Regulation of the cyclin-Dependent Kinase Inhibitor p57Kip2 Expression by p63

The cyclin-dependent kinase (CDK) inhibitor p57(Kip2) is a negative regulator of cell proliferation, binding to a variety of cyclin-CDK complexes and inhibiting their kinase activities. The p57(Kip2) gene was recognized as a target gene for p73 beta, one member of the p53 family. In spite of this, the phenotypes of p73 and p57(Kip2) knockout mice do not resemble each other while there is a phenotypic overlap betweeen the p57(Kip2) null mice, the p63 null mice and patients affected by p63 associated syndromes, suggesting that p57(kip2) could be indeed a downstream target of p63. By ChIP we determined that in the HaCaT cell line the Delta Np63 alpha protein is associated to three different regions of the p57(Kip2) gene. Delta Np63 can activate both the endogenous p57(Kip2) gene and a reporter vector containing a - 2191 promoter fragment of the p57(Kip2) gene. Natural p63 mutants, associated to the AEC syndrome, show a partial or complete lack of transactivation potential of the p57(kip2) promoter, while three other natural p63 mutants, associated to the EEC, LMS and SHFM-4 syndromes, were less affected. These data suggests that p63 play an important role in the regulation of p57(Kip2) expression and that this regulation is subverted in AEC p63 mutants.