Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   
X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

MAD1L1 (mitotic arrest deficient 1 like 1)

Written2018-02Keli Lima, João Agostinho Machado-Neto
Department of Clinical, Toxicological and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, klkelilima@gmail.com (KL), Department of Pharmacology, Institute of Biomedical Sciences of the University of São Paulo jamachadoneto@usp.br (JAMN), São Paulo, Brazil.

Abstract MAD1L1 is coiled-coil protein that binds to improperly attached kinetochrore, what results in recruitment and interaction with MAD2L1, activation of the mitotic checkpoint complex, inhibition of the anaphase-promoting complex/cyclosome and cell cycle arrest. During interphase, MAD1L1 regulates mitosis entrance at nuclear pore complexes (MAD2L1-dependent mechanism) and Golgi apparatus-related functions (MAD2L1-independent mechanism). Alterations in MAD1L1 are associated with chromosomal instability, aneuploidy, and cancer susceptibility. The present review contains data on MAD1L1 DNA, RNA, protein encoded and function.

Keywords MAD1L1; Mitotic arrest deficient 1 like 1; MAD1; Spindle checkpoint; Cell cycle; Chromosome segregation

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMAD1 (mitotic arrest deficient, yeast, homolog)-like 1
MAD1 mitotic arrest deficient-like 1 (yeast)
MAD1 mitotic arrest deficient like 1
Alias_symbol (synonym)HsMAD1
TXBP181
MAD1
PIG9
TP53I9
Other aliasMAD1 Mitotic Arrest Deficient Like 1
Mitotic Checkpoint MAD1 Protein Homolog
Tax-Binding Protein 181
MAD1-Like Protein 1
Tumor Protein P53 Inducible Protein 9
HMAD1
HGNC (Hugo) MAD1L1
LocusID (NCBI) 8379
Atlas_Id 41226
Location 7p22.3  [Link to chromosome band 7p22]
Location_base_pair Starts at 1815792 and ends at 2232948 bp from pter ( according to hg19-Feb_2009)  [Mapping MAD1L1.png]
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
t(5;7)(q34;p22) with fusion gene RARS/MAD1L1

DNA/RNA

Description The entire MAD1L1 gene is approximately 417.1 Kb (start: 1815792 and end: 2232971 bp; orientation: Minus strand). The MAD1L1 gene encodes for 6 transcript variants. The transcript variant 1 (start: 1815792 and end: 2232948 bp; orientation: Minus strand; 19 exons; mRNA: 2754 bp) is the longest transcript variant. Transcript variant 2 (mRNA: 2717 bp), transcript variant 3 (mRNA: 2714 bp) and transcript variant 4 (mRNA: 2538 bp) differs in the 5' UTR compared to transcript variant 1. The transcript variants 1-4 encode the protein isoform a (718 aa protein). The transcript variant 5 (mRNA: 2376 bp; 17 exons) lacks some exons in the 5' UTR and displays an alternate exon in the 5' coding region, what results in an alternative start codon, frameshift, and a shorter and distinct protein (isoform b; 626 aa). The transcript variant 6 is the shortest transcript variant (start: 1815792 and end: 1940550 bp; 4 exons; mRNA: 1318 bp), it displays an alternative 5'-terminal exon, uses an in-frame start codon and encodes the protein isoform c (174 aa).

Protein

 
  Figure 1. MAD1L1 protein structure. MAD1L1 protein contains a MAD1L1 oligomerization domain, MAD2L1-binding domain and RLK motif (Arg-Leu-Lys; essential for BUB1 and BUB3 interactions). This figure was adapted from Canman et al., 2002; Sironi et al., 2002.
Description MAD1L1 is a 718-residue coiled-coil protein that interacts with MAD2L1, and is composite of a MAD1L1 oligomerization domain, MAD2L1-binding domain and RLK motif (Arg-Leu-Lys; essential for BUB1 and BUB3 interactions) (Canman et al., 2002; Sironi et al., 2002) (Figure 1). MAD1L1-MAD2L1 complexes form a tetramer-like structure due to the parallel intermolecular coiled-coil between α 1 helices from different MAD1L1 molecules (Nasmyth, 2005; Sironi et al., 2002).
Expression Ubiquitous.
Localisation During mitosis, MAD1L1 is localized predominantly at unattached kinetochore. During interphase, MAD1L1 is localized in perinuclear region, nuclear pore complex, centrosome and Golgi apparatus (Campbell et al., 2001; Rodriguez-Bravo et al., 2014; Wan et al., 2014).
 
  Figure 2. MAD1L1 functions in spindle assembly checkpoint. (Upper panel) During mitosis, MAD1L1 binds to improperly attached kinetochrore, what results in recruitment and interaction with MAD2L1, and activation of the mitotic checkpoint complex (MCC). The MCC inhibits the anaphase-promoting complex/cyclosome (APC/C) and leads to cell cycle arrest. (Lower panel) In absence of unattached kinetochores, MAD1L1/MAD2L1 complex is not recruited, what results in chromosome segregation during anaphase. This figure was created using Servier Medical Art tools (http://www.servier.com).
Function MAD1L1 belongs to the assembly control of the mitotic spindle, which acts as a component capable of blocking the onset of the anaphase if the chromosomes are not correctly aligned on the metaphase plate (Hardwick and Murray, 1995). The MAD1L1 protein has approximately 83 kDa and interacts with other proteins, such as MAD2L1, to perform its functions (Campbell et al., 2001; Wright et al., 2017). The complex MAD1L1/MAD2L1 binds to improperly attached kinetochrore, induces MAD1L1 phosphorylation by MPS1, and acts as an anchor for the formation of other protein interactions, including MAD2L1-CDC20 complex. The molecular events upon MAD1L1 and unattached kinetochores interaction lead to the formation of mitotic checkpoint complex (MCC), inhibition of anaphase-promoting complex/cyclosome (APC/C), and cell cycle arrest (Reviewed by Schuyler et al., 2012 and London and Biggins, 2014) (Figure 2).
Rodriguez-Bravo and colleagues (Rodriguez-Bravo et al., 2014) reported that the MAD1L1-MAD2L1 complex anchored to the nuclear pore complexes emits an inhibitory signal that limits the speed of the mitosis, facilitating corrections of possible errors, which would avoid a cell cycle arrest. Alterations in MAD1L1 are associated with chromosomal instability and aneuploidy (Avram et al., 2014; Tsukasaki et al., 2001).
Wan and colleagues (Wan et al., 2014) reported an elegant mechanistic study that described the non-related spindle assembly checkpoint and MAD2L1 independent functions for MADlL1. During interphase, MAD1L1 is localized in the Golgi apparatus, and participates in integrin secretion, adhesion, mobility, cell migration and PTK2 (FAK) signaling pathway (Wan et al., 2014).
Homology MAD1L1 has a high homology among different species (Table 1).
Table 1. Comparative identity of human MAD1L1 with other species
% Identity for: Homo sapiens MAD1L1SymbolProteinDNA

vs. P. troglodytes

MAD1L199.499.4

vs. M. mulatta

MAD1L198.496.7

vs. C. lupus

MAD1L184.084.3

vs. B. taurus

MAD1L184.785.4

vs. M. musculus

Mad1l181.481.4

vs. R. norvegicus

Mad1l183.482.3

vs. G. gallus

MAD1L170.073.2

vs. X. tropicalis

mad1l163.065.0

vs. D. rerio

mad1l154.160.6

vs. D. melanogaster

Mad128.945.0

vs. A. gambiae

AgaP_AGAP00663228.847.7

(Source: http://www.ncbi.nlm.nih.gov/homologene)

Mutations

Somatic Recurrent mutations in the MAD1L1 gene are rare, and 153 missense substitution, 69 synonymous substitution, 8 nonsense substitution, 1 frameshift insertion and 8 frameshift deletion mutations are reported in COSMIC (Catalogue of Somatic Mutations in Cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic). Similar findings were reported in cBioPortal (http://www.cbioportal.org), which includes 41824 cancer samples: somatic mutation frequency in MAD1L1 was 0.5% (195 mutations, being 166 missense and 29 truncating mutations). Analyzing together, mutation, amplification, deep deletion and multiple alterations, the total of cancer samples with any type of alteration was 570 (1.4%).

Implicated in

  
Entity Colorectal cancer
Note In HCT116 colorectal carcinoma cell line, MAD1L1 silencing disturbed the spindle checkpoint and leaded to aneuploidy (Kienitz et al., 2005). On the other hand, the induction of MAD1L1 overexpression resulted in aberrant mitotic timing, aneuploidy and resistance to apoptosis in DLD1 cells, a chromosomally stable colorectal cancer cell line (Ryan et al., 2012). The presence of the genotype His/His for the MAD1L1 Arg558His (rs1801368) polymorphism was associated with increased risk for colorectal cancer, using a dominant model, in a Chinese cohort (Zhong et al., 2015).
  
  
Entity Liver cancer
Note MAD1L1 expression was observed in 70% of new early diagnosed cases and 30% of recurrence hepatocellular carcinoma patients, suggesting that the loss of MAD1L1 may be involved in disease progression (Nam et al., 2008). MAD1L1 was found to be methylated in 50% of hepatocellular carcinoma cell lines and primary samples tested. Low MAD1L1 methylation was associated with increased tumor size and recurrence in hepatocellular carcinoma patients (Cui et al., 2016). Sze and colleagues (Sze et al., 2008) identified a novel splicing variant of MAD1L1, which was found overexpressed in 24% of hepatocellular carcinoma samples. Using functional studies, the authors showed that the ectopic expression of this novel splicing variant results mitotic checkpoint impairment and aneuploidy hematoma cell lines (Sze et al., 2008).
  
  
Entity Lung cancer
Note An initial screening for MAD1L1 mutations in 49 lung cancer patients found one sample with somatic mutation (T299A) and 1 sample with a possible germline mutation (R556H). Coe and colleagues (Coe et al., 2006) reported that the gain of a region on 7p22.3, including 350 Kbp fragment centered at MAD1L1, was observed in 13 out of 14 small-cell lung cancers (H187, H378, H889, H1607, H1672, H2107, H2141, H2171, HCC33, H82, H289, H524, H526, and H841) and in none of normal (BL289, BL1607, BL1672, BL2107, BL2141, and BL2171) cell lines analyzed. Using immunohistochemistry analysis, MAD1L1 positive expression was found to be higher in lymph node metastasis and primary tumor samples from small-cell lung cancer patients compared to adjacent non-cancerous tissue samples (Li et al., 2016). In small-cell lung cancer, the presence of MAD1L1 expression was associated with advanced stage of the disease, increased tumor size, higher incidence of lymph node metastasis and recurrence, and it was an independent predictor of poor survival outcomes (Li et al., 2016). In a cohort containing 1000 lung cancer patients and 1000 healthy donors, the genotype His/His for the MAD1L1 Arg558His (rs1801368) polymorphism was associated with lung cancer risk (Guo et al., 2010).
  
  
Entity Breast cancer
Note MAD1L1 was frequently higher expressed in tumor compared to non-malignant or normal breast cancer samples (Ryan et al., 2012; Yuan et al., 2006) and increased levels of MAD1L1 were associated with poor survival outcomes (Ryan et al., 2012). Conversely, high cytoplasm expression of MAD1L1 was observed in both, normal and breast cancer samples. However, nuclear MAD1L1 expression was significantly more frequent in breast cancer (28%) than normal (2%) samples (Sun et al., 2013). In the same study, the author also reported that nuclear MAD1L1 was associated with lower age onset, increased tumor size, higher tumor stage, presence of TP53 mutations and disease subtypes, and positive nuclear MAD1L1 was an independent predictor of worse clinical outcomes in breast cancer patients (Sun et al., 2013). In MCF-7, a breast cancer cell line, siRNA-mediate MAD1L1 silencing increased migration and reduced E-cadherin expression (Chen et al., 2012).
  
  
Entity Gastric cancer
Note Using proteomic approaches in primary samples of gastric carcinomas and its corresponding non-cancerous gastric mucosa, MAD1L1 was identified as lower expressed in gastric carcinoma samples (Nishigaki et al., 2005). Later, the same research group reported that MAD1L1 was downregulated in 47% of gastric adenomas and 60% of gastric carcinomas, and advanced carcinomas presented lower levels compared to early carcinomas (Osaki et al., 2007). In MKN-1, a gastric carcinoma cell line, ectopic MAD1L1 expression reduced proliferation and cell cycle progression (Osaki et al., 2007).
  
  
Entity Head and neck/oral cancer
Note Bhattacharjya and colleagues (Bhattacharjya et al., 2013) described a negative correlation between MAD1L1 and MIR125B, a miRNA associated with the suppression of malignant phenotype, in primary samples from head and neck/oral cancer patients. Recently, the t(5;7)(q34;p22) with fusion gene RARS /MAD1L1 was identified in 10% of nasopharyngeal carcinoma and head and neck cancer samples (Zhong et al., 2017). Functional studies indicated that RARS/MAD1L1 enhances cell proliferation, clonogenicity and tumorigenicity (Zhong et al., 2017).
  
  
Entity Kidney cancer
Note Using quantitative PCR, Pinto and colleagues (Pinto et al., 2007) reported that MAD1L1 is expressed at low levels in chromophobe renal cell carcinoma compared to normal kidney samples. The authors also reported that MAD1L1 mRNA levels are reduced in samples from clear cell kidney carcinoma compared to healthy donors (Pinto et al., 2008).
  
  
Entity Ovarian cancer
Note MAD1L1 mRNA levels were found to be downregulated in chemoresistant compared to chemosensitive epithelial ovarian tumors (Ju et al., 2009). Santibáñez and colleagues (Santibanez et al., 2013) reported that the genotype AA for the polymorphism MAD1L1 G1673A (rs1801368) was associated with advanced epithelial ovarian cancer risk and that the allele A was significantly associated with increased aneuploid cells in ovarian tumor samples. Functional studies indicate that the AA genotype is also associated with higher frequency of micronuclei and nondisjunction events (Santibanez et al., 2013).
  
  
Entity Glioma
Note MAD1L1 gene expression was increased in grade IV gliomas compared to normal brain tissues (Bie et al., 2011).
  
  
Entity Leukemia
Note MAD1L1 is highly expressed in leukemia cell lines (Jurkat and K562) compared to normal peripheral blood mononuclear cells. In normal leukocytes, cell proliferation induction by PHA plus IL2 increased MAD1L1 expression (Iwanaga and Jeang, 2002).
  
  
Entity Lymphoma
Note Using proteomics and transcriptomics approaches, MAD1L1 was higher expressed in follicular lymphoma - compared to mantle cell lymphoma -derived cell lines (Weinkauf et al., 2007) .
  
  
Entity Myeloproliferative neoplasm
Note Using whole-genome sequencing, Sloma and colleagues (Sloma et al., 2017) reported the presence of R270W heterozygous mutation in MAD1L1 gene in unusual case of BCR / ABL1 - and JAK2 V617F -positive chronic myeloid leukemia during chronic phase and accelerate phase. However, upon blast crisis evolution, the MAD1L1R270W mutation was found in homozygosis. The authors also reported the MAD1L1R270W mutation in an additional case of JAK2V617F -positive essential thrombocythemia (1 out of 101 myeloproliferative neoplasm cases tested) (Sloma et al., 2017).
  
  
Entity Prostate cancer
Note MAD1L1 heterozygous mutations were found in 2 out of 7 prostate cancer cell lines (LNCaP: MAD1L1R556C, and LPC4: MAD1L1R359Q) and 2 out of 33 (MAD1L1R59C and a stop codon at 318) primary samples from prostate carcinoma patients (Tsukasaki et al., 2001).
  
  
Entity Testicular germ cell tumor
Note Using a large cohort of testicular germ cell tumor and healthy donors, and genome-wide association study as approach, Chung and colleagues (Chung et al., 2013) identified that the SNP rs12699477 of MAD1L1 was associated with testicular germ cell tumor risk.
  

To be noted

Initially, the MAD1L1 (mitotic arrest deficient 1 like 1) gene located in chromosome 7p22.3 was known as MAD1. However, the MXD1 (MAX dimerization protein 1) gene located in chromosome 2p13.3 was also known as MAD1, what generated confusion in the literature. Therefore, it is recommended that the HUGO nomenclature should be used in current studies involving both genes to avoid misinterpretation.
Data from the crossing between MAD1L1+/- mice suggest that total deletion of the gene resulted in embryonic lethality (Iwanaga et al., 2007). MAD1L1 haploinsufficient mice had a higher incidence of cancer, including hepatocellular carcinoma, rhabdomyosarcoma, osteosarcoma, hemangiosarcoma, uterine sarcoma and lung cancer. In addition, treatment with antineoplastic drug, vincristine, significantly increased tumor development in MAD1L1+/- mice, but not in MAD1L1+/+ mice, indicating that MAD1L1 plays a relevant role in genomic stability and carcinogenesis (Iwanaga et al., 2007; Rao et al., 2009).
Recently, a genetic variation of MAD1L1 gene (rs1801368) has been identified as a potential candidate for contributing to mosaic loss of chromosome Y and cancer susceptibility in large cohorts (Wright et al., 2017).

Bibliography

Mitotic checkpoint proteins Mad1 and Mad2 - structural and functional relationship with implication in genetic diseases
Avram S, Mernea M, Mihailescu DF, Seiman CD, Seiman DD, Putz MV
Curr Comput Aided Drug Des 2014;10(2):168-81
PMID 24724894
 
The accuracy of survival time prediction for patients with glioma is improved by measuring mitotic spindle checkpoint gene expression
Bie L, Zhao G, Cheng P, Rondeau G, Porwollik S, Ju Y, Xia XQ, McClelland M
PLoS One 2011;6(10):e25631
PMID 22022424
 
Mitotic checkpoint proteins HsMAD1 and HsMAD2 are associated with nuclear pore complexes in interphase
Campbell MS, Chan GK, Yen TJ
J Cell Sci 2001 Mar;114(Pt 5):953-63
PMID 11181178
 
Anaphase onset does not require the microtubule-dependent depletion of kinetochore and centromere-binding proteins
Canman JC, Sharma N, Straight A, Shannon KB, Fang G, Salmon ED
J Cell Sci 2002 Oct 1;115(Pt 19):3787-95
PMID 12235289
 
UDPgalactose:glucosylceramide beta 1----4-galactosyltransferase activity in human proximal tubular cells from normal and familial hypercholesterolemic homozygotes
Chatterjee S, Castiglione E
Biochim Biophys Acta 1987 Jan 20;923(1):136-42
PMID 3099851
 
The spindle checkpoint protein MAD1 regulates the expression of E-cadherin and prevents cell migration
Chen Y, Yeh PC, Huang JC, Yeh CC, Juang YL
Oncol Rep 2012 Feb;27(2):487-91
PMID 22024768
 
Meta-analysis identifies four new loci associated with testicular germ cell tumor
Chung CC, Kanetsky PA, Wang Z, Hildebrandt MA, Koster R, Skotheim RI, Kratz CP, Turnbull C, Cortessis VK, Bakken AC, Bishop DT, Cook MB, Erickson RL, Fosså SD, Jacobs KB, Korde LA, Kraggerud SM, Lothe RA, Loud JT, Rahman N, Skinner EC, Thomas DC, Wu X, Yeager M, Schumacher FR, Greene MH, Schwartz SM, McGlynn KA, Chanock SJ, Nathanson KL
Nat Genet 2013 Jun;45(6):680-5
PMID 23666239
 
Gain of a region on 7p22
Coe BP, Lee EH, Chi B, Girard L, Minna JD, Gazdar AF, Lam S, MacAulay C, Lam WL
3, containing MAD1L1, is the most frequent event in small-cell lung cancer cell lines Genes Chromosomes Cancer
PMID 16130125
 
Genome-wide identification of differential methylation between primary and recurrent hepatocellular carcinomas
Cui C, Lu Z, Yang L, Gao Y, Liu W, Gu L, Yang C, Wilson J, Zhang Z, Xing B, Deng D, Sun ZS
Mol Carcinog 2016 Jul;55(7):1163-74
PMID 26138747
 
Functional evaluation of missense variations in the human MAD1L1 and MAD2L1 genes and their impact on susceptibility to lung cancer
Guo Y, Zhang X, Yang M, Miao X, Shi Y, Yao J, Tan W, Sun T, Zhao D, Yu D, Liu J, Lin D
J Med Genet 2010 Sep;47(9):616-22
PMID 20516147
 
Mad1p, a phosphoprotein component of the spindle assembly checkpoint in budding yeast
Hardwick KG, Murray AW
J Cell Biol 1995 Nov;131(3):709-20
PMID 7593191
 
Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice
Iwanaga Y, Chi YH, Miyazato A, Sheleg S, Haller K, Peloponese JM Jr, Li Y, Ward JM, Benezra R, Jeang KT
Cancer Res 2007 Jan 1;67(1):160-6
PMID 17210695
 
Expression of mitotic spindle checkpoint protein hsMAD1 correlates with cellular proliferation and is activated by a gain-of-function p53 mutant
Iwanaga Y, Jeang KT
Cancer Res 2002 May 1;62(9):2618-24
PMID 11980658
 
Identification of genes with differential expression in chemoresistant epithelial ovarian cancer using high-density oligonucleotide microarrays
Ju W, Yoo BC, Kim IJ, Kim JW, Kim SC, Lee HP
Oncol Res 2009;18(2-3):47-56
PMID 20066894
 
Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol
Kienitz A, Vogel C, Morales I, Müller R, Bastians H
Oncogene 2005 Jun 16;24(26):4301-10
PMID 15782113
 
Mitotic arrest deficient-like 1 is correlated with poor prognosis in small-cell lung cancer after surgical resection
Li D, Meng Q, Zhang H, Feng T, Liu M, Cai L
Tumour Biol 2016 Apr;37(4):4393-8
PMID 26499943
 
Signalling dynamics in the spindle checkpoint response
London N, Biggins S
Nat Rev Mol Cell Biol 2014 Nov;15(11):736-47
PMID 25303117
 
Mitotic checkpoint gene MAD1 in hepatocellular carcinoma is associated with tumor recurrence after surgical resection
Nam CW, Park NH, Park BR, Shin JW, Jung SW, Na YW, Seo JH
J Surg Oncol 2008 Jun 1;97(7):567-71
PMID 18491369
 
How do so few control so many? Cell
Nasmyth K
2005 Mar 25;120(6):739-46 Review
PMID 15797376
 
Proteomic identification of differentially-expressed genes in human gastric carcinomas
Nishigaki R, Osaki M, Hiratsuka M, Toda T, Murakami K, Jeang KT, Ito H, Inoue T, Oshimura M
Proteomics 2005 Aug;5(12):3205-13
PMID 16003825
 
MAD1 (mitotic arrest deficiency 1) is a candidate for a tumor suppressor gene in human stomach
Osaki M, Inoue T, Yamaguchi S, Inaba A, Tokuyasu N, Jeang KT, Oshimura M, Ito H
Virchows Arch 2007 Oct;451(4):771-9
PMID 17674037
 
Expression changes of the MAD mitotic checkpoint gene family in renal cell carcinomas characterized by numerical chromosome changes
Pinto M, Soares MJ, Cerveira N, Henrique R, Ribeiro FR, Oliveira J, Jerónimo C, Teixeira MR
Virchows Arch 2007 Apr;450(4):379-85
PMID 17333263
 
Overexpression of the mitotic checkpoint genes BUB1 and BUBR1 is associated with genomic complexity in clear cell kidney carcinomas
Pinto M, Vieira J, Ribeiro FR, Soares MJ, Henrique R, Oliveira J, Jerónimo C, Teixeira MR
Cell Oncol 2008;30(5):389-95
PMID 18791270
 
Enhanced genomic instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic studies in mice
Rao CV, Yamada HY, Yao Y, Dai W
Carcinogenesis 2009 Sep;30(9):1469-74
PMID 19372138
 
Nuclear pores protect genome integrity by assembling a premitotic and Mad1-dependent anaphase inhibitor
Rodriguez-Bravo V, Maciejowski J, Corona J, Buch HK, Collin P, Kanemaki MT, Shah JV, Jallepalli PV
Cell 2014 Feb 27;156(5):1017-31
PMID 24581499
 
Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons
Ryan SD, Britigan EM, Zasadil LM, Witte K, Audhya A, Roopra A, Weaver BA
Proc Natl Acad Sci U S A 2012 Aug 14;109(33):E2205-14
PMID 22778409
 
The MAD1 1673 G A polymorphism alters the function of the mitotic spindle assembly checkpoint and is associated with a worse response to induction chemotherapy and sensitivity to treatment in patients with advanced epithelial ovarian cancer
Santibez M, Gallardo D, Morales F, López A, Prada D, Mendoza J, Castro C, de León DC, Oñate LF, Perez D, Mohar A, Herrera LA
Pharmacogenet Genomics 2013 Apr;23(4):190-9
PMID 23407047
 
The Mad1-Mad2 balancing act--a damaged spindle checkpoint in chromosome instability and cancer
Schuyler SC, Wu YF, Kuan VJ
J Cell Sci 2012 Sep 15;125(Pt 18):4197-206
PMID 23093575
 
Crystal structure of the tetrameric Mad1-Mad2 core complex: implications of a 'safety belt' binding mechanism for the spindle checkpoint
Sironi L, Mapelli M, Knapp S, De Antoni A, Jeang KT, Musacchio A
EMBO J 2002 May 15;21(10):2496-506
PMID 12006501
 
Whole-genome analysis reveals unexpected dynamics of mutant subclone development in a patient with JAK2-V617F-positive chronic myeloid leukemia
Sloma I, Mitjavila-Garcia MT, Feraud O, Griscelli F, Oudrhiri N, El Marsafy S, Gobbo E, Divers D, Proust A, Smadja DM, Desterke C, Carles A, Ma Y, Hirst M, Marra MA, Eaves CJ, Bennaceur-Griscelli A, Turhan AG
Exp Hematol 2017 Sep;53:48-58
PMID 28602946
 
Increased expression of mitotic arrest deficient-like 1 (MAD1L1) is associated with poor prognosis and insensitive to Taxol treatment in breast cancer
Sun Q, Zhang X, Liu T, Liu X, Geng J, He X, Liu Y, Pang D
Breast Cancer Res Treat 2013 Jul;140(2):323-30
PMID 23860928
 
Role of a novel splice variant of mitotic arrest deficient 1 (MAD1), MAD1beta, in mitotic checkpoint control in liver cancer
Sze KM, Ching YP, Jin DY, Ng IO
Cancer Res 2008 Nov 15;68(22):9194-201
PMID 19010891
 
Mutations in the mitotic check point gene, MAD1L1, in human cancers
Tsukasaki K, Miller CW, Greenspun E, Eshaghian S, Kawabata H, Fujimoto T, Tomonaga M, Sawyers C, Said JW, Koeffler HP
Oncogene 2001 May 31;20(25):3301-5
PMID 11423979
 
A Golgi-localized pool of the mitotic checkpoint component Mad1 controls integrin secretion and cell migration
Wan J, Zhu F, Zasadil LM, Yu J, Wang L, Johnson A, Berthier E, Beebe DJ, Audhya A, Weaver BA
Curr Biol 2014 Nov 17;24(22):2687-92
PMID 25447996
 
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
Weinkauf M, Christopeit M, Hiddemann W, Dreyling M
Electrophoresis 2007 Dec;28(23):4416-26
PMID 17990259
 
Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility
Wright DJ, Day FR, Kerrison ND, Zink F, Cardona A, Sulem P, Thompson DJ, Sigurjonsdottir S, Gudbjartsson DF, Helgason A, Chapman JR, Jackson SP, Langenberg C, Wareham NJ, Scott RA, Thorsteindottir U, Ong KK, Stefansson K, Perry JRB
Nat Genet 2017 May;49(5):674-679
PMID 28346444
 
Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability
Yuan B, Xu Y, Woo JH, Wang Y, Bae YK, Yoon DS, Wersto RP, Tully E, Wilsbach K, Gabrielson E
Clin Cancer Res 2006 Jan 15;12(2):405-10
PMID 16428479
 
The RARS-MAD1L1 Fusion Gene Induces Cancer Stem Cell-like Properties and Therapeutic Resistance in Nasopharyngeal Carcinoma
Zhong Q, Liu ZH, Lin ZR, Hu ZD, Yuan L, Liu YM, Zhou AJ, Xu LH, Hu LJ, Wang ZF, Guan XY, Hao JJ, Lui VWY, Guo L, Mai HQ, Chen MY, Han F, Xia YF, Grandis JR, Zhang X, Zeng MS
Clin Cancer Res 2018 Feb 1;24(3):659-673
PMID 29133573
 
MAD1L1 Arg558His and MAD2L1 Leu84Met interaction with smoking increase the risk of colorectal cancer
Zhong R, Chen X, Chen X, Zhu B, Lou J, Li J, Shen N, Yang Y, Gong Y, Zhu Y, Yuan J, Xia X, Miao X
Sci Rep 2015 Jul 17;5:12202
PMID 26183163
 

Citation

This paper should be referenced as such :
Keli Lima, Joao Agostinho Machado-Neto
MAD1L1 (mitotic arrest deficient 1 like 1)
Atlas Genet Cytogenet Oncol Haematol. 2018;22(10):429-434.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MAD1L1ID41226ch7p22.html

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(7;7)(p22;p22) TTYH3/MAD1L1

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 4 ]
  t(5;7)(q34;p22) RARS/MAD1L1
t(7;7)(p12;p22) GRB10/MAD1L1
CYTH3/MAD1L1 (7p22)
t(7;11)(p22;p15) MAD1L1/SERGEF

External links

Nomenclature
HGNC (Hugo)MAD1L1   6762
Cards
AtlasMAD1L1ID41226ch7p22
Entrez_Gene (NCBI)MAD1L1  8379  mitotic arrest deficient 1 like 1
AliasesMAD1; PIG9; TP53I9; TXBP181
GeneCards (Weizmann)MAD1L1
Ensembl hg19 (Hinxton)ENSG00000002822 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000002822 [Gene_View]  ENSG00000002822 [Sequence]  chr7:1815792-2232948 [Contig_View]  MAD1L1 [Vega]
ICGC DataPortalENSG00000002822
TCGA cBioPortalMAD1L1
AceView (NCBI)MAD1L1
Genatlas (Paris)MAD1L1
WikiGenes8379
SOURCE (Princeton)MAD1L1
Genetics Home Reference (NIH)MAD1L1
Genomic and cartography
GoldenPath hg38 (UCSC)MAD1L1  -     chr7:1815792-2232948 -  7p22.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MAD1L1  -     7p22.3   [Description]    (hg19-Feb_2009)
GoldenPathMAD1L1 - 7p22.3 [CytoView hg19]  MAD1L1 - 7p22.3 [CytoView hg38]
ImmunoBaseENSG00000002822
Mapping of homologs : NCBIMAD1L1 [Mapview hg19]  MAD1L1 [Mapview hg38]
OMIM176807   602686   
Gene and transcription
Genbank (Entrez)AF083811 AF123318 AK090959 AK310481 AK310831
RefSeq transcript (Entrez)NM_001013836 NM_001013837 NM_001304523 NM_001304524 NM_001304525 NM_003550
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MAD1L1
Cluster EST : UnigeneHs.654838 [ NCBI ]
CGAP (NCI)Hs.654838
Alternative Splicing GalleryENSG00000002822
Gene ExpressionMAD1L1 [ NCBI-GEO ]   MAD1L1 [ EBI - ARRAY_EXPRESS ]   MAD1L1 [ SEEK ]   MAD1L1 [ MEM ]
Gene Expression Viewer (FireBrowse)MAD1L1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8379
GTEX Portal (Tissue expression)MAD1L1
Human Protein AtlasENSG00000002822-MAD1L1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9Y6D9   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9Y6D9  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9Y6D9
Splice isoforms : SwissVarQ9Y6D9
PhosPhoSitePlusQ9Y6D9
Domains : Interpro (EBI)Mad1   
Domain families : Pfam (Sanger)MAD (PF05557)   
Domain families : Pfam (NCBI)pfam05557   
Conserved Domain (NCBI)MAD1L1
DMDM Disease mutations8379
Blocks (Seattle)MAD1L1
PDB (RSDB)1GO4    4DZO   
PDB Europe1GO4    4DZO   
PDB (PDBSum)1GO4    4DZO   
PDB (IMB)1GO4    4DZO   
Structural Biology KnowledgeBase1GO4    4DZO   
SCOP (Structural Classification of Proteins)1GO4    4DZO   
CATH (Classification of proteins structures)1GO4    4DZO   
SuperfamilyQ9Y6D9
Human Protein Atlas [tissue]ENSG00000002822-MAD1L1 [tissue]
Peptide AtlasQ9Y6D9
HPRD04065
IPIIPI00940535   IPI00873518   IPI00892910   IPI00894166   IPI00893885   IPI00894035   IPI00893747   IPI00893354   IPI00893466   IPI00893181   IPI00892791   IPI00892514   
Protein Interaction databases
DIP (DOE-UCLA)Q9Y6D9
IntAct (EBI)Q9Y6D9
FunCoupENSG00000002822
BioGRIDMAD1L1
STRING (EMBL)MAD1L1
ZODIACMAD1L1
Ontologies - Pathways
QuickGOQ9Y6D9
Ontology : AmiGOkinetochore  kinetochore  kinetochore  condensed chromosome kinetochore  protein binding  nuclear envelope  nuclear envelope  centrosome  spindle  cytosol  mitotic cell cycle checkpoint  mitotic spindle assembly checkpoint  mitotic spindle assembly checkpoint  negative regulation of T cell proliferation  identical protein binding  kinetochore binding  nuclear pore nuclear basket  thymus development  cell division  attachment of mitotic spindle microtubules to kinetochore  mitotic spindle  mitotic spindle  regulation of metaphase plate congression  mitotic spindle pole  
Ontology : EGO-EBIkinetochore  kinetochore  kinetochore  condensed chromosome kinetochore  protein binding  nuclear envelope  nuclear envelope  centrosome  spindle  cytosol  mitotic cell cycle checkpoint  mitotic spindle assembly checkpoint  mitotic spindle assembly checkpoint  negative regulation of T cell proliferation  identical protein binding  kinetochore binding  nuclear pore nuclear basket  thymus development  cell division  attachment of mitotic spindle microtubules to kinetochore  mitotic spindle  mitotic spindle  regulation of metaphase plate congression  mitotic spindle pole  
Pathways : KEGGCell cycle    Progesterone-mediated oocyte maturation    Viral carcinogenesis   
REACTOMEQ9Y6D9 [protein]
REACTOME PathwaysR-HSA-68877 [pathway]   
