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.
Highlights
Mitotic arrest deficient 1 (Mad1) plays a well-characterized role in the mitotic checkpoint
The ProMyelocytic Leukemia (PML) protein, which is fused to retinoic acid receptor alpha (RARα) due to a reciprocal translocation between chromosomes 15 and 17 in >98% of acute PML patients, forms the core of PML NBs26. >100 proteins localize to PML nuclear bodies (NBs), including proteins involved in cell cycle arrest, apoptosis, transcription, and metabolism[27]
SUMO1 and SUMO2 are highly concentrated in PML NBs34–36, suggesting that Mad[1] puncta localize there
Summary
Mitotic arrest deficient 1 (Mad1) plays a well-characterized role in the mitotic checkpoint. Upregulated Mad[1] localizes to ProMyelocytic Leukemia (PML) nuclear bodies in breast cancer and cultured cells. Upregulation of Mad[1] 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 Mad[1] in tumor promotion via p53 destabilization. Mad[1] plays a well-characterized role during mitosis, and expression of many mitotic proteins peaks during mitosis, Mad[1] expression levels remain constant throughout the cell cycle[2]. We show that upregulated Mad[1] localizes to PML NBs. Protein levels of the p53 tumor suppressor remain low in the absence of cellular stresses due to continuous ubiquitination by MDM2 followed by degradation[28,29,30]. In response to a variety of cellular stresses including DNA damage, PML sequesters
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