Disease relevance of MXI1

• Commonly occurring loss and mutation of the MXI1 gene in prostate cancer [1].
• 3. The MXI1 gene at 10q24-25 is another candidate tumor suppressor that has only rarely been studied in melanomas, with conflicting results [2].
• Deletions in the long arm of chromosome 10 in lymphomas with t(14;18): a pathogenetic role of the tumor supressor genes PTEN/MMAC1 and MXI1 [3]?
• MXI1, a putative tumor suppressor gene, suppresses growth of human glioblastoma cells [4].
• We and others have previously mapped the MXI1 gene to the distal portion of chromosome 10q, a region that is rearranged or affected by allelic loss in many astrocytic brain tumors [4].

High impact information on MXI1

• PICH contributes to the mitotic checkpoint by recruiting Mad2 to kinetochores and is proposed to regulate checkpoint signaling by monitoring tension at centromeres [5].
• Waiting for anaphase: Mad2 and the spindle assembly checkpoint [6].
• MXI1 maps to chromosome 10q24-q25, a region that is deleted in some cases of prostate cancer [7].
• MXI1 thus displays allelic loss and mutation in some cases of prostate cancer that may contribute to the pathogenesis or neoplastic evolution of this common malignancy [7].
• Mutation of the MXI1 gene in prostate cancer [7].

Chemical compound and disease context of MXI1

• No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters. The CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group [8].

Biological context of MXI1

• Because more than 90% of prostate tumors contain no cytogenetic abnormality of 10q, the relevance of MXI1 loss and/or mutation to the vast majority of cases remains unclear [1].
• MXI1 allelic loss was seen more frequently in recurrent/metastatic tumors (59%), as compared with in primary (33%) lesions [2].
• Genomic organization of human MXI1, a putative tumor suppressor gene [9].
• Furthermore, cell cycle analysis demonstrated that induction of MXI1 results in accumulation of cells in the G2-M phase [4].
• Thus, these studies support the notion that MXI1 normally functions to suppress cell growth and suggest that loss of MXI1 function may play a role in human glioblastoma development [4].

Anatomical context of MXI1

• To determine whether MXI1 can indeed function as a suppressor of growth, we have introduced a steroid-inducible MXI1 expression vector into the U87MG cell line, a glioblastoma cell line lacking endogenous MXI1 expression [4].
• Mxi1 isoforms are expressed in hematological cell lines and normal bone marrow [10].
• We also examined 29 human tumor cell lines consisting of 12 esophageal cancers, 7 glioma/glioblastomas and 10 others for Mxi1 mutations in exons 1, 2, 4 (HLH domain), 5 and 6 [11].
• These proteins include the microtubule motors CENP-E and cytoplasmic dynein, and proteins involved with the mitotic spindle checkpoint, Mad2, Bub1R, and the 3F3/2 phosphoantigen [12].
• Suppression of Mad2 was also observed in aryl hydrocarbon receptor-deficient mouse embryonic fibroblasts, suggesting that TCDD suppresses Mad2 by a novel TCDD receptor signaling mechanism [13].

Associations of MXI1 with chemical compounds

• In this study, we investigated if MAD2 played a part in cellular sensitivity to DNA-damaging agents, especially cisplatin, and whether it was regulated through mitotic checkpoint [14].
• Dioxin suppresses the checkpoint protein, MAD2, by an aryl hydrocarbon receptor-independent pathway [13].
• LD doxorubicin-induced SLP was preceded by multinucleation and downregulation of multiple proteins with mitotic checkpoint function, including CENP-A, Mad2, BubR1, and Chk1 [15].
• Interestingly, Mad2 protein expression with PXL treatment followed by 5-FU gradually increased after the PXL removal and 5-FU exposure [16].
• The combination of MDI and Aerochamber was significantly better at delivering budesonide to a filter in front of the test lung (14.2% of aerosolized dose) than were either the MDI and Aerovent (3.6%) or the Ultravent or MAD2 jet nebulizers (0.02% and 0.68% of initial reservoir dose) [17].

Other interactions of MXI1

• MXI1, a member of the MYC family of transcription factors, is thought to negatively regulate MYC function and may therefore be a potential tumor suppressor gene [9].
• Fifty-four percent (15 of 28) of the informative cases showed loss of heterozygosity for one or both MXI1 markers, as compared with 67% (16 of 24) of the informative cases for MTS1 [2].
• Detailed physical analysis of a 1.5-megabase YAC contig containing the MXI1 and ADRA2A genes [18].
• The distal long arm of chromosome 10 harbors genes of biomedical interest such as MXI1, a putative tumor suppressor gene, and those encoding the adrenergic receptors alpha2A (ADRA2A) and beta1 (ADRB1) [18].
• In addition, we utilized SSCP analysis to test two other candidate genes on 10q: FAS, a cell surface receptor which transduces an apoptotic, cell death signal and MXI1, a transcriptional repressor [19].

Analytical, diagnostic and therapeutic context of MXI1

• We prospectively evaluated prostate tumors for loss of MXI1 by fluorescence in situ hybridization (FISH) and cytogenetic techniques [1].
• Using detailed restriction mapping and partial DNA sequencing analysis, we have determined the genomic organization of the human MXI1 gene to facilitate a search for mutations that affect MXI1 function [9].
• Sequence analysis revealed no somatic mutations in any of the six MXI1 coding exons, similar to findings in prostate tumors with MXI1 allelic loss [4].
• As part of a physical and genetic study of this genomic region, we constructed a 1.5-Mb YAC contig mapping to 10q25 that contains MXI1 and ADRA2A as well as a number of STSs [18].
• Southern blot analyses did not reveal any gross rearrangements of MXI1 [20].

References