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MTUS1 (mitochondrial tumor suppressor 1)

Written2008-12Xiaofeng Zhou, Jinsheng Yu, Xiqiang Liu
Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, Chicago, IL USA

(Note : for Links provided by Atlas : click)


ATIP (angiotensin II receptor 2- interacting protein)
AGTR2-interacting protein
HGNC Alias symbMTSG1
HGNC Alias nameAT2 receptor-interacting protein
 AT2R binding protein
 mitochondrial tumor suppressor gene 1
HGNC Previous namemitochondrial tumor suppressor 1
 microtubule associated tumor suppressor 1
LocusID (NCBI) 57509
Atlas_Id 41451
Location 8p22  [Link to chromosome band 8p22]
Location_base_pair Starts at 17643794 and ends at 17697737 bp from pter ( according to hg19-Feb_2009)  [Mapping MTUS1.png]
Local_order MTUS1 is located in a frequent LOH region (8p21.3-p22) of approximately 7 Mb in several tumor types. This genomic area is a gene-rich region, which contains 55 known genes. Among those genes, there are several known candidate tumor suppressor genes and cancer related genes, including MTUS1, pericentriolar material-1 ( PCM1 ), leucine zipper putative tumor suppressor-1 ( LZTS1 ), deleted in breast cancer 1 ( DBC-1 ), Rho-related BTB domain-containing protein 2 ( RHOBTB2 ), early growth response 3 ( EGR3 ), tumor necrosis factor receptor superfamily member 10A ( TNFRSF10A ), and member 10B ( TNFRSF10B ).
  Genes located in the frequent LOH region at 8p21.3-p22. The frequent LOH region at 8p21.3-p22 was displayed using UCSC Genome Browser. Genes located in this genomic region and their corresponding mRNAs were plotted.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CCNT2 (2q21.3) / MTUS1 (8p22)EIF3L (22q13.1) / MTUS1 (8p22)MTUS1 (8p22) / FGL1 (8p22)
MTUS1 (8p22) / OASL (12q24.31)PPP2R2A (8p21.2) / MTUS1 (8p22)
Note The MTUS1 gene is located on the reverse strand of the human chromosome 8 (8p22). Starts at 17545583, and ends at 17702666 bp from pter.


Note The MTUS1 gene consists of 17 known exons. Alternative exon utilization leads to the generation of 5 known transcript variants (designated as variant 1 to 5), and consequentially 5 different protein isoforms (designated as isoform 1 to 5). It has been suggested that the transcription of variant 1, 2, and 3 are driven by a common gene promoter, while variant 4 and 5 are driven by 2 additional promoters. This hypothesis is supported by the observation of differential tissue distribution of different MTUS1 variants, which further suggests the differential regulation of MTUS1 gene transcription through these different promoters.
  Organization of the MTUS1 gene. A) The schematic representation of genomic organization of MTUS1 gene located on the minus strand of chromosome 8p21.3-p22. The genomic locations of the detected nucleotide sequence variants (both polymorphisms and somatic mutations) for MTUS1 gene were indicated. The nucleotide sequence variants that lead to amino acid changes were identified with *. The & indicates exon deletion. B) The alternative exon utilization by MTUS1 transcript variants. The v indicates translational initiating ATG codon. The ^ indicates stop codon. The 5U indicates 5' untranslated region, and the 3U indicates 3' untranslated region. An in-frame stop codon is located in exon 3. This in-frame stop codon makes the transcript variant 3 (dash-lined) a candidate for nonsense-mediated mRNA decay (NMD). C) The protein isoforms resulted from the MTUS1 transcript variants and cellular localization signals. The alternative names for the isoforms were given in parenthesis. Black circles indicate nuclear localization signals. Black triangle indicates a putative transmembrane region. White triangle indicates a mitochondrial targeting signal. The existence of the in-frame stop codon suggests that isoform 3 (dash-lined) is interrupted at exon 3.
Transcription The production of transcript variant 1, 2 and 3, which are driven by a common promoter, are produced by alternative splicing of exon 3 and exon 4. The splice junctions contain the conserved nucleotides (GT-AG) for the donor and acceptor splice sites. An in-frame stop codon in exon 3 indicates that the MTUS1 protein isoform 3 (the only isoform to utilize exon 3) may be interrupted at this position. This sequence feature also makes the transcript variant 3 a candidate for nonsense-mediated mRNA decay (NMD). Indeed, it is absent (or weakly expressed) in all normal tissues examined. While both transcript variant 1 and 2 show similar tissue distribution patterns, variant 1 is more expressed than variant 2 in most tissues. However, in the salivar gland, variant 2 accounts for more than 90% of all the MTUS1 transcript members. Apparently, the exon 4 is the only alternatively spliced exon out of 17 exons of the MTUS1 gene, which leads to the production of MTUS1 transcript variant 1 and 2. Alternatively, variant 2 may be a transcript from the MTUS1 gene with a recently identified polymorphic copy number variant at DNA level (Var del Ex4 that lacking the coding exon 4). Interestingly, an association of this MTUS1 gene Var del Ex4 polymorphism and familial breast cancer has been observed in a Germany patient cohort.


