Figure 3.

Functional evolution and regulation within the p53 family highlighting the unique regulatory mechanism of the most ancient family member TAp63α. (A) All family members and isoforms have acquired distinct regulatory roles in the functional evolution from germ-line quality control via embryonic development and stem-cell maintenance to tumor suppression. (B) Although activation leads to a very similar transcriptional program inducing cell-cycle arrest and apoptosis, the transactivation (TA) isoforms display fundamental differences in the regulation of their transactivation potential. (C) In TAp63α, the TA and transactivation inhibitory (TI) domains of a dimer interact on top of the tetramerization interface establishing a closed, dimeric autoinhibitory conformation. TAp63α monomers are indicated in different colors for clarity. DNA-damage-induced phosphorylation disrupts the interdomain interaction network allowing formation of active tetrameric protein that subsequently induces oocyte death. Protein phosphatases (PPases) may revert activating phosphorylations, preventing the disruption of the autoinhibitory conformation. DN, Dominant negative; PTM, posttranslational modification.