CK2-site phosphorylation of p53 is induced in DeltaNp63 expressing basal stem cells in UVB irradiated human skin.
The activity of the tumor suppressor protein p53 is controlled by a balance between E3-ligase mediated p53 protein degradation and protein kinase-mediated assembly of p53:p300 transcription machinery. Genetic studies in mice have shown that mutation of the CK2 phospho-acceptor site in p53 increases UV-induced skin cancer formation,(11) highlighting an unexpected role for p53 phosphorylation in mediating p53-dependent tumor suppression. However, it is not known in which cell types CK2-mediated phosphorylation of p53 occurs. Using human skin as a model to determine whether there is cell-selectivity in modulating p53 phosphorylation, we have found a selective induction of p53 phosphorylation at the CK2-site in the basal cells of UV irradiated human skin. Dual-immunofluorescence also revealed that Ser392 and Ser15 phosphorylation of p53 also occur in the same basal cells, although often within distinct regions of the nucleus. Given that p63alphaDeltaN is required for p53 activation after DNA damage, we examined and found a high proportion of cells co-express p63alphaDeltaN and CK2-phosphorylated p53 after UV-irradiation. As controls, the proliferation marker Ki67 and p63alphaDeltaN generally exhibit mutually exclusive expression. These data identify a physiological model with which to identify signaling pathways that mediate cross-talk between p63alphaDeltaN and activating p53 kinase pathways after DNA damage in basal cell populations.
Finlan
Lee E
LE
The University of Edinburgh, CRUK p53 Signal Transduction Group, Edinburgh, UK.
Nenutil
Rudolf
R
Ibbotson
Sally H
SH
Vojtesek
Borek
B
Hupp
Ted R
TR
D000818:Animals; D047390:Casein Kinase II / Q000502:physiology*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000528:radiation effects*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; C495901:TP53 protein, human; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D047390:Casein Kinase II