Ultraviolet radiation induces phosphorylation and ubiquitin-mediated degradation of DeltaNp63alpha.
DeltaNp63alpha, a homologue of the tumor suppressor p53, acts as a transcriptional repressor with dominant negative effects towards p53. Additionally, DeltaNp63alpha is overexpressed in a number of squamous cell carcinomas, suggesting a potential role in oncogenesis. However, the mechanisms regulating p63 have yet to be elucidated. The goal of the current study was to determine the effect of various genotoxic stresses on DeltaNp63alpha posttranslational modification and stability in normal and transformed squamous epithelial cells. We found that DeltaNp63alpha protein levels decreased after ultraviolet radiation and paclitaxel treatment of both normal and transformed cells. After UV and paclitaxel treatment, DeltaNp63alpha phosphorylation was significantly modulated. Additionally, DeltaNp63alpha protein levels were regulated in a proteasome-dependent manner in control and UV treated cells with increased DeltaNp63alpha ubiquitination after UV treatment or proteasome inhibition. Our studies provide insight to a mechanism for DeltaNp63alpha regulation during normal cell proliferation and, in particular, after stress. Further, the inverse regulation of p53 and DeltaNp63alpha protein levels after cell stress through opposing regulation of proteasome-mediated degradation may allow for rapid transcriptional changes of specific target genes that are consistent with the roles of these family members in tumor suppression and cell growth.
Westfall
Matthew D
MD
Department of Biochemistry, Center in Molecular Toxicology, The Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Joyner
Amanda S
AS
Barbieri
Christopher E
CE
Livingstone
Mark
M
Pietenpol
Jennifer A
JA
D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D016147:Genes, Tumor Suppressor / Q000528:radiation effects; D016158:Genes, p53 / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects; D017239:Paclitaxel / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D014157:Transcription Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism*; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D061988:Proteasome Inhibitors; C495901:TP53 protein, human; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D017239:Paclitaxel