Mage-A Cancer/Testis Antigens Inhibit p53 Function by Blocking Its Interaction with Chromatin

Abstract

The p53 tumor suppressor plays a major protective role in tumor prevention by coordinating changes in gene expression that lead to the elimination of cancer cells. Mage-A proteins comprise a family of metastasisassociated transcriptional regulators that potently inhibit p53 function. Here, we show that Mage-A interacts with 3 distinct peptides each of which is located within the DNA binding surface of the core domain of p53 and encompasses amino acids that are critical for site-specific DNA binding. These data suggest that Mage-A may block the association of p53 with its cognate sites in chromatin. Consistent with this idea, silencing of Mage-A expression leads to upregulation of several p53-responsive genes in a p53-dependent manner and stimulates by several fold the interaction of p53 with the p21, MDM2, and PUMA promoters. Notably, these effects can occur in the absence of genotoxic stress, leading in a p53-dependent manner, to cell-cycle delay and increased cell death. These data reveal a novel mechanism by which Mage-A proteins may suppress the p53 transcriptional program during tumor development and highlight the p53/Mage-A interaction as a prospective therapeutic target.

Myeloid-derived suppressor cells enhance the expression of melanoma-associated antigen A4 in a Lewis lung cancer murine model

“…MDSCs secrete multiple factors that may support the growth and survival of tumor cells (39)(40)(41)(42), and it would be of interest to confirm whether MDSCs secrete soluble factors that regulate MAGE-A4 expression. In further support of this, it has previously been reported that CT antigen expression is association with cell cycle progression and proliferation (43)(44)(45), apoptosis (13) and susceptibility of cancer cells to cytokines (46), suggesting that the CT antigen itself may be associated with prognosis.…”

“…MDSCs are a heterogeneous group of pathologically activated immature myeloid cells and myeloid precursors that possess potent immunosuppressive activity (10)(11)(12). MDSCs have been identified in the peripheral blood, lymphoid tissue and tumor tissue in a number of experimental mouse models (13). Other studies have also demonstrated that MDSCs inhibit the effector…”

MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs

“…13 923 melanoma cells have been described. 12 HA-MageA1, -A2, -A4 and -A6 were cloned in pCDNA3 (Invitrogen). GST-MageA2, and GST-MageA4 were obtained by subcloning in pGEX-4T1 (GE Healthcare Biosciences, Buckinghamshire, UK).…”

“…10 Subsequently, other groups also described an opposite correlation between MAGE-A gene expression and p53 activity. 7,11,12 Interestingly, only MageA4 has been shown to be involved in some potentially anti-tumor functions such as gankyrin oncoprotein inhibition 13 and apoptosis induction. 14,15 It has been demonstrated that escape to cellular senescence is one of the first barriers to be bypassed during transformation.…”

Cancer testis antigen expression in testicular germ cell tumorigenesis

“…Recently, it has been shown that MAGEA cancer testis antigens inhibit the function of p53 by blocking its interaction with chromatin. 18 In several cancer types, eg multiple myeloma, bladder cancer, non-small cell lung cancer, hepatocellular carcinoma, breast, colorectal and pancreatic ductal adenocarcinoma, the high expression of cancer testis-X genes is associated with poor differentiation grade, progressive disease and worse prognosis. [19][20][21][22] There are only limited studies on cancer testis antigen expression in testicular germ cell tumors.…”