Expression - MTUS1 isoform 1 and 2 are the major MTUS1 transcripts in all tissues except brain
- MTUS1 isoform 3 is absent (or weakly expressed) in all normal tissues examined
- MTUS1 isoform 4 is exclusively expressed in the brain, and is particularly abundant in the cerebellum and in the fetal brain.
Localisation MTUS1 isoform 5 is the only isoform localized in mitochondria.
Function The MTUS1 isoform 5 was the first one among the 5 different isoforms to be characterized independently in 2 laboratories, as a gene that is transiently upregulated during initiation of differentiation and quiescence in a 3-dimensional human umbilical vein endothelial cell culture, and as a early component of growth inhibitory signaling cascade that interacts with angiotensin II AT2 receptor. The exon 8, which is exclusively utilized by MTUS1 isoform 5, contains a mitochondrial targeting signal. This protein isoform has indeed been shown to co-localize with mitochondria, which eventually lead to its current name mitochondrial tumor suppressor 1. These early evidences on MTUS1 isoform 5 suggest the tumor suppressor function of this gene. As a consequence, the majority of the functional analyses have been focused on this specific isoform. As demonstrated in a pancreatic tumor cell line (MIA PaCa-2), recombinant expression of MTUS1 isoform 5 led to a 30% reduction in cell growth as measured by BrdU uptake. Using a CHO cell line stably transfected with both angiotensin II AT2 receptor and MTUS1 isoform 5, Nouet et al. demonstrated that the growth factors (insulin, bFGF, EGF) induced extracellular regulated kinase ( ERK2 ) activation was inhibited. This MTUS1 isoform 5 mediated inhibitory effect was also observed at cell proliferation level as measured by DNA synthesis. The results from Nouet et al., 2006 study also suggested that MTUS1 isoform 5 functions through cooperating with the angiotensin II AT2 receptor to trans-inactivate growth factor receptor tyrosine kinases. The localization of the MTUS1 isoform 5 to mitochondria also lead to speculation that this protein achieves its tumor suppressor function by regulating different mitochondrial functions, such as the maintenance of energy supply, the production of reactive oxygen intermediates and their interactions with other cell cycle regulators.
While ample evidence suggested the tumor suppressor function of isoform 5, it is important to notice that isoform 1 and 2 are the major MTUS1 transcripts in all tissues except brain, and account for an average of 72% of total MTUS1 mRNA. Evidence supporting the tumor suppressor function of MTUS1 isoform 1 and 2 come from the study on Xenopus Icis gene, a homolog of MTUS1 isoform 1/2. Using inactivating antibodies, Ohi et al. found that absence of Icis caused excessive microtubule growth and inhibited spindle formation, a function consistent with tumor suppressor activity. Prior to anaphase, Icis localized to inner centromeres in a Mitotic Centromere Associated Kinesin ( Mcak )-dependent manner. From Xenopus extracts, Icis coimmunoprecipitated Mcak and the inner centromere proteins Incenp and AuroraB, which are thought to promote chromosome biorientation. Immunoelectron microscopy detected Icis on the surface of inner centromeres, in an ideal location to depolymerize microtubules associated laterally with inner centromeres. Ohi et al. hypothesized that Mcak-Icis may destabilize these microtubules and provide a mechanism that prevents kinetochore-microtubule attachment errors.
The MTUS1 isoform 1 and isoform 2 differ in their use of exon 4; exon 4 is contained in isoform 1 but not in isoform 2 (Figure 2). This difference may be a result of alternative splicing. Alternatively, this isoform 2 may be a protein product from the MTUS1 gene with a recently identified polymorphic copy number variant at DNA level (Var del Ex4 that lacking the exon 4).
The existence of MTUS1 isoform 3 is not entirely certain. The expression of MTUS1 isoform 3 appears to be under the control of the same gene promoter that drives the expression of the isoform 1 and 2. However, as a result of alternative splicing, exon 3, which contains an in-frame stop codon, is incorporated into the transcript. This sequence feature makes the transcript variant 3 a candidate for nonsense-mediated mRNA decay (NMD). Indeed, it is absent (or weakly expressed) in all normal tissues examined. Hence, the sequence for this variant in the GenBank (NM_001001927) was permanently suppressed. Nevertheless, it is possible that this alternative splice to include exon 3 in the transcript may provide a mechanism to switch-off the expression of isoform 1 and 2 at posttranscriptional level.
The MTUS1 isoform 4 is exclusively expressed in the brain, and is particularly abundant in the cerebellum and in the fetal brain. It appears that the expression of isoform 4 is driven by a gene promoter specific to central nervous system. These findings suggest multiple cellular/physiological functions of MTUS1 gene, including tumor suppression as well as brain function and/or development.
Homology Xenopus Icis gene is a homolog of MTUS1 isoform 1 and 2.


Somatic Sequence analyses of this gene in liver cancer and head and neck cancer revealed that MTUS1 gene is prone to various point mutations and small deletions. Many of these mutations lead to substitutions of conserved amino acid residues or interfere with the physiological splice sites that may functionally silence the MTUS1 gene. In particular, a point mutation in exon 7 (Var3 G17615042T), identified in an 8p21.3-p22 LOH-positive liver cancer cell line, abolished a physiological splicing acceptor site of exon 7. Additional experiment confirmed that this point mutation indeed leads to a transcript that lacking exon 7. Thus, this point mutation results in the deletion of the entire exon 7, which codes for several important motifs, including a nuclear localization signal.

Implicated in

Entity Various Cancers
Note Mitochondrial tumor suppressor gene 1 (MTUS1) is a recently identified tumor suppressor gene that resides in a frequent LOH region (8p21.3-p22) in many tumor types. Sequence analyses of MTUS1 gene suggest that this gene is rich in genetic polymorphisms, including single nucleotide polymorphism (SNP) and copy number variation (CNV), and it is susceptible to various point mutations during tumorigenesis. Consistent down-regulation of MTUS1 gene expression was observed in various cancer cell lines and tissue samples.
Entity Breast cancer
Note A copy number variant in MTUS1 gene is significantly associated with a decreased risk for both familial and high-risk familial breast cancer in a Germany patient cohort. This finding was made based on a case-control study on a large homogeneous study cohort (case n = 593, control n = 732) of a single ethnic group. These authors hypothesized that the lack of this exon 4 may lead to increased tumor suppressor activity. Further molecular analyses will be needed to functionally characterize this apparent phenotypic difference. While the true biological consequence(s) of this MTUS1 exon 4 deletion is still unknown, this study clearly suggested a functional difference between MTUS1 isoform 1 and isoform 2.
Entity Pancreatic cancer
Note In a pancreatic tumor cell line (MIA PaCa-2), recombinant expression of MTUS1 isoform 5 led to a 30% reduction in cell growth as measured by BrdU uptake.
Entity Head and neck squamous cell carcinoma
Note Consistent down-regulation in expression was observed in HNSCC for MTUS1 as measured by real-time quantitative RT-PCR. Sequence analysis of MTUS1 gene in HNSCC revealed several important sequence variants in the exon regions of this gene.
Entity Hepatocellular carcinoma
Note Sequence analysis of MTUS1 gene in hepatocellular carcinoma revealed several important sequence variants in the exon regions of this gene.


Haploinsufficiency and reduced expression of genes localized to the 8p chromosomal region in human prostate tumors.
Chaib H, MacDonald JW, Vessella RL, Washburn JG, Quinn JE, Odman A, Rubin MA, Macoska JA.
Genes Chromosomes Cancer. 2003 Jul;37(3):306-13.
PMID 12759929
Mutation analysis of the 8p22 candidate tumor suppressor gene ATIP/MTUS1 in hepatocellular carcinoma.
Di Benedetto M, Pineau P, Nouet S, Berhouet S, Seitz I, Louis S, Dejean A, Couraud PO, Strosberg AD, Stoppa-Lyonnet D, Nahmias C.
Mol Cell Endocrinol. 2006 Jun 27;252(1-2):207-15. Epub 2006 May 2.
PMID 16650523
Copy number variant in the candidate tumor suppressor gene MTUS1 and familial breast cancer risk.
Frank B, Bermejo JL, Hemminki K, Sutter C, Wappenschmidt B, Meindl A, Kiechle-Bahat M, Bugert P, Schmutzler RK, Bartram CR, Burwinkel B.
Carcinogenesis. 2007 Jul;28(7):1442-5. Epub 2007 Feb 13.
PMID 17301065
Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP.
Nouet S, Amzallag N, Li JM, Louis S, Seitz I, Cui TX, Alleaume AM, Di Benedetto M, Boden C, Masson M, Strosberg AD, Horiuchi M, Couraud PO, Nahmias C.
J Biol Chem. 2004 Jul 9;279(28):28989-97. Epub 2004 Apr 29.
PMID 15123706
An inner centromere protein that stimulates the microtubule depolymerizing activity of a KinI kinesin.
Ohi R, Coughlin ML, Lane WS, Mitchison TJ.
Dev Cell. 2003 Aug;5(2):309-21.
PMID 12919681
Five genes from chromosomal band 8p22 are significantly down-regulated in ovarian carcinoma: N33 and EFA6R have a potential impact on overall survival.
Pils D, Horak P, Gleiss A, Sax C, Fabjani G, Moebus VJ, Zielinski C, Reinthaller A, Zeillinger R, Krainer M.
Cancer. 2005 Dec 1;104(11):2417-29.
PMID 16270321
Identification of three distinct regions of allelic deletions on the short arm of chromosome 8 in hepatocellular carcinoma.
Pineau P, Nagai H, Prigent S, Wei Y, Gyapay G, Weissenbach J, Tiollais P, Buendia MA, Dejean A.
Oncogene. 1999 May 20;18(20):3127-34.
PMID 10340384
Identification of a new tumor suppressor gene located at chromosome 8p21.3-22.
Seibold S, Rudroff C, Weber M, Galle J, Wanner C, Marx M.
FASEB J. 2003 Jun;17(9):1180-2. Epub 2003 Apr 8.
PMID 12692079
Transfer of chromosome 8 into two breast cancer cell lines: total exclusion of three regions indicates location of putative in vitro growth suppressor genes.
Wilson P, Cuthbert A, Marsh A, Arnold J, Flanagan J, Mulford C, Trott D, Baker E, Purdie D, Newbold R, Chenevix-Trench G.
Cancer Genet Cytogenet. 2003 Jun;143(2):100-12.
PMID 12781443
Genomic assessments of the frequent loss of heterozygosity region on 8p21.3-p22 in head and neck squamous cell carcinoma.
Ye H, Pungpravat N, Huang BL, Muzio LL, Mariggio MA, Chen Z, Wong DT, Zhou X.
Cancer Genet Cytogenet. 2007 Jul 15;176(2):100-6.
PMID 17656251
Localization of a tumor suppressor gene associated with the progression of human breast carcinoma within a 1-cM interval of 8p22-p23.1.
Yokota T, Yoshimoto M, Akiyama F, Sakamoto G, Kasumi F, Nakamura Y, Emi M.
Cancer. 1999 Jan 15;85(2):447-52.
PMID 10023714
Frequent allelic imbalances at 8p and 11q22 in oral and oropharyngeal epithelial dysplastic lesions.
Zhou X, Jordan RC, Li Y, Huang BL, Wong DT.
Cancer Genet Cytogenet. 2005 Aug;161(1):86-9.
PMID 16080964


This paper should be referenced as such :
Zhou, X ; Yu, J ; Liu, X
MTUS1 (mitochondrial tumor suppressor 1)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(11):853-857.
Free journal version : [ pdf ]   [ DOI ]

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(8;8)(p21;p22) PPP2R2A/MTUS1

