The functional domains in p53 family proteins exhibit both common and distinct properties

p53 is a sequence-specific transcription factor that functions to transactivate genes that mediate cell cycle arrest, DNA repair, apoptosis, and other p53-dependent activities. In 1997 and 1998, p73 and p63, respectively, were identified and emerged as p53 homologues (reviewed by Yang et al.). The p53 family proteins share significant similarity at the aminoacid level within three domains: the transcriptional activation domain (AD), the sequence-specific DNA-binding domain (DBD), and the tetramerization domain (TD) (Figure 1a). Like p53, both p63 and p73 bind to the canonical p53-responsive element and transactivate p53 target genes (reviewed by Harms et al.). Unlike p53, the genes encoding p63 and p73 are rarely mutated in human cancer and knockout mice demonstrate developmental defects rather than a propensity for tumor formation (reviewed by Yang et al.). However, recent evidence suggests that p63 and p73 do indeed play a role in tumor suppression since heterozygous p63 and p73 mice are prone to tumor formation. Thus, the p53 family proteins possess both common as well as nonoverlapping functions. At the 12th International p53 Workshop, we and others presented data identifying the functional domains in the p53 family proteins required for transcriptional activity, cell cycle arrest, and apoptosis (reviewed by Braithwaite et al.). As each domain plays an integral role in facilitating the differential functions of these transcription factors, here, we discuss the common and distinct properties of the transcriptional ADs, the DBD, nuclear localization and nuclear export signals (nuclear localization signal (NLS) and nuclear export signals (NES)), the TD, the basic domain (BD) that is present in p53 but not in p63 or p73, and the sterile-a-motif (SAM) domain that is present in some p63 and p73 isoforms but is lacking in p53.