Full p53 transcriptional activation potential is dispensable for tumor suppression in diverse lineages
| Autor: | Eunice Y. Lee, Laura D. Attardi, Thomas M. Johnson, Matthew P. Scott, Eunice J. Park, Dadi Jiang, Colleen A. Brady |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Transcriptional Activation
Cell cycle checkpoint Lymphoma B-Cell Transgene Mutant Mice Transgenic medicine.disease_cause Transactivation Mice Puma Neoplasms medicine Animals Humans Cell Lineage Gene Knock-In Techniques Gene Mice Knockout Mutation Multidisciplinary biology Biological Sciences biology.organism_classification Genes p53 Cancer research Carcinogenesis Medulloblastoma |
| Popis: | Over half of all human cancers, of a wide variety of types, sustain mutations in the p53 tumor suppressor gene. Although p53 limits tumorigenesis through the induction of apoptosis or cell cycle arrest, its molecular mechanism of action in tumor suppression has been elusive. The best-characterized p53 activity in vitro is as a transcriptional activator, but the identification of numerous additional p53 biochemical activities in vitro has made it unclear which mechanism accounts for tumor suppression. Here, we assess the importance of transcriptional activation for p53 tumor suppression function in vivo in several tissues, using a knock-in mouse strain expressing a p53 mutant compromised for transcriptional activation, p53 25,26 . p53 25,26 is severely impaired for the transactivation of numerous classical p53 target genes, including p21, Noxa , and Puma , but it retains the ability to activate a small subset of p53 target genes, including Bax . Surprisingly, p53 25,26 can nonetheless suppress tumor growth in cancers derived from the epithelial, mesenchymal, central nervous system, and lymphoid lineages. Therefore, full transactivation of most p53 target genes is dispensable for p53 tumor suppressor function in a range of tissue types. In contrast, a transcriptional activation mutant that is completely defective for transactivation, p53 25,26,53,54 , fails to suppress tumor development. These findings demonstrate that transcriptional activation is indeed broadly critical for p53 tumor suppressor function, although this requirement reflects the limited transcriptional activity observed with p53 25,26 rather than robust transactivation of a full complement of p53 target genes. |
| Databáze: | OpenAIRE |
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