External links

HGNC (Hugo)MTUS1   29789
Entrez_Gene (NCBI)MTUS1  57509  microtubule associated scaffold protein 1
GeneCards (Weizmann)MTUS1
Ensembl hg19 (Hinxton)ENSG00000129422 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000129422 [Gene_View]  ENSG00000129422 [Sequence]  chr8:17643794-17697737 [Contig_View]  MTUS1 [Vega]
ICGC DataPortalENSG00000129422
TCGA cBioPortalMTUS1
Genatlas (Paris)MTUS1
SOURCE (Princeton)MTUS1
Genetics Home Reference (NIH)MTUS1
Genomic and cartography
GoldenPath hg38 (UCSC)MTUS1  -     chr8:17643794-17697737 -  8p22   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MTUS1  -     8p22   [Description]    (hg19-Feb_2009)
GoldenPathMTUS1 - 8p22 [CytoView hg19]  MTUS1 - 8p22 [CytoView hg38]
genome Data Viewer NCBIMTUS1 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AA368734 AB033114 AF086371 AF121259 AF293357
RefSeq transcript (Entrez)NM_001001924 NM_001001925 NM_001001927 NM_001001931 NM_001166393 NM_001330470 NM_001363057 NM_001363058 NM_001363059 NM_001363060 NM_001363061 NM_001363062 NM_020749
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MTUS1
Alternative Splicing GalleryENSG00000129422
Gene ExpressionMTUS1 [ NCBI-GEO ]   MTUS1 [ EBI - ARRAY_EXPRESS ]   MTUS1 [ SEEK ]   MTUS1 [ MEM ]
Gene Expression Viewer (FireBrowse)MTUS1 [ Firebrowse - Broad ]
GenevisibleExpression of MTUS1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)57509
GTEX Portal (Tissue expression)MTUS1
Human Protein AtlasENSG00000129422-MTUS1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9ULD2   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9ULD2  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9ULD2
Splice isoforms : SwissVarQ9ULD2
Domains : Interpro (EBI)MTUS1   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)MTUS1
DMDM Disease mutations57509
Blocks (Seattle)MTUS1
Human Protein Atlas [tissue]ENSG00000129422-MTUS1 [tissue]
Peptide AtlasQ9ULD2
IPIIPI00428447   IPI00472533   IPI00102820   IPI00867528   IPI00470640   IPI00428450   IPI00953513   
Protein Interaction databases
IntAct (EBI)Q9ULD2
Ontologies - Pathways
Ontology : AmiGOextracellular space  nucleus  nucleolus  cytoplasm  mitochondrion  Golgi apparatus  microtubule organizing center  spindle  microtubule  plasma membrane  microtubule binding  regulation of macrophage chemotaxis  microtubule cytoskeleton  
Ontology : EGO-EBIextracellular space  nucleus  nucleolus  cytoplasm  mitochondrion  Golgi apparatus  microtubule organizing center  spindle  microtubule  plasma membrane  microtubule binding  regulation of macrophage chemotaxis  microtubule cytoskeleton  
NDEx NetworkMTUS1
Atlas of Cancer Signalling NetworkMTUS1
Wikipedia pathwaysMTUS1
Orthology - Evolution
GeneTree (enSembl)ENSG00000129422
Phylogenetic Trees/Animal Genes : TreeFamMTUS1
Homologs : HomoloGeneMTUS1
Homology/Alignments : Family Browser (UCSC)MTUS1
Gene fusions - Rearrangements
Fusion : MitelmanPPP2R2A/MTUS1 [8p21.2/8p22]  
Fusion PortalMTUS1 8p22 FGL1 8p22 LUAD
Fusion PortalPPP2R2A 8p21.2 MTUS1 8p22 PRAD
Fusion : Fusion_HubABCB9--MTUS1    ATXN1--MTUS1    BBS9--MTUS1    C21ORF49--MTUS1    CCNT2--MTUS1    CRMP1--MTUS1    EIF3L--MTUS1    KDM5A--MTUS1    MTMR7--MTUS1    MTUS1--ALMS1    MTUS1--ASAH1    MTUS1--ATP10A    MTUS1--ATP5C1    MTUS1--C1ORF63    MTUS1--DNAJC15   
Fusion : QuiverMTUS1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMTUS1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MTUS1
Exome Variant ServerMTUS1
GNOMAD BrowserENSG00000129422
Varsome BrowserMTUS1
Genetic variants : HAPMAP57509
Genomic Variants (DGV)MTUS1 [DGVbeta]
DECIPHERMTUS1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMTUS1 
ICGC Data PortalMTUS1 
TCGA Data PortalMTUS1 
Broad Tumor PortalMTUS1
OASIS PortalMTUS1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMTUS1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DMTUS1
Mutations and Diseases : HGMDMTUS1
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 MTUS1
DgiDB (Drug Gene Interaction Database)MTUS1
DoCM (Curated mutations)MTUS1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MTUS1 (select a term)
NCG6 (London) select MTUS1
Cancer3DMTUS1(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry MTUS1
NextProtQ9ULD2 [Medical]
Target ValidationMTUS1
Huge Navigator MTUS1 [HugePedia]
snp3D : Map Gene to Disease57509
BioCentury BCIQMTUS1
Clinical trials, drugs, therapy
Protein Interactions : CTD57509
Pharm GKB GenePA134968054
Clinical trialMTUS1
canSAR (ICR)MTUS1 (select the gene name)
DataMed IndexMTUS1
PubMed53 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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