Dataset Information

Mutant and Wild-Type Tumor Suppressor p53 Induces p300 Autoacetylation.

ABSTRACT: The transcriptional co-activator p300 is essential for p53 transactivation, although its precise role remains unclear. We report that p53 activates the acetyltransferase activity of p300 through the enhancement of p300 autoacetylation. Autoacetylated p300 accumulates near the transcription start sites accompanied by a similar enrichment of activating histone marks near those sites. Abrogation of p53-p300 interaction by a site-directed peptide inhibitor abolished p300-mediated histone acetylation, suggesting a crucial role played by the activation in p53-mediated gene regulation. Gain-of-function mutant p53, known to impart aggressive proliferative properties in tumor cells, also activates p300 autoacetylation. The same peptide abolished many of the gain-of-function properties of mutant p53 as well. Reversal of gain-of-function properties of mutant p53 suggests that molecules targeting the p53-p300 interface may be good candidates for anti-tumor drugs.

SUBMITTER: Kaypee S

PROVIDER: S-EPMC6147029 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Mutant and Wild-Type Tumor Suppressor p53 Induces p300 Autoacetylation.

Kaypee Stephanie S Sahadevan Smitha Asoka SA Patil Shilpa S Ghosh Piya P Roy Neeladri Sekhar NS Roy Siddhartha S Kundu Tapas K TK

iScience 20180607

The transcriptional co-activator p300 is essential for p53 transactivation, although its precise role remains unclear. We report that p53 activates the acetyltransferase activity of p300 through the enhancement of p300 autoacetylation. Autoacetylated p300 accumulates near the transcription start sites accompanied by a similar enrichment of activating histone marks near those sites. Abrogation of p53-p300 interaction by a site-directed peptide inhibitor abolished p300-mediated histone acetylation ...[more]

PMID: 30240745

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Project description:Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, and is associated with a poor prognosis due to frequent distant metastasis and lack of effective targeted therapies. Previously, we identified maternal embryonic leucine zipper kinase (MELK) to be highly expressed in TNBCs as compared with ER-positive breast cancers. Here we determined the molecular mechanism by which MELK is overexpressed in TNBCs. Analysis of publicly available data sets revealed that MELK mRNA is elevated in p53-mutant breast cancers. Consistent with this observation, MELK protein levels are higher in p53-mutant vs. p53 wild-type breast cancer cells. Furthermore, inactivation of wild-type p53, by loss or mutation of the p53 gene, increases MELK expression, whereas overexpression of wild-type p53 in p53-null cells reduces MELK promoter activity and MELK expression. We further analyzed MELK expression in breast cancer data sets and compared that with known wild-type p53 target genes. This analysis revealed that MELK expression strongly correlates with genes known to be suppressed by wild-type p53. Promoter deletion studies identified a p53-responsive region within the MELK promoter that did not map to the p53 consensus response elements, but to a region containing a FOXM1-binding site. Consistent with this result, knockdown of FOXM1 reduced MELK expression in p53-mutant TNBC cells and expression of wild-type p53 reduced FOXM1 expression. ChIP assays demonstrated that expression of wild-type p53 reduces binding of E2F1 (a critical transcription factor controlling FOXM1 expression) to the FOXM1 promoter, thereby, reducing FOXM1 expression. These results show that wild-type p53 suppresses FOXM1 expression, and thus MELK expression, through indirect mechanisms. Overall, these studies demonstrate that wild-type p53 represses MELK expression by inhibiting E2F1A-dependent transcription of FOXM1 and that mutation-driven loss of wild-type p53, which frequently occurs in TNBCs, induces MELK expression by suppressing FOXM1 expression and activity in p53-mutant breast cancers.

Dataset Information

Mutant and Wild-Type Tumor Suppressor p53 Induces p300 Autoacetylation.

Publications

Mutant and Wild-Type Tumor Suppressor p53 Induces p300 Autoacetylation.

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