NDEx NetworkMAD1L1
Atlas of Cancer Signalling NetworkMAD1L1
Wikipedia pathwaysMAD1L1
Orthology - Evolution
OrthoDB8379
GeneTree (enSembl)ENSG00000002822
Phylogenetic Trees/Animal Genes : TreeFamMAD1L1
HOGENOMQ9Y6D9
Homologs : HomoloGeneMAD1L1
Homology/Alignments : Family Browser (UCSC)MAD1L1
Gene fusions - Rearrangements
Fusion : MitelmanCYTH3/MAD1L1 [7p22.1/7p22.3]  [t(7;7)(p22;p22)]  
Fusion : MitelmanGRB10/MAD1L1 [7p12.1/7p22.3]  [t(7;7)(p12;p22)]  
Fusion : MitelmanMAD1L1/SERGEF [7p22.3/11p15.1]  [t(7;11)(p22;p15)]  
Fusion : MitelmanRARS/MAD1L1 [5q34/7p22.3]  [t(5;7)(q34;p22)]  
Fusion : MitelmanTTYH3/MAD1L1 [7p22.3/7p22.3]  [t(7;7)(p22;p22)]  
Fusion PortalCYTH3 7p22.1 MAD1L1 7p22.3 BRCA
Fusion PortalGRB10 7p12.1 MAD1L1 7p22.3 LUAD
Fusion PortalMAD1L1 7p22.3 SERGEF 11p15.1 HNSC
Fusion PortalTTYH3 7p22.3 MAD1L1 7p22.3 LAML
Fusion : FusionGDB15350    20537    20538    20539    20540    2182    22159    34795    40073    5090    773    9209    9321   
Fusion : Fusion_HubADAP1--MAD1L1    API5--MAD1L1    APLP2--MAD1L1    C7ORF50--MAD1L1    COL5A1--MAD1L1    CREBBP--MAD1L1    CYTH3--MAD1L1    DAZAP1--MAD1L1    DOCK1--MAD1L1    DSCR3--MAD1L1    ECHDC2--MAD1L1    ELFN1--MAD1L1    FAM20C--MAD1L1    FBXL18--MAD1L1    FHOD3--MAD1L1   
GALNT16--MAD1L1    GLI3--MAD1L1    GRB10--MAD1L1    GSR--MAD1L1    GTDC1--MAD1L1    HDAC4--MAD1L1    HEXB--MAD1L1    HMGB1--MAD1L1    HOXA3--MAD1L1    IKZF3--MAD1L1    INPP5A--MAD1L1    IQCE--MAD1L1    KCTD7--MAD1L1    LUC7L--MAD1L1    MAD1L1--AHSA2   
MAD1L1--C11ORF24    MAD1L1--C7ORF50    MAD1L1--CALM1    MAD1L1--CAPN2    MAD1L1--CHST12    MAD1L1--CNTNAP2    MAD1L1--DCAF6    MAD1L1--EIF3B    MAD1L1--GAK    MAD1L1--GDI2    MAD1L1--GPC1    MAD1L1--GUK1    MAD1L1--IQCE    MAD1L1--MAD1L1    MAD1L1--MAFK   
MAD1L1--MROH3P    MAD1L1--PHF13    MAD1L1--PRKAR1B    MAD1L1--PTP4A1    MAD1L1--PWWP2B    MAD1L1--RARS    MAD1L1--RGS12    MAD1L1--RPA3    MAD1L1--SERGEF    MAD1L1--SKIL    MAD1L1--TNK2    MAD1L1--TTYH3    MAD1L1--UBA52    MAD1L1--UBB    MAD1L1--UNC50   
MAD1L1--ZADH2    MAFK--MAD1L1    MEST--MAD1L1    NECAP1--MAD1L1    PHF14--MAD1L1    PPP1R12C--MAD1L1    PRKAR1B--MAD1L1    RAB40C--MAD1L1    RAPGEF5--MAD1L1    SMARCA4--MAD1L1    SNX8--MAD1L1    SRGN--MAD1L1    SUN1--MAD1L1    TANGO2--MAD1L1    TBC1D16--MAD1L1   
TIAL1--MAD1L1    TMEM184A--MAD1L1    TTC3--MAD1L1    TTYH3--MAD1L1    UBAP2L--MAD1L1    VAMP3--MAD1L1   
Fusion : QuiverMAD1L1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMAD1L1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MAD1L1
dbVarMAD1L1
ClinVarMAD1L1
1000_GenomesMAD1L1 
Exome Variant ServerMAD1L1
ExAC (Exome Aggregation Consortium)ENSG00000002822
GNOMAD BrowserENSG00000002822
Varsome BrowserMAD1L1
Genetic variants : HAPMAP8379
Genomic Variants (DGV)MAD1L1 [DGVbeta]
DECIPHERMAD1L1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMAD1L1 
Mutations
ICGC Data PortalMAD1L1 
TCGA Data PortalMAD1L1 
Broad Tumor PortalMAD1L1
OASIS PortalMAD1L1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMAD1L1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DMAD1L1
Mutations and Diseases : HGMDMAD1L1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch MAD1L1
DgiDB (Drug Gene Interaction Database)MAD1L1
DoCM (Curated mutations)MAD1L1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MAD1L1 (select a term)
intoGenMAD1L1
NCG5 (London)MAD1L1
Cancer3DMAD1L1(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM176807    602686   
Orphanet
DisGeNETMAD1L1
MedgenMAD1L1
Genetic Testing Registry MAD1L1
NextProtQ9Y6D9 [Medical]
TSGene8379
GENETestsMAD1L1
Target ValidationMAD1L1
Huge Navigator MAD1L1 [HugePedia]
snp3D : Map Gene to Disease8379
BioCentury BCIQMAD1L1
ClinGenMAD1L1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8379
Chemical/Pharm GKB GenePA372
Clinical trialMAD1L1
Miscellaneous
canSAR (ICR)MAD1L1 (select the gene name)
DataMed IndexMAD1L1
Probes
Litterature
PubMed136 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMAD1L1
EVEXMAD1L1
GoPubMedMAD1L1
iHOPMAD1L1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Nov 13 21:34:59 CET 2019
Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.