HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis

Abstract

In mouse models and cell lines, murine double minute 2 (MDM2) and MDM4 have been shown to synergistically promote proteasome-mediated degradation of p21 and p53. MDM4 also inhibits p53-mediated transcriptional activation of p21. p53 expression results in increased p21 expression, a negative cell-cycle regulatory protein and an inhibitor of cyclin D1. As mantle cell lymphoma is characterized by cyclin D1 overexpression, we assessed for human homolog of MDM4 (HDM4) expression and its effect on p21 in mantle cell lymphoma. Using immunohistochemical methods, in reactive lymph nodes (n ¼ 19) germinal center cells strongly expressed HDM4 in the nucleus and the cytoplasm, but mantle zone B-cells were only dimly positive. In mantle cell lymphoma tumors, aberrant HDM4 nuclear expression was observed in 18 of 19 (95%) cases. In contrast, HDM4 in other B-cell non-Hodgkin lymphoma types retained its normal pattern of expression. To further characterize the differential upregulation of HDM4 in mantle cell lymphoma, HDM4 was assessed by quantitative real-time polymerase chain reaction in four mantle cell lymphoma cell lines (Granta 519, Z-138, SP-53, and Mino) and six mantle cell lymphoma tumors. Both the splicing variant HDM4-S, containing only the p53-binding domain, and full length HDM4 were increased compared with normal CD19 þ B-cells (Po0.05). Using small interfering RNA to inhibit HDM4 in the SP53 and Mino cell lines showed increased p21 and active caspase-3, the latter indicating increased apoptosis. Our results show that HDM4 is overexpressed in mantle cell lymphoma and, at least in part, exerts its effect by suppressing p21 expression, thereby enhancing cell-cycle progression. Inhibition of HDM4 may serve as a potential approach in the design of therapy for patients with mantle cell lymphoma.

Gene and protein analysis reveals that p53 pathway is functionally inactivated in cytogenetically normal Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

“…This result positions Mdmx protein as an important inhibitor of the p53 pathway especially in APL as well as in CN-AML. Our findings are in line with reports that revealed upregulated Mdmx protein in various human malignancies [32–35, 37, 38, 40] including AML with complex karyotype [41] and showed the ability of Mdmx to inhibit p53 activity in AML cell lines [135]. Here we present evidence for the link between Mdmx levels and functional inhibition of p53 in CN-AML and APL patients.…”

RETRACTED: Mutual regulation of MDM4 and TOP2A in cancer cell proliferation

“…Murine double minute 4 (MDM4), also known as MDMx, is amplified or overexpressed in various human cancers (Danovi et al ., ; Han et al ., ; Li et al ., ; Liang et al ., ; Riemenschneider et al ., ; Wade et al ., ). Thus, overexpression of MDM4 appears to favor cancer cell survival.…”

The Roles of MDM2 and MDMX in Cancer

“…MDMX-S is overexpressed in some carcinomas and sarcomas (99, 122, 123). The overexpression of MDMX and MDMX-S has also been demonstrated in mantle cell lymphoma, in which it has been suggested that it suppresses p21 and therefore promotes cell-cycle progression (124). …”