mice, we found that cells deficient for TAp63 exhibited a profound increase in proliferation compared to wild-type keratinocytes. Furthermore, keratinocytes deficient for TAp63 express keratin 5, a marker for the basal layer of the epithelium, but did not express keratin 10, a marker of epithelial differentiation, after the induction of differentiation. Additionally, day 18.5 embryos that lack TAp63 had an expanded basal layer and defects in the spinous and granular layers of the epithelium. Taken together, these data indicate that loss of TAp63 increases proliferation and inhibits the differentiation of epithelial cells. These data support a role for TAp63 as a tumor suppressor gene. To further understand the roles of the TA and ΔN isoforms of p63 in tumor suppression and metastasis, we are currently generating a ΔNp63 conditional knockout mouse. These studies will shed much needed light on the activities of the TA and ΔN isoforms of p63 in cancer.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA