Differential regulation of plasminogen activator and inhibitor gene transcription by the tumor suppressor p53.
AUTOR(ES)
Kunz, C
RESUMO
The ability of p53 to activate or repress transcription suggests that its biological function as tumor suppressor is in part accomplished by regulating a number of genes including such required for inhibition of cell growth. We here give evidence that p53 also may regulate genes responsible for the proteolytic degradation of the extracellular matrix, which is considered a crucial feature for local invasion and metastasis of neoplastic cells. An important and highly regulated cascade of such proteolytic events involves the plasminogen activator system. We show that wild-type p53 represses transcription from the enhancer and promoter of the human urokinase-type (u-PA) and the tissue-type plasminogen activator (t-PA) gene through a non-DNA binding mechanism. Oncogenic mutants lost the repressing activity. In contrast, wild-type but not mutant p53 specifically binds to and activates the promoter of the plasminogen activator inhibitor type-1 (PAI-1) gene. Interestingly, one of the p53 mutants (273his) inhibited PAI-1 promoter activity. Our results suggest that altered function of oncogenic forms of p53 may lead to altered expression of the plasminogen activators and their inhibitor(s) and thus to altered activation of the plasminogen/plasmin system during tumor progression.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=307270Documentos Relacionados
- Modulation of the transcriptional activity of thyroid hormone receptors by the tumor suppressor p53.
- Complex formation between the lymphotropic papovavirus large tumor antigen and the tumor suppressor protein p53.
- Repression of RNA Polymerase I Transcription by the Tumor Suppressor p53
- The tumor suppressor p53 regulates its own transcription.
- Species- and tissue-specific expression of the C-terminal alternatively spliced form of the tumor suppressor p53.