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VMP1 (vacuole membrane protein 1)

Identity

Other namesDKFZp566I133
EPG3
TMEM49
HGNC (Hugo) VMP1
LocusID (NCBI) 81671
Location 17q23.1
Location_base_pair Starts at 57784863 and ends at 57917952 bp from pter ( according to hg19-Feb_2009)

DNA/RNA

 
  Genomic organization of the VMP1/TMEM49 gene.
Description 12 exons, spans approximately 133 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon is located to exon 2, and the stop codon to exon 12.
Transcription mRNA of 2,17 kb.

Protein

 
  Schematic representation of VMP1 protein and localization of transmembrane domains.
Description The pancreatitis-associated protein vacuole membrane protein 1 (VMP1) is a transmembrane protein of 406 amino-acid length containing 6 putative transmembrane domains and with no known homologues in yeast.
Expression VMP1 was characterized because is not constitutively expressed in pancreatic acinar cells and it is highly activated early during experimental acute pancreatitis in acinar cells.
Localisation Autophagosomal membrane.
Function VMP1 is an autophagy-related membrane protein. VMP1 expression triggers autophagy, even under nutrient-replete conditions. VMP1 is required for autophagosome development through interaction with Beclin1. Recently, it has been demonstrated that participