title: Ionizing radiation-induced TAp63α phosphorylation at C-terminal S/TQ motifs requires the N-terminal transactivation (TA) domain.
abstract: TAp63α, a homolog of p53 and one of six alternatively spliced p63 isoforms, is a critical mediator of the ionizing radiation (IR)-induced DNA damage response in female germ cells and also tumor suppression in somatic cells. The ΔNp63α isoform, lacking the N-terminal transactivation (TA) domain, is associated with oncogenic potential. The mechanism of p63 functional regulation is not well understood. TAp63α is phosphorylated by ionizing radiation (IR)-induced DNA damage and gene transactivation is likely to be involved. Based on information gleaned from studies on p53, we explored the possibility that TAp63α S/TQ sites may be phosphorylated by IR-induced DNA damage. Our findings show a wortmanin-sensitive kinase phosphorylates TAp63α at C-terminal Ser-Gln and Thr-Gln (S/TQ) sites but not N-terminal S/TQ sites. ΔNp63α, lacking the TA domain, and TAp63γ, lacking C-terminal domains, including S/TQ sites, fail to undergo IR-induced phosphorylation. We propose a model for TA domain-dependent C-terminal phosphorylation drawing from previously described self-inactivating intramolecular interaction between N-terminal TA domain and C-terminal Transactivation Inhibitory Domain (TID) of TAp63α. A specific topology adopted only by TAp63α, but not possible for ΔNp63α or TAp63γ, may lead to TAp63α-specific kinase recruitment, phosphorylation and self-inactivation release. TID-lacking TAp63γ, like p53, is constitutively active and thus may forgo phosphorylation-dependent activation. Thus, p53 is regulated by protein stabilization and TAp63α by protein activation but both appear to involve S/TQ phosphorylation. The difference in phosphorylation potential of TAp63α and ΔNp63α may in part help explain why the two similar isoforms have diametrically opposite tumor suppression and oncogene functions, respectively.
authors.affiliation: Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul, South Korea.
authors.forename: Dal-Ah
authors.initials: DA
authors.lastname: Kim
authors.forename: Byong-Linne
authors.initials: BL
authors.lastname: Lee
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Suh
mesh_terms: D020816:Amino Acid Motifs; D000730:Androstadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011839:Radiation, Ionizing; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin