Gene Summary

Gene:MAD1L1; MAD1 mitotic arrest deficient-like 1 (yeast)
Aliases: MAD1, PIG9, TP53I9, TXBP181
Summary:MAD1L1 is a component of the mitotic spindle-assembly checkpoint that prevents the onset of anaphase until all chromosome are properly aligned at the metaphase plate. MAD1L1 functions as a homodimer and interacts with MAD2L1. MAD1L1 may play a role in cell cycle control and tumor suppression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:mitotic spindle assembly checkpoint protein MAD1
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (21)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Neoplastic Cell Transformation
  • Mitosis
  • Base Sequence
  • Protein-Serine-Threonine Kinases
  • Repressor Proteins
  • Spindle Apparatus
  • Cancer Gene Expression Regulation
  • Cell Proliferation
  • Chromosome 7
  • Lung Cancer
  • Prostate Cancer
  • Structure-Activity Relationship
  • Amino Acid Sequence
  • Stomach Cancer
  • Apoptosis
  • Neoplasm Proteins
  • World Health Organization
  • Phosphoproteins
  • Colorectal Cancer
  • DNA-Binding Proteins
  • Cell Cycle Proteins
  • Tumor Suppressor Proteins
  • Breast Cancer
  • Calcium-Binding Proteins
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Reactive Oxygen Species
  • Nuclear Proteins
  • U937 Cells
  • Proto-Oncogene Proteins c-myc
  • Bladder Cancer
  • Aneuploidy
  • Colonic Neoplasms
  • Genomic Instability
  • Ubiquitin-Protein Ligases
  • Telomerase
  • Single Nucleotide Polymorphism
  • Mad2 Proteins
  • ras Proteins
  • Gene Expression
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MAD1L1 (cancer-related)

Matson DR, Stukenberg PT
CENP-I and Aurora B act as a molecular switch that ties RZZ/Mad1 recruitment to kinetochore attachment status.
J Cell Biol. 2014; 205(4):541-54 [PubMed] Free Access to Full Article Related Publications
The RZZ (Rod, ZW10, and Zwilch) complex and Mad1 proteins tightly associate with kinetochores to generate the spindle checkpoint signal, but they are released when a kinetochore forms mature microtubule attachments. Here we demonstrate that the centromere protein CENP-I is required to generate a stable association of RZZ and Mad1 with kinetochores. CENP-I also inhibits their removal by dynein stripping. This regulation of Mad1 and RZZ dissociation functions independently of Aurora B, which regulates their association. We show that the microtubule status of each kinetochore independently dictates the recruitment of Aurora B kinase, kinase activity on a kinetochore substrate, and loading of spindle checkpoint proteins. This dynamic regulation of Mad1 association by Aurora B is only uncovered when CENP-I is depleted, consistent with our finding that CENP-I inhibits the dissociation of Mad1. We conclude that the dual activities of Aurora B and CENP-I generate a molecular switch that maintains a robust spindle checkpoint signal at prometaphase kinetochores until they attain mature attachments to microtubules.

Sze KM, Chu GK, Mak QH, et al.
Proline-rich acidic protein 1 (PRAP1) is a novel interacting partner of MAD1 and has a suppressive role in mitotic checkpoint signalling in hepatocellular carcinoma.
J Pathol. 2014; 233(1):51-60 [PubMed] Related Publications
Loss of mitotic checkpoint of cells contributes to chromosomal instability and leads to carcinogenesis. Mitotic arrest deficient 1 (MAD1) is a key component in mitotic checkpoint signalling. In this study, we identified a novel MAD1 interacting partner, proline-rich acidic protein 1 (PRAP1), using yeast-two hybrid screening, and investigated its role in mitotic checkpoint signalling in hepatocellular carcinoma (HCC). We demonstrated the physical interaction of PRAP1 with MAD1 and of PRAP1 with MAD1 isoform MAD1β, using a co-immunoprecipitation assay. Moreover, stable expression of PRAP1 in mitotic checkpoint-competent HCC cells, BEL-7402 and SMMC-7721, induced impairment of the mitotic checkpoint (p < 0.01), formation of chromosome bridges (p < 0.01) and aberrant chromosome numbers (p < 0.001). Interestingly, ectopic expression PRAP1 in HCC cells led to significant under-expression of MAD1. In human HCC tumours, 40.4% (23/57) of HCCs showed under-expression of PRAP1 protein as compared with their corresponding non-tumorous livers; up-regulation of MAD1 protein was significantly associated with down-regulation of PRAP1 (p = 0.030). Our data revealed that PRAP1 is a protein interacting partner of MAD1 and that PRAP1 is able to down-regulate MAD1 and suppress mitotic checkpoint signalling in HCC.

Sun Q, Zhang X, Liu T, et al.
Increased expression of mitotic arrest deficient-like 1 (MAD1L1) is associated with poor prognosis and insensitive to Taxol treatment in breast cancer.
Breast Cancer Res Treat. 2013; 140(2):323-30 [PubMed] Related Publications
Aneuploidy is a characteristic of human cancers, and recent studies have suggested that defects of mitotic checkpoints play a role in carcinogenesis. Mitotic Arrest Deficient-Like 1 (MAD1L1), whose altered expression is associated with chromosomal instability, is a checkpoint gene. We examined MAD1L1 protein expression from 461 breast cancer tissues and patients' normal breast tissues by tissue microarray to study the correlation between the MAD1L1 expression and the clinicopathological features. MAD1L1 protein expression was significantly increased in the nuclei of cancer cells (28.4 %) compared with that in normal mammary cells (2.2 %), and was correlated with Her-2 status, cancer subtypes, p53 status, and age. High level of MAD1L1 expression in nuclei was associated with worse OS (p = 0.018). Furthermore, patients with high level of MAD1L1 expression (in nuclei) and undergone Taxol chemotherapy treatment have shorter overall survival than ones without Taxol treatment in this study (p = 0.026). In conclusion, our data demonstrated a significant correlation between nuclear expression of MAD1L1 protein and adverse prognosis in breast cancer. MAD1L1 might be used as a prognostic biomarker for breast cancer and expression of MAD1L1 in nuclei is also a predict biomarker of contraindication to pacilitaxel treatment in breast cancer.

Chung CC, Kanetsky PA, Wang Z, et al.
Meta-analysis identifies four new loci associated with testicular germ cell tumor.
Nat Genet. 2013; 45(6):680-5 [PubMed] Free Access to Full Article Related Publications
We conducted a meta-analysis to identify new susceptibility loci for testicular germ cell tumor (TGCT). In the discovery phase, we analyzed 931 affected individuals and 1,975 controls from 3 genome-wide association studies (GWAS). We conducted replication in 6 independent sample sets comprising 3,211 affected individuals and 7,591 controls. In the combined analysis, risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS (per-allele odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.12-1.26; P = 1.11 × 10(-8)), 7p22.3 in MAD1L1 (OR = 1.21, 95% CI = 1.14-1.29; P = 5.59 × 10(-9)), 16q22.3 in RFWD3 (OR = 1.26, 95% CI = 1.18-1.34; P = 5.15 × 10(-12)) and 17q22 (rs9905704: OR = 1.27, 95% CI = 1.18-1.33; P = 4.32 × 10(-13) and rs7221274: OR = 1.20, 95% CI = 1.12-1.28; P = 4.04 × 10(-9)), a locus that includes TEX14, RAD51C and PPM1E. These new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and the DNA damage response.

Ni M, Chen Y, Fei T, et al.
Amplitude modulation of androgen signaling by c-MYC.
Genes Dev. 2013; 27(7):734-48 [PubMed] Free Access to Full Article Related Publications
Androgen-stimulated growth of the molecular apocrine breast cancer subtype is mediated by an androgen receptor (AR)-regulated transcriptional program. However, the molecular details of this AR-centered regulatory network and the roles of other transcription factors that cooperate with AR in the network remain elusive. Here we report a positive feed-forward loop that enhances breast cancer growth involving AR, AR coregulators, and downstream target genes. In the absence of an androgen signal, TCF7L2 interacts with FOXA1 at AR-binding sites and represses the basal expression of AR target genes, including MYC. Direct AR regulation of MYC cooperates with AR-mediated activation of HER2/HER3 signaling. HER2/HER3 signaling increases the transcriptional activity of MYC through phosphorylation of MAD1, leading to increased levels of MYC/MAX heterodimers. MYC in turn reinforces the transcriptional activation of androgen-responsive genes. These results reveal a novel regulatory network in molecular apocrine breast cancers regulated by androgen and AR in which MYC plays a central role as both a key target and a cooperating transcription factor to drive oncogenic growth.

Cho K, Shin HW, Kim YI, et al.
Mad1 mediates hypoxia-induced doxorubicin resistance in colon cancer cells by inhibiting mitochondrial function.
Free Radic Biol Med. 2013; 60:201-10 [PubMed] Related Publications
Cancer cells acquire resistance to chemotherapy under hypoxia, which is mainly driven by the transcription factor HIF (hypoxia-inducible factor). Yet, it is uncertain which molecules mediate such resistance. While profiling gene expression in colon cancer cells, we found that Mad1 (MAX dimerization protein 1) is substantially induced during hypoxia. The hypoxic induction of Mad1 was confirmed by RT-PCR and Western blotting. The Mad1 expression was attenuated by HIF-1α small interfering (si) RNAs, but less so by HIF-2α siRNAs. Moreover, luciferase reporter and chromatin immunoprecipitation analyses revealed that HIF-1 transactivates the MAD1 gene by directly targeting a putative hypoxia-response element in the MAD1 promoter. We next investigated if Mad1 is responsible for the hypoxia-induced drug resistance. We treated colon cancer cells with doxorubicin and found that the cells under hypoxia survived more than those under normoxia. The doxorubicin resistance was not induced in Mad1-knocked-down cells even under hypoxia. Mad1 knockdown reactivated the caspase-9/caspase-3/PARP apoptotic pathway under hypoxia. Moreover, doxorubicin-induced production of reactive oxygen species was significantly reduced under hypoxia, which was reversed by Mad1 knockdown. During hypoxia, mitochondria became bigger in size and less active in respiration, both of which were attenuated by Mad1 knockdown. These data indicate that hypoxia-induced Mad1 lowers doxorubicin-stimulated generation of reactive oxygen species through mitochondrial inhibition and subsequently contributes to tumor resistance to doxorubicin. Therefore, Mad1 could be a potential target for sensitizing cancer cells to redox-cycling drugs such as doxorubicin.

Reuss DE, Mucha J, Hagenlocher C, et al.
Sensitivity of malignant peripheral nerve sheath tumor cells to TRAIL is augmented by loss of NF1 through modulation of MYC/MAD and is potentiated by curcumin through induction of ROS.
PLoS One. 2013; 8(2):e57152 [PubMed] Free Access to Full Article Related Publications
Malignant peripheral nerve sheath tumor (MPNST) is a rare aggressive form of sarcoma often associated with the tumor syndrome neurofibromatosis type 1 (NF1). We investigated the effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) on NF1 associated MPNST and determinants of TRAIL sensitivity. MPNST cell lines with complete neurofibromin deficiency were sensitive to apoptotic cell death induced by TRAIL whereas MPNST cells with retained neurofibromin expression or normal human Schwann cells were resistant. Increased sensitivity to TRAIL was associated with overexpression of death receptors, especially DR5. Re-expression of the GAP related domain of neurofibromin (NF1-GRD) suppressed DR5 expression and decreased sensitivity to TRAIL. We show that death receptor expression and TRAIL sensitivity critically depend on c-MYC and that c-MYC amounts are increased by MEK/ERK and PI3K/AKT signalling pathways which are suppressed by neurofibromin. Furthermore PI3K/AKT signalling strongly suppresses the MYC-antagonist MAD1 which significantly contributes to TRAIL sensitivity. Re-expression of the NF1-GRD decreased c-MYC and increased MAD1 amounts suggesting that neurofibromin influences TRAIL sensitivity at least in part by modulating the MYC/MAX/MAD network. The phytochemical curcumin further increased the sensitivity of neurofibromin deficient MPNST cells to TRAIL. This was presumably mediated by ROS, as it correlated with increased ROS production, was blocked by N-acetylcysteine and mimicked by exogenous ROS.

Sandhu SK, Volinia S, Costinean S, et al.
miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eμ-miR-155 transgenic mouse model.
Proc Natl Acad Sci U S A. 2012; 109(49):20047-52 [PubMed] Free Access to Full Article Related Publications
Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell-mediated immune response. Here we provide a mechanistic insight into miR-155-induced leukemogenesis in the Eμ-miR-155 mouse model through genome-wide transcriptome analysis of naïve B cells and target studies. We found that a key transcriptional repressor and proto-oncogene, Bcl6 is significantly down-regulated in Eμ-miR-155 mice. The reduction of Bcl6 subsequently leads to de-repression of some of the known Bcl6 targets like inhibitor of differentiation (Id2), interleukin-6 (IL6), cMyc, Cyclin D1, and Mip1α/ccl3, all of which promote cell survival and proliferation. We show that Bcl6 is indirectly regulated by miR-155 through Mxd1/Mad1 up-regulation. Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis. Meta-analysis of the diffuse large B-cell lymphoma patient microarray data showed that miR-155 expression is inversely correlated with Bcl6 and Hdac4. Hence this study provides a better understanding of how miR-155 causes disruption of the BCL6 transcriptional machinery that leads to up-regulation of the survival and proliferation genes in miR-155-induced leukemias.

Bie L, Zhao G, Cheng P, et al.
The accuracy of survival time prediction for patients with glioma is improved by measuring mitotic spindle checkpoint gene expression.
PLoS One. 2011; 6(10):e25631 [PubMed] Free Access to Full Article Related Publications
Identification of gene expression changes that improve prediction of survival time across all glioma grades would be clinically useful. Four Affymetrix GeneChip datasets from the literature, containing data from 771 glioma samples representing all WHO grades and eight normal brain samples, were used in an ANOVA model to screen for transcript changes that correlated with grade. Observations were confirmed and extended using qPCR assays on RNA derived from 38 additional glioma samples and eight normal samples for which survival data were available. RNA levels of eight major mitotic spindle assembly checkpoint (SAC) genes (BUB1, BUB1B, BUB3, CENPE, MAD1L1, MAD2L1, CDC20, TTK) significantly correlated with glioma grade and six also significantly correlated with survival time. In particular, the level of BUB1B expression was highly correlated with survival time (p<0.0001), and significantly outperformed all other measured parameters, including two standards; WHO grade and MIB-1 (Ki-67) labeling index. Measurement of the expression levels of a small set of SAC genes may complement histological grade and other clinical parameters for predicting survival time.

Velpula KK, Dasari VR, Tsung AJ, et al.
Transcriptional repression of Mad-Max complex by human umbilical cord blood stem cells downregulates extracellular signal-regulated kinase in glioblastoma.
Stem Cells Dev. 2012; 21(10):1779-93 [PubMed] Free Access to Full Article Related Publications
Previously, we have shown that human umbilical cord blood stem cell (hUCBSC) treatment downregulate cyclin D1 in glioma cells. To study the cell cycle progression and investigate the upstream molecules regulating cyclin D1 expression, we analyzed the involvement of extracellular signal-regulated kinase (ERK) and its functionality after treatment with hUCBSC. We observed downregulation of pERK after hUCBSC treatment at both transcriptional and translational levels. Increased translocation of ERK from cytoplasm to the nucleus was observed in glioma cells, whereas hUCBSC cocultures with glioma cells showed suppressed nuclear translocation. This finding suggests that hUCBSC regulates ERK by suppressing its phosphorylation at phospho-Thr(202)/Tyr(204) retarding pERK nuclear translocation. ERK promoter analysis has shown c-Myc binding sites, indicative of possible transcriptional interactions that regulate cyclin D1 and ERK expression levels. Treatment of U251 and 5310 glioma cells with U0126, a MEK/ERK inhibitor receded pERK and c-Myc levels. In another experiment, U251 and 5310 cells treated with 10074-G5, c-Myc/Max inhibitor displayed reduction in pERK and c-Myc levels suggestive of a positive feedback loop between ERK/c-Myc/Max molecules. In the present study, we show that glioma cells exhibit abundant c-Myc expression and increased c-Myc/Max activity. In contrast, the glioma cells cocultured with hUCBSC demonstrated high Mad1 expression that competitively binds to Max to repress the c-Myc/Max mediated gene transcription. Our studies thus elucidate the potential role of hUCBSC in controlling glioma cell cycle progression and invasion by limiting Max binding to c-Myc, thus regulating the expression of glioma cell cycle and invasion associated molecules such as ERK, integrins via increased levels of Mad1 expression.

Meeran SM, Patel SN, Chan TH, Tollefsbol TO
A novel prodrug of epigallocatechin-3-gallate: differential epigenetic hTERT repression in human breast cancer cells.
Cancer Prev Res (Phila). 2011; 4(8):1243-54 [PubMed] Free Access to Full Article Related Publications
Epigallocatechin-3-gallate (EGCG), a major component of green tea polyphenols (GTP), has been reported to downregulate telomerase activity in breast cancer cells thereby increasing cellular apoptosis and inhibiting cellular proliferation. However, the major concerns with GTPs are their bioavailability and stability under physiologic conditions. In the present study, we show that treatments with EGCG and a novel prodrug of EGCG (pro-EGCG or pEGCG) dose- and time-dependently inhibited the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells but not normal control MCF10A cells. Furthermore, both EGCG and pro-EGCG inhibited the transcription of hTERT (human telomerase reverse transcriptase), the catalytic subunit of telomerase, through epigenetic mechanisms in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells. The downregulation of hTERT expression was found to be because of hTERT promoter hypomethylation and histone deacetylations, mediated at least partially through inhibition of DNA methyltransferase and histone acetyltransferase activities, respectively. In addition, we also observed that EGCG and pEGCG can remodel chromatin structures of the hTERT promoter by decreasing the level of acetyl-H3, acetyl-H3K9, and acetyl-H4 to the hTERT promoter. EGCG and pEGCG induced chromatin alterations that facilitated the binding of many hTERT repressors such as MAD1 and E2F-1 to the hTERT regulatory region. Depletion of E2F-1 and MAD1 by using siRNA reversed the pEGCG downregulated hTERT expression and associated cellular apoptosis differently in ER-positive and ER-negative breast cancer cells. Collectively, our data provide new insights into breast cancer prevention through epigenetic modulation of telomerase by using pro-EGCG, a more stable form of EGCG, as a novel chemopreventive compound.

Bosco N, Pelliccia F, Rocchi A
Characterization of FRA7B, a human common fragile site mapped at the 7p chromosome terminal region.
Cancer Genet Cytogenet. 2010; 202(1):47-52 [PubMed] Related Publications
Common fragile sites (CFS) are specific regions of the mammalian chromosomes that are particularly prone to gaps and breaks. They are a cause of genome instability, and the location of many CFS correlates with breakpoints of aberrations recurrent in some cancers. The molecular characterization of some CFS has not clarified the causes of their fragility. In this work, by using fluorescence in situ hybridization analysis with BAC and PAC clones, we determined the DNA sequence of the CFS FRA7B. The FRA7B sequence was then analyzed to identify coding sequences and some structural features possibly involved in fragility. FRA7B spans about 12.2 megabases, and is therefore one of the largest CFS analyzed. It maps at the 7p21.3-22.3 chromosome bands, therefore at the interface of G- and R-band regions that are probably difficult to replicate. A 90-kilobase long sequence that presents very high flexibility values was identified at the very beginning of the more fragile CFS region. Three large genes (THSD7A, SDK1, and MAD1L1) and two miRNA genes (MIRN589 and MIRN339) map in the fragile region. The chromosome band 7p22 is a recurrent breakpoint in chromosome abnormalities in different types of neoplasm. FRA7B is the first characterized CFS located in a chromosome terminal region.

Huynh KM, Soh JW, Dash R, et al.
FOXM1 expression mediates growth suppression during terminal differentiation of HO-1 human metastatic melanoma cells.
J Cell Physiol. 2011; 226(1):194-204 [PubMed] Related Publications
Induction of terminal differentiation represents a potentially less toxic cancer therapy. Treatment of HO-1 human metastatic melanoma cells with IFN-β plus mezerein (MEZ) promotes terminal differentiation with an irreversible loss of growth potential. During this process, the transcription factor FOXM1 is down-regulated potentially inhibiting transactivation of target genes including those involved in G(2)/M progression and cell proliferation. We investigated the mechanism of FOXM1 down-regulation and its physiological role in terminal differentiation. Genetic and pharmacological studies revealed that FOXM1 down-regulation was primarily caused by MEZ activation of PKCα and co-treatment with IFN-β plus MEZ augmented the effect of PKCα. Promoter analysis with a mutated E-box on the FOXM1 promoter, and in vitro and in vivo binding assays confirm a direct role of c-Myc on FOXM1 expression. Reduction of c-Myc and overexpression of Mad1 by IFN-β plus MEZ treatment should cause potent and persistent reduction of FOXM1 expression during terminal differentiation. Overexpression of FOXM1 restored expression of cell cycle-associated genes and increased the proportion of cells in the S phase. Our experiments support a model for terminal differentiation in which FOXM1 down-regulation via activation of PKCα followed by suppression of c-Myc expression, are causal events in promoting growth inhibition during terminal differentiation.

Meeran SM, Patel SN, Tollefsbol TO
Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines.
PLoS One. 2010; 5(7):e11457 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a common dietary component that has histone deacetylase inhibition activity and exciting potential in cancer prevention. The mechanisms by which SFN imparts its chemopreventive properties are of considerable interest and little is known of its preventive potential for breast cancer.
PRINCIPAL FINDINGS: We found that SFN significantly inhibits the viability and proliferation of breast cancer cells in vitro while it has negligible effects on normal breast cells. Inhibition of telomerase has received considerable attention because of its high expression in cancer cells and extremely low level of expression in normal cells. SFN treatment dose- and time-dependently inhibited human telomerase reverse transcriptase (hTERT), the catalytic regulatory subunit of telomerase, in both MCF-7 and MDA-MB-231 human breast cancer cells. DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3a, were also decreased in SFN-treated breast cancer cells suggesting that SFN may repress hTERT by impacting epigenetic pathways. Down-regulation of DNMTs in response to SFN induced site-specific CpG demethylation occurring primarily in the first exon of the hTERT gene thereby facilitating CTCF binding associated with hTERT repression. Chromatin immunoprecipitation (ChIP) analysis of the hTERT promoter revealed that SFN increased the level of active chromatin markers acetyl-H3, acetyl-H3K9 and acetyl-H4, whereas the trimethyl-H3K9 and trimethyl-H3K27 inactive chromatin markers were decreased in a dose-dependent manner. SFN-induced hyperacetylation facilitated the binding of many hTERT repressor proteins such as MAD1 and CTCF to the hTERT regulatory region. Depletion of CTCF using siRNA reduced the SFN-induced down-regulation of hTERT mRNA transcription in these breast cancer cells. In addition, down-regulation of hTERT expression facilitated the induction of cellular apoptosis in human breast cancer cells.
SIGNIFICANCE: Collectively, our results provide novel insights into SFN-mediated epigenetic down-regulation of telomerase in breast cancer prevention and may open new avenues for approaches to SFN-mediated cancer prevention.

Wang HB, Wang XW, Zhou G, et al.
PinX1 inhibits telomerase activity in gastric cancer cells through Mad1/c-Myc pathway.
J Gastrointest Surg. 2010; 14(8):1227-34 [PubMed] Related Publications
INTRODUCTION: The aim of this study was to investigate the role of Mad1/c-Myc in telomerase regulation in gastric cancer cells in order to gain insight into telomerase activity and to evaluate PinX1 as a putative inhibitor of gastric cancer.
METHODS: PinX1 and PinX1siRNA eukaryotic expression vectors were constructed by recombinant technology and transfected into gastric carcinoma cells using Lipofectamine 2000. Telomerase activity was measured by the telomeric repeat amplification protocol. Apoptosis of gastric cancer cells was analyzed by flow cytometry and transmission electron microscopy. Reverse transcription-polymerase chain reaction and Western blotting were used to assess the expression levels of PinX1 and Mad1/c-Myc.
RESULTS: We found that PinX1-negative gastric cancer cells showed significantly higher telomerase activity than did the PinX1-postive cells. PinX1-transfection reduced telomerase activity in PinX1-negative gastric cancer cells and exhibited an upregulation of Mad1 and downregulation of c-Myc expression. Pinx1 RNAi treatment led to downregulation of Mad1 and upregulation of c-Myc.
CONCLUSION: Suppression of telomerase activity mediated by PinX1 is involved in the Mad1/c-Myc pathway.

Guo Y, Zhang X, Yang M, et al.
Functional evaluation of missense variations in the human MAD1L1 and MAD2L1 genes and their impact on susceptibility to lung cancer.
J Med Genet. 2010; 47(9):616-22 [PubMed] Related Publications
BACKGROUND: Human MAD1 mitotic arrest deficient-like 1 (MAD1L1) and MAD2 mitotic arrest deficient-like 1 (MAD2L1) are two interactive proteins playing important roles in maintaining spindle checkpoint function. This study examined the functional relevance of missense coding single nucleotide polymorphisms (SNPs) in MAD1L1 and MAD2L1 and their association with susceptibility to lung cancer.
METHODS: SNPs in the MAD2L1 coding region were discovered by sequencing and impact of MAD1L1 and MAD2L1 variants on spindle checkpoint function was examined by flow cytometry and mitotic index assay. The associations of MAD1L1 and MAD2L1 variants with lung cancer were analysed in a case-control cohort of 1000 patients and 1000 controls. ORs and 95% CIs were estimated by logistic regression.
RESULTS: A novel C-to-A SNP at codon 84 of MAD2L1 (Leu84Met substitution) was discovered. Cells expressing MAD2L1-84Met and MAD1L1-558His had impaired spindle checkpoint function, with a lower 4N-DNA content and mitotic index when treated with nocodazole. Case-control analysis showed that the MAD2L1 Leu84Met SNP was associated with increased risk of lung cancer in an allele dose dependent manner, with the ORs being 2.55 (95% CI 1.95 to 3.33) for the Leu/Met and 2.68 (95% CI 2.05 to 3.48) for the Met/Met genotype compared with the Leu/Leu genotype. The MAD1L1 558 His/His genotype was also associated with 1.4-fold elevated lung cancer risk compared with the Arg/Arg genotype.
CONCLUSION: These results suggest that genetic variants in MAD1L1 and MAD2L1 confer susceptibility to lung cancer, which might result from reduced spindle checkpoint function due to attenuated function of MAD1L1 and/or MAD2L1.

Azouz A, Wu YL, Hillion J, et al.
Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells.
Leukemia. 2010; 24(3):613-22 [PubMed] Related Publications
The expression of hTERT gene, encoding the catalytic subunit of telomerase, is a feature of most cancer cells. Changes in the chromatin environment of its promoter and binding of transcriptional factors have been reported in differentiating cells when its transcription is repressed. However, it is not clear whether these changes are directly involved in this repression or only linked to differentiation. In a maturation-resistant acute promyelocytic leukemia (APL) cell line (NB4-LR1), we have previously identified a new pathway of retinoid-induced hTERT repression independent of differentiation. Using a variant of this cell line (NB4-LR1(SFD)), which resists to this repression, we show that although distinct patterns of histone modifications and transcription factor binding at the proximal domain of hTERT gene promoter could concur to modulate its expression, this region is not sufficient to the on/off switch of hTERT by retinoids. DNA methylation analysis of the hTERT promoter led to the identification of two distinct functional domains, a proximal one, fully unmethylated in both cell lines, and a distal one, significantly methylated in NB4-LR1(SFD) cells, whose methylation was further re-enforced by retinoid treatment. Interestingly, we showed that the binding to this distal domain of a known hTERT repressor, WT1, was defective only in NB4-LR1(SFD) cells. We propose that epigenetic modifications targeting this distal region could modulate the binding of hTERT repressors and account either for hTERT reactivation and resistance to retinoid-induced hTERT downregulation.

Ju W, Yoo BC, Kim IJ, et al.
Identification of genes with differential expression in chemoresistant epithelial ovarian cancer using high-density oligonucleotide microarrays.
Oncol Res. 2009; 18(2-3):47-56 [PubMed] Related Publications
A major obstacle in treatment of epithelial ovarian cancer is chemoresistance. The aim of this study was to determine whether distinct gene expression profiles are associated with chemoresistance in epithelial ovarian carcinoma. We performed global gene expression analysis in 13 primary epithelial ovarian cancer tissues including 5 primary chemosensitive tumors and 8 primary chemoresistant tumors using Affymetrix HGU133A microarray. The gene expression patterns of chemosensitive tumors were compared with those of chemoresistant tumors using fold change. Validity of microarray results was examined by semiquantitative RT-PCR. We identified over 320 genes differentially expressed in chemoresistant epithelial ovarian cancer (> or = twofold). Upregulated genes in chemoresistant tumors included cell cycle regulating genes (TOP2A, BCAT1, CDCA8, CCNA2, CENPE), and genes with previously known mechanisms in tumorigenesis (S100A9, APOA1, RNF125, IFI16). Downregulated genes in chemoresistant tumors included genes related to cell adhesion (MUC5B, CITED2), transcription regulating genes (FOXD1, MAD1L1, PAX2), genes involving signal transduction (SOSTDC1, SNX1, SFRP1, FOXA2, PLK2), and stress protein gene (TP53AP1). These data show that gene expression profiling can discriminate primary chemoresistant from primary chemosensitive ovarian cancers. This type of molecular profiling could provide a basis for additional functional studies.

Toaldo C, Pizzimenti S, Cerbone A, et al.
PPARgamma ligands inhibit telomerase activity and hTERT expression through modulation of the Myc/Mad/Max network in colon cancer cells.
J Cell Mol Med. 2010; 14(6A):1347-57 [PubMed] Related Publications
In human cells the length of telomeres depends on telomerase activity. This activity and the expression of the catalytic subunit of human telomerase reverse transcriptase (hTERT) is strongly up-regulated in most human cancers. hTERT expression is regulated by different transcription factors, such as c-Myc, Mad1 and Sp1. In this study, we demonstrated that 15d-PG J2 and rosiglitazone (an endogenous and synthetic peroxisome proliferators activated receptor gamma (PPARgamma) ligand, respectively) inhibited hTERT expression and telomerase activity in CaCo-2 colon cancer cells. Moreover, both ligands inhibited c-Myc protein expression and its E-box DNA binding activity. Additionally, Mad1 protein expression and its E-box DNA binding activity were strongly increased by 15d-PG J2 and, to a lesser extent, by rosiglitazone. Sp1 transcription factor expression and its GC-box DNA binding activity were not affected by both PPARgamma ligands. Results obtained by transient transfection of CaCo-2 cells with pmaxFP-Green-PRL plasmid constructs containing the functional hTERT core promoter (including one E-box and five GC-boxes) and its E-box deleted sequences, cloned upstream of the green fluorescent protein reporter gene, demonstrated that 15d-PG J2, and with minor effectiveness, rosiglitazone, strongly reduced hTERT core promoter activity. E-boxes for Myc/Mad/Max binding showed a higher activity than GC-boxes for Sp1. By using GW9662, an antagonist of PPARgamma, we demonstrated that the effects of 15d-PG J2 are completely PPARgamma independent, whereas the effects of rosiglitazone on hTERT expression seem to be partially PPARgamma independent. The regulation of hTERT expression by 15d-PG J2 and rosiglitazone, through the modulation of the Myc/Max/Mad1 network, may represent a new mechanism of action of these substances in inhibiting cell proliferation.

Zell JA, Ziogas A, Ignatenko N, et al.
Associations of a polymorphism in the ornithine decarboxylase gene with colorectal cancer survival.
Clin Cancer Res. 2009; 15(19):6208-16 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is required for normal growth and is elevated in many cancers, including colorectal cancer. We examined associations of the +316 ODC1 single nucleotide polymorphism (SNP) with colorectal cancer-specific survival among colorectal cancer cases, and then investigated its functional significance in colon cancer cells.
EXPERIMENTAL DESIGN: The study included 400 incident stage I-III colorectal cancer cases from the population-based University of California Irvine Gene-Environment Study of Familial Colorectal Cancer (diagnosed from 1994 to 1996 with follow-up through March 2008). The primary outcome was colorectal cancer-specific survival dependent on ODC1 (rs2302615) genotype (GG versus GA/AA). In human colon cancer cell lines, ODC1 allele-specific binding of E-box transcription factors was determined via Western blotting and chromatin immunoprecipitation assays. ODC1 allele-specific promoter activity was determined using promoter constructs in combination with vectors expressing either the transcriptional activator c-MYC or the repressor MAD1.
RESULTS: Genotype-specific survival differences were observed among colorectal cancer cases: compared with cases with the ODC1 GG genotype (hazards ratio, 1; reference) the adjusted colorectal cancer-specific survival hazards ratio was 2.02 (95% confidence interval, 1.17-3.50) for ODC1 GA/AA cases (P = 0.012). In colon cancer cells, the ODC1 SNP, flanked by two E-boxes, predicts ODC1 promoter activity. The E-box activator c-MYC and repressors MAD1 and MAD4 preferentially bind to ODC1 minor A-alleles, compared with major G-alleles, in cultured cells.
CONCLUSIONS: These results have implications for conditional regulation of polyamine homeostasis and suggest a model in which the ODC1 SNP may be protective for colon adenoma recurrence and detrimental for survival after colon cancer diagnosis.

Papanikolaou V, Iliopoulos D, Dimou I, et al.
The involvement of HER2 and p53 status in the regulation of telomerase in irradiated breast cancer cells.
Int J Oncol. 2009; 35(5):1141-9 [PubMed] Related Publications
Cancer cell characteristics may play a pivotal role in the response to therapy by activating or deactivating different molecular pathways. In the present study, we investigated the implication of breast cancer cell features, such as HER2 and p53 in the activation of telomerase upon exposure to ionizing radiation. Telomerase is among the most important cancer biomarkers, conferring to tumor cells unlimited proliferative capacity, increased survival potential and resistance to several types of cellular stress. We investigated possible mechanisms regulating telomerase in six irradiated breast cancer cell lines (MCF-7, MCF-7/HER2, MDA-MB-231, SK-BR-3, BT-474 and HBL-100) differing in their HER2, p53 and ERalpha status. hTERT mRNA expression was evaluated by real-time PCR and telomerase activity by the TRAP assay. HER2, c-myc, p53 and p21 protein levels were evaluated by Western blotting. Silencing of hTERT and HER2 was achieved by small interfering RNA technology. Chromatin immunoprecipitation was used to evaluate H3 histone acetylation status, as well as myc/mad/max and p53 transcription factors interaction with the hTERT promoter. Our results showed for the first time, that only HER2-positive cells, independently of their p53 status, upregulated hTERT/telomerase, while knockdown of hTERT increased radio-sensitivity. Knockdown of HER2 also led to increased radio-sensitivity and downregulation of hTERT/telomerase. We also demonstrated that c-myc and mad1 regulate hTERT expression in all irradiated breast cancer cells. We conclude, for the first time, that HER2 phenotype upregulates hTERT through c-myc activation and confers radio-resistance to breast cancer cells.

Wu S, Hultquist A, Hydbring P, et al.
TGF-beta enforces senescence in Myc-transformed hematopoietic tumor cells through induction of Mad1 and repression of Myc activity.
Exp Cell Res. 2009; 315(18):3099-111 [PubMed] Related Publications
Inhibition of tumor growth factor (TGF)-beta-mediated cell cycle exit is considered an important tumorigenic function of Myc oncoproteins. Here we found that TGF-beta1 enforced G(1) cell cycle arrest and cellular senescence in human U-937 myeloid tumor cells ectopically expressing v-Myc, which contains a stabilizing mutation frequently found in lymphomas. This correlated with induced expression of the Myc antagonist Mad1, resulting in replacement of Myc for Mad1 at target promoters, reduced histone acetylation and strong repression of Myc-driven transcription. The latter was partially reversed by histone deacetylase (HDAC) inhibitors, consistent with involvement of Mad1. Importantly, knockdown of MAD1 expression prevented TGF-beta1-induced senescence, underscoring that Mad1 is a crucial component of this process. Enforced Mad1 expression sensitized U-937-myc cells to TGF-beta and restored phorbol ester-induced cell cycle exit, but could not alone induce G(1) arrest, suggesting that Mad1 is required but not sufficient for cellular senescence. Our results thus demonstrate that TGF-beta can override Myc activity despite a stabilizing cancer mutation and induce senescence in myeloid tumor cells, at least in part by induction of Mad1. TGF-beta-induced senescence, or signals mimicking this pathway, could therefore potentially be explored as a therapeutic principle for treating hematopoietic and other tumors with deregulated MYC expression.

Acosta JC, Ferrándiz N, Bretones G, et al.
Myc inhibits p27-induced erythroid differentiation of leukemia cells by repressing erythroid master genes without reversing p27-mediated cell cycle arrest.
Mol Cell Biol. 2008; 28(24):7286-95 [PubMed] Free Access to Full Article Related Publications
Inhibition of differentiation has been proposed as an important mechanism for Myc-induced tumorigenesis, but the mechanisms involved are unclear. We have established a genetically defined differentiation model in human leukemia K562 cells by conditional expression of the cyclin-dependent kinase (Cdk) inhibitor p27 (inducible by Zn(2+)) and Myc (activatable by 4-hydroxy-tamoxifen). Induction of p27 resulted in erythroid differentiation, accompanied by Cdk inhibition and G(1) arrest. Interestingly, activation of Myc inhibited p27-mediated erythroid differentiation without affecting p27-mediated proliferation arrest. Microarray-based gene expression indicated that, in the presence of p27, Myc blocked the upregulation of several erythroid-cell-specific genes, including NFE2, JUNB, and GATA1 (transcription factors with a pivotal role in erythropoiesis). Moreover, Myc also blocked the upregulation of Mad1, a transcriptional antagonist of Myc that is able to induce erythroid differentiation. Cotransfection experiments demonstrated that Myc-mediated inhibition of differentiation is partly dependent on the repression of Mad1 and GATA1. In conclusion, this model demonstrates that Myc-mediated inhibition of differentiation depends on the regulation of a specific gene program, whereas it is independent of p27-mediated cell cycle arrest. Our results support the hypothesis that differentiation inhibition is an important Myc tumorigenic mechanism that is independent of cell proliferation.

Pinto M, Vieira J, Ribeiro FR, et al.
Overexpression of the mitotic checkpoint genes BUB1 and BUBR1 is associated with genomic complexity in clear cell kidney carcinomas.
Cell Oncol. 2008; 30(5):389-95 [PubMed] Related Publications
BACKGROUND: A defective mitotic checkpoint has been proposed to contribute to chromosomal instability (CIN). We have previously shown that expression changes of the mitotic arrest deficiency (MAD) gene family plays a role in renal cell cancer (RCC) characterized by numerical chromosomal changes, namely papillary and chromophobe carcinomas, but nothing is known about the expression of mitotic checkpoint genes in the clear cell histotype (ccRCC).
METHODS: We analyzed the mRNA expression levels of the major mitotic checkpoint genes of the budding uninhibited by benzimidazole family (BUB1, BUBR1, BUB3) and of the MAD gene family (MAD1, MAD2L1, MAD2L2) by real-time quantitative PCR in 39 ccRCC and in 36 normal kidney tissue samples. We have additionally analyzed these tumors by comparative genomic hybridization (CGH) in order to evaluate the relationship between mitotic checkpoint defects and the pattern of chromosome changes in this subset of RCC.
RESULTS: BUB1, BUBR1, MAD1 and MAD2L1 showed significant expression differences in tumor tissue compared to controls (BUB1, BUBR1 and MAD2L1 were overexpressed, whereas MAD1 was underexpressed). Overexpression of BUB1 and BUBR1 was significantly correlated with the number of genomic copy number changes (p<0.001 for both genes) and with Furhman grade of the tumors (p=0.006 and p=0.005, respectively).
CONCLUSIONS: We conclude that BUB1 and BUBR1 overexpression plays a role in cytogenetic and morphologic progression of ccRCC.

Lin CJ, Cencic R, Mills JR, et al.
c-Myc and eIF4F are components of a feedforward loop that links transcription and translation.
Cancer Res. 2008; 68(13):5326-34 [PubMed] Related Publications
The Myc/Max/Mad family of transcription factors and the eukaryotic initiation factor 4F (eIF4F) complex play fundamental roles in regulating cell growth, proliferation, differentiation, and oncogenic transformation. eIF4F is involved in the recruitment of ribosomes to mRNAs and is thought to generally be the rate-limiting phase of translation. Here, we show that c-Myc directly activates transcription of the three subunits of eIF4F (eIF4E, eIF4AI, and eIF4GI). These transcriptional effects are mediated through canonical E-boxes (5'CACGTG3') present in the promoters of these genes. In addition, the c-Myc antagonist Mad1 down-regulates the expression of eIF4F subunits. We also show that MycER activation stimulates protein synthesis at the level of translation initiation. Increased eIF4F levels result in stimulation of c-Myc mRNA translation specifically, as assessed by quantitative reverse transcription-PCR. We use a murine model of lymphomagenesis to show the expression of eIF4F subunits is also up-regulated by c-Myc in vivo. Our results suggest the presence of a feedforward loop involving c-Myc and eIF4F that serves to link transcription and translation and that could contribute to the effects of c-Myc on cell proliferation and neoplastic growth.

Boult JK, Tanière P, Hallissey MT, et al.
Oesophageal adenocarcinoma is associated with a deregulation in the MYC/MAX/MAD network.
Br J Cancer. 2008; 98(12):1985-92 [PubMed] Free Access to Full Article Related Publications
Oesophageal adenocarcinoma, which arises from an acquired columnar lesion, Barrett's metaplasia, is rising in incidence more rapidly than any other cancer in the Western world. Elevated expression of c-MYC has been demonstrated in oesophageal adenocarcinoma; however, the expression of other members of the MYC/MAX/MAD network has not been addressed. The aims of this work were to characterise the expression of c-MYC, MAX and the MAD family in adenocarcinoma development and assess the effects of overexpression on cellular behaviour. mRNA expression in samples of Barrett's metaplasia and oesophageal adenocarcinoma were examined by qRT-PCR. Semi-quantitative immunohistochemistry and western blotting were used to examine cellular localisation and protein levels. Cellular proliferation and mRNA expression were determined in SEG1 cells overexpressing c-MYCER or MAD1 using a bromodeoxyuridine assay and qRT-PCR, respectively. Consistent with previous work expression of c-MYC was deregulated in oesophageal adenocarcinoma. Paradoxically, increased expression of putative c-MYC antagonists MAD1 and MXI1 was observed in tumour specimens. Overexpression of c-MYC and MAD proteins in SEG1 cells resulted in differential expression of MYC/MAX/MAD network members and reciprocal changes in proliferation. In conclusion, the expression patterns of c-MYC, MAX and the MAD family were shown to be deregulated in the oesophageal cancer model.

Nam CW, Park NH, Park BR, et al.
Mitotic checkpoint gene MAD1 in hepatocellular carcinoma is associated with tumor recurrence after surgical resection.
J Surg Oncol. 2008; 97(7):567-71 [PubMed] Related Publications
OBJECTIVE: Underlying mechanism of mitotic checkpoint gene mitosis arrest deficiency 1 (MAD1) in human hepatocellular carcinoma (HCC) is rarely known.
MATERIALS AND METHODS: We studied genetic change of the MAD1 gene as well as protein expression in 44 HCC and their associated non-cancerous surrounding liver tissues.
RESULTS: Genotype AG of MAD1 G-1849 A promoter was highly significant in microscopic vascular invasion than other genotypes (P = 0.006). Moreover, the mean tumor size of HCC with genotype AG (7.71 cm) was significantly larger than those of other genotypes (AA, 4.41 cm; GG, 4.59 cm; P = 0.033). After a median follow-up of 22 months, 18 (41%) of the 44 patients relapsed. Eleven (32.4%) of 34 with MAD1 protein expression and 7 (70%) of 10 with no expression of MAD1 protein showed tumor recurrence. The incidence of tumor recurrence in patients with the lost MAD1 expression was significantly higher than in those with the expressed MAD1 protein (P = 0.011).
CONCLUSION: These results suggest that MAD1 promoter genotype may be involved in tumor progression. Moreover, the loss of MAD1 protein expression may be related to the tumor recurrence after surgical resection of HCC.

Weinkauf M, Christopeit M, Hiddemann W, Dreyling M
Proteome- and microarray-based expression analysis of lymphoma cell lines identifies a p53-centered cluster of differentially expressed proteins in mantle cell and follicular lymphoma.
Electrophoresis. 2007; 28(23):4416-26 [PubMed] Related Publications
We used a standardized electrophoresis protocol to identify differentially expressed proteins based on a sample pooling approach comparing three follicular lymphoma and three mantle cell lymphoma-derived cell lines. One hundred and seventy-five consistently differentially expressed proteins were identified out of more than 1600 protein spots per gel. Of these 175 protein spots, 38 of the 41 most highly expressed proteins were identified by MS analysis (MALDI-TOF), involving different cellular programs such as DNA repair (Rad50), cell cycle control (Mad1L1), transcription (SAFB), and apoptosis (Luca-15 protein). Expression data were confirmed by Western blot analysis of identified proteins and 2-D gel hybridization of proteins with known overexpression (G1/S-specific cyclin-D1, apoptosis regulator Bcl-2). Comparison of proteome analysis to RNA expression array data revealed only a modest correlation of RNA and protein level emphasizing the relevance of post-translational regulation in lymphomagenesis (p = 0.36). Most interestingly, additional data bank search identified 13 out of 17 referenced proteins (76%) as members of a TP53-dependent network of cell regulation.

Cetinkaya C, Hultquist A, Su Y, et al.
Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells.
Mol Cancer Ther. 2007; 6(10):2634-41 [PubMed] Related Publications
The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN-gamma synergistically potentiates retinoic acid (RA)-induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastoma cells with RA+IFN-gamma down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heterodimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Mad1/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA+IFN-gamma treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN-gamma and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma.

Osaki M, Inoue T, Yamaguchi S, et al.
MAD1 (mitotic arrest deficiency 1) is a candidate for a tumor suppressor gene in human stomach.
Virchows Arch. 2007; 451(4):771-9 [PubMed] Related Publications
Mitotic arrest deficiency 1 (MAD1) is a component of the spindle checkpoint factors that monitor fidelity of chromosomal segregation. We previously confirmed that the level of MAD1 protein was decreased in gastric carcinoma compared with non-tumoral mucosa by conducting proteome-based analyses (Nishigaki R, Osaki M, Hiratsuka M, Toda T, Murakami K, Jeang KT, Ito H, Inoue T, Oshimura M, Proteomics 5:3205-3213, 29). In this study, an immunohistochemical analysis was performed to examine MAD1 expression histologically in gastric mucosa and tumor. MAD1 was detected in the supranuclear portion of normal epithelial, intestinal metaplasia, and adenoma cells, but its expression was not restricted to any specific area in carcinoma cells. Lower levels of expression were noted in 16 (47.1%) of 34 adenomas and in 52 (60.5%) of 86 carcinomas, whereas all normal mucosae and intestinal metaplasias were grouped into cases with higher level of expression. Moreover, the expression of MAD1 was significantly lower in advanced carcinomas than early carcinomas and in intestinal than diffuse type, respectively (P < 0.05). Exogenous expression of wild-type MAD1, but not the mutant MAD1, inhibited cell proliferation and resulted in G2/M accumulation in MKN-1, a gastric carcinoma cell line. Taken together, our findings suggest that the MAD1 gene could be a candidate tumor suppressor gene and that down-regulation of MAD1 expression contribute to tumorigenesis in human stomach.

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