Abstract
The MDMX (MDM4) oncogene is amplified or overexpressed in a significant percentage of human tumors. MDMX is thought to function as an oncoprotein by binding p53 tumor suppressor protein to inhibit p53-mediated transcription, and by complexing with MDM2 oncoprotein to promote MDM2-mediated degradation of p53. However, down-regulation or loss of functional MDMX has also been observed in a variety of human tumors that are mutated for p53, often correlating with more aggressive cancers and a worse patient prognosis. We have previously reported that endogenous levels of MdmX can suppress proliferation and promote pseudo-bipolar mitosis in primary and tumor cells derived from p53-deficient mice, and that MdmX-p53 double deficient mice succumb to spontaneously formed tumors more rapidly than p53-deficient mice. These results suggest that the MdmX oncoprotein may act as a tumor-suppressor in cancers with compromised p53 function. By using orthotopic transplantation and lung colonization assays in mice we now establish a p53-independent anti-oncogenic role for MdmX in tumor progression. We also demonstrate that the roles of MdmX in genome stability and in proliferation are two distinct functions encoded by the separate MdmX protein domains. The central Zn-finger domain suppresses multipolar mitosis and chromosome loss, whereas the carboxy-terminal RING domain suppresses proliferation of p53-deficient cells. Furthermore, we determine that it is the maintenance of genome stability that underlies MdmX role in suppression of tumorigenesis in hyperploid p53 mutant tumors. Our results offer a rationale for the increased metastatic potential of p53 mutant human cancers with aberrant MdmX function and provide a caveat for the application of anti-MdmX treatment of tumors with compromised p53 activity.
Highlights
The p53 transcription factor regulates expression of wide variety of genes involved in cellular response to stress, and mutation of p53 gene is the most common genetic lesion in human cancers
We find the inhibition of underwent normal bipolar mitosis and continued to divide cell proliferation and maintenance of genome stability to be in bipolar fashion until the end of filming
To characterize the ability of MdmX to suppress cell proliferation and multipolar mitosis, we utilized mouse MdmX expression constructs encoding either the FL, or mutant MdmX lacking carboxy-terminal RING domain, central zinc-finger domain or both. These constructs were co-transfected along with a puromycin drug selection marker into the epithelial tumor cells derived from MdmX/p53-double knockout (DKO) mice, and pools of puromycin-resistant stably transfected cells were recovered for further analyses
Summary
The p53 transcription factor regulates expression of wide variety of genes involved in cellular response to stress, and mutation of p53 gene is the most common genetic lesion in human cancers. MDM gene amplification and/or overexpression have been observed in a variety of human cancers, including leukemia and lymphoma, breast cancer, glioblastoma, soft tissue sarcoma, osteosarcoma and retinoblastoma.[9,10,11] As most tumors with amplified copy numbers of MDM genes retain wild-type p53,10,12 the increased level of MDM2 or MDMX proteins is thought to promote oncogenesis by inhibiting p53 activity in these cells. Experiments involving Mdm[2] or MdmX overexpression in cells or mice suggest that MDM oncoproteins may have p53-independent roles in regulating cell growth and tumorigenesis[13,14,15,16,17] the precise contributions of these p53-independent, proto-oncogenic effects in human cancers remains uncertain.
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