Mad1 destabilizes p53 by preventing PML from sequestering MDM2

Abstract

Mitotic arrest deficient 1 (Mad1) plays a well-characterized role in the mitotic checkpoint. However, interphase roles of Mad1 that do not impact mitotic checkpoint function remain largely uncharacterized. Here we show that upregulation of Mad1, which is common in human breast cancer, prevents stress-induced stabilization of the tumor suppressor p53 in multiple cell types. Upregulated Mad1 localizes to ProMyelocytic Leukemia (PML) nuclear bodies in breast cancer and cultured cells. The C-terminus of Mad1 directly interacts with PML, and this interaction is enhanced by sumoylation. PML stabilizes p53 by sequestering MDM2, an E3 ubiquitin ligase that targets p53 for degradation, to the nucleolus. Upregulated Mad1 displaces MDM2 from PML, freeing it to ubiquitinate p53. Upregulation of Mad1 accelerates growth of orthotopic mammary tumors, which show decreased levels of p53 and its downstream effector p21. These results demonstrate an unexpected interphase role for Mad1 in tumor promotion via p53 destabilization.

Down-regulation of microRNA-138 improves immunologic function via negatively targeting p53 by regulating liver macrophage in mice with acute liver failure

“…It was shown that the activation of p53 is affected by cell type, stimulation form, and cellular environment [34,35]. It means that p53 activates the downstream target genes of different genomes in response to different stimulation signals [36,37]. Therefore, ConA treatment affects the expression of downstream genes and other cell signal proteins regulated by p53.…”

TERT—Regulation and Roles in Cancer Formation

“…It guarantees precise chromosome segregation by delaying separation of replicated sister chromatids ( 113 , 114 ). Mitotic arrest deficient 1 (MAD1) is a major element of the mitotic checkpoint, and it recruits its binding partner MAD2 to nuclear pores ( 113 , 115 ). During mitosis, MAD1 localizes to unattached kinetochores, where it serves as a docking site for MAD2.…”

Mitotic and DNA Damage Response Proteins: Maintaining the Genome Stability and Working for the Common Good

“…Overexpression of MAD1 prevents nucleolar MDM2 localization and promotes p53 degradation by binding to the PML protein. Then, MAD1 negatively regulates the response to DNA damage mediated by p53 ( Figure 3C ) ( Wan et al, 2019 ). It will be significant to determine if the negative function of MAD1 on p53 occurs only during its overexpression and if these levels are comparable with those of tumors.…”