Differential regulation of p63 and p73 expression.
Two homologs of the tumor suppressor p53, named p63 and p73, are each expressed from at least two start sites of mRNA synthesis, yielding full-length, transactivating (TA) isoforms, and also aminoterminally truncated (DeltaN) isoforms that act as antagonists to p53. The expression of TAp73-transcripts is induced by E2F and negatively regulated by transforming growth factor beta (TGFbeta). The DeltaNp73 promoter is induced by p53, resulting in negative feedback to control p53 activity. Here, we have analysed the expression of p63 in comparison with p73. In contrast to the induction of DeltaNp73, the expression of DeltaNp63 was reduced by p53 particularly in human keratinocytes, at the mRNA and protein levels. Accordingly, the 3' promoter of p73, but not that of p63, was activated by p53 in reporter assays. DeltaNp73 mRNA and DeltaNp73 protein, but not the p63 gene products, also accumulated when HaCat cells (lacking functional p53) were grown to high density. TAp73, but not TAp63, expression was suppressed by TGFbeta in these cells, and the TAp73, but not the TAp63, promoter was induced by E2F-1. Thus, in contrast to the functional similarities of their respective products, the expression levels of p63 and p73 are regulated by different mechanisms. This might be responsible for the discordant biological roles of p63 and p73 in development, as well as their deviant expression characteristics in cancer.
Waltermann
Angelika
A
Institut für Virologie, Philipps-Universität Marburg, Robert Koch Str. 17, D-35037 Marburg, Germany.
Kartasheva
Natalia N
NN
Dobbelstein
Matthias
M
D002452:Cell Count; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000235:genetics*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins
C081876:CKAP4 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human