One function of p63 is the regulation of developmental processes . Several mutations in the p63 DNA - binding domain are responsible for a family of human syndromes characterized by a combination of ectrodactyly , ectodermal dysplasia and facial clefting ( 37)(38)(39)58 ) . These observations led us to test the influence of disease - related p63 mutants on transcriptional activation of S100A2 . In reporter assays , we found an even stronger transcriptional activation employing two TAp63 g mutants derived from SHFM patients compared to wild - type p63 ( Figure 5 ) . In contrast , three p63 mutants responsible for the EEC syndrome had essentially lost their activation potential on the S100A2 promoter . A TAp63 g mutant related to the ADULT syndrome yielded some residual S100A2 activation when compared to wild - type TAp63 g ( Figure 5 ) . Interestingly , these observations correlate with severity of the epidermal syndrome phenotype since SHFM patients , in contrast to patients suffering from EEC and ADULT syndromes , are characterized by a lack of epidermal dysplasia ( 62 ) . Therefore , it is tempting to speculate that the ability of p63 to stimulate expression of S100A2 plays a role in developing the phenotype of these patients . Further research is required to establish a stronger link . S100A2 was identified as a potential tumor suppressor by subtractive hybridization between normal and tumorderived mammary epithelial cells in man ( 14 ) . Consistent with these findings S100A2 expression is markedly downregulated in several tumor tissues ( 15)(16)(17)(18 ) . However , it was shown that S100A2 expression is increased in other tumors ( 21)(22)(23)(24)(25)(26 ) . It was discussed that overexpression is an early event in tumorigenesis . Furthermore , a physical interaction between S100A2 and p53 proteins enhances transcriptional activity of p53 which implies antitumorigenic properties of S100A2 ( 27 ) . A possible interaction also between p63 and S100A2 proteins has not yet been investigated . Recently , it was demonstrated that S100A2 expression is able to diminish expression of Cox-2 protein which provides further evidence for a tumor suppressive function of S100A2 ( 28 ) . Interestingly , in line with these observations we showed that expression of S100A2 increases following DNA damage ( Figure 6A and C ) . The enhanced expression of S100A2 correlates with binding of p63 g protein to the S100A2 promoter ( Figure 6D ) . Generally , detection of different p63 isoforms on the mRNA and protein levels is difficult . It is possible to differentiate between TAp63 and ÁNp63 mRNA variants . On the protein level we were able to observe p63 g versus total p63 protein expression . After DNA damage we exclusively find an increase in the TAp63 isoforms on the mRNA level . Combining these observations with the data from the ChIP assays suggests that TAp63 g is induced after DNA damage and subsequent binding to the S100A2 promoter mediates its regulation ( Figure 6D ) . Supportive of this notion is the finding that p53 - negative Hep3B cells also show an increase in transcription of S100A2 together with enhanced expression of the TAp63 isoforms after DNA damage is observed ( Figure 6C ) . In conclusion , it is possible that regulation of S100A2 transcription by TAp63 g is a supporting mechanism to complement and enhance cellular response in preventing tumor transformation ( 34 ) . This is consistent with earlier observations implying that TAp63 g is able to substitute partially p53 function in hepatocellular carcinomas lacking p53 expression by transactivating the maspin tumor suppressor ( 55 ) .