TA-p63-gamma regulates expression of DeltaN-p63 in a manner that is sensitive to p53.
Genetic analysis indicates that TP63 is required for establishment and preservation of self-renewing progenitors within the basal layer of several epithelial structures, however, the specific contributions of transactivating (TA-p63) and dominant-negative (DeltaN-p63) isoforms remain largely undefined. Recent studies have suggested a model in which TA-p63 plays an important role in the establishment of progenitor populations in which expression of DeltaN-p63 contributes to the preservation of self-renewing capacity. Our previous studies indicate that DeltaN-p63 is a transcriptional target of p53, however, the absence of overt epithelial deficiencies in p53-/- mice and reports of increased expression of DeltaN-p63 in p53-/- mice suggest p53-independent mechanisms also contribute to expression of DeltaN-p63. Here, we present data indicating that, prolonged loss of p53 leads to the activation of a p53-independent mechanism for transcriptional regulation of DeltaN-p63. This p53-independent mechanism is sensitive to ectopic p53 but not to a p53 mutant that lacks the transactivation domain. We further show that in cells in which p53 is expressed TA-p63-gamma protein is destabilized in a manner that is p53 dependent and sensitive to pharmacologic inhibition of the 26S proteosome. Consistent with this observation, we demonstrate that loss of p53 leads to the stabilization of TA-p63-gamma that is reversible by ectopic p53. Finally, we present evidence that disruption of TA-p63-gamma expression leads to decreased expression of DeltaN-p63 and that overexpression of TA-p63-gamma was sufficient to enhance the activity of the DeltaN-p63 promoter. Taken together, our studies indicate that TA-p63-gamma is capable of activating expression of DeltaN-p63 and that this mechanism may account for p53-independent expression of DeltaN-p63.
Li
N
N
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
Li
H
H
Cherukuri
P
P
Farzan
S
S
Harmes
D C
DC
DiRenzo
J
J
D001940:Breast / Q000166:cytology; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000032:analysis; D013234:Stem Cells / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003513:Cycloheximide