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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
Transcriptional repression by the C-terminal domain of p53
1Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
We have previously shown that monomeric p53 can transactivate target genes in vivo and that C-terminal fragments of p53 are oncogenic. To further elaborate these findings a series of C-terminal truncations of p53 was generated. The transactivation capacity and the ability of the truncated p53 to suppress oncogene-mediated transformation were studied. We found that p53 truncated at amino acid 303 (p53wtdl303) can still function in both assays, though less efficiently than full length wild type (wt) p53. Transforming C-terminal fragments inhibited transactivation induced by full length wt p53. Surprisingly, they also inhibited transactivation by wtdl303, with which they do not share any overlapping sequences. Furthermore, the C-terminal fragments repressed the transactivation domains of several viral and cellular transcriptional activators. These data raise the possibility that the C-terminal domain of p53 may compete with the p53 transactivation domain for a common basal transcription factor.
Insights
Monomeric p53 protein (p53) transactivates genes, but C-terminal fragments can be oncogenic. Truncated p53 retains some function, while C-terminal fragments inhibit p53
Area of Science:
- Molecular Biology
- Cancer Research
- Gene Regulation
Background:
- Monomeric p53 protein (p53) exhibits transactivation capabilities for target genes in vivo.
- C-terminal fragments of p53 have been identified as oncogenic.
- Previous research established the roles of p53 in gene regulation and oncogenesis.
Purpose of the Study:
- To investigate the functional consequences of C-terminal truncations of p53.
- To assess the transactivation capacity of truncated p53 variants.
- To determine the impact of C-terminal fragments on oncogene-mediated transformation and p53 activity.
Main Methods:
- Generation of a series of C-terminal p53 truncations.
- Assays to evaluate transactivation capacity of truncated p53.
- Experiments to study the suppression of oncogene-mediated transformation by truncated p53.
- Analysis of the inhibitory effects of C-terminal fragments on wild-type p53 and truncated p53 transactivation.
Main Results:
- p53 truncated at amino acid 303 (p53wtdl303) retains partial transactivation and tumor suppressor functions, albeit less efficiently than full-length wild-type p53.
- Oncogenic C-terminal fragments of p53 inhibit transactivation by both full-length wild-type p53 and p53wtdl303.
- These C-terminal fragments also repress the transactivation domains of various viral and cellular transcriptional activators.
Conclusions:
- The C-terminal domain of p53 may play a role in regulating its transactivation function.
- C-terminal fragments of p53 can interfere with transcriptional activation, potentially through competition for a common basal transcription factor.
- These findings suggest a novel mechanism of p53 regulation and potential therapeutic targets in cancer.
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