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Two cellular proteins that bind to wild-type but not mutant p53.

ABSTRACT: p53 is a tumor-suppressor protein that can activate and repress transcription. Using the yeast two-hybrid system, we identified two previously uncharacterized human proteins, designated 53BP1 and 53BP2, that bind to p53. 53BP1 shows no significant homology to proteins in available databases, whereas 53BP2 contains two adjacent ankyrin repeats and a Src homology 3 domain. In vitro binding analyses indicate that both of these proteins bind to the central domain of p53 (residues 80-320) required for site-specific DNA binding. Consistent with this finding, p53 cannot bind simultaneously to 53BP1 or 53BP2 and to a DNA fragment containing a consensus p53 binding site. Unlike other cellular proteins whose binding to p53 has been characterized, both 53BP1 and 53BP2 bind to the wild-type but not to two mutant p53 proteins identified in human tumors, suggesting that binding is dependent on p53 conformation. The characteristics of these interactions argue that 53BP1 and 53BP2 are involved in some aspect of p53-mediated tumor suppression.

SUBMITTER: Iwabuchi K

PROVIDER: S-EPMC44145 | biostudies-other | 1994 Jun

REPOSITORIES: biostudies-other

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Two cellular proteins that bind to wild-type but not mutant p53.

Iwabuchi K K Bartel P L PL Li B B Marraccino R R Fields S S

Proceedings of the National Academy of Sciences of the United States of America 19940601 13

p53 is a tumor-suppressor protein that can activate and repress transcription. Using the yeast two-hybrid system, we identified two previously uncharacterized human proteins, designated 53BP1 and 53BP2, that bind to p53. 53BP1 shows no significant homology to proteins in available databases, whereas 53BP2 contains two adjacent ankyrin repeats and a Src homology 3 domain. In vitro binding analyses indicate that both of these proteins bind to the central domain of p53 (residues 80-320) required fo ...[more]

PMID: 8016121

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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

Two cellular proteins that bind to wild-type but not mutant p53.

Publications

Two cellular proteins that bind to wild-type but not mutant p53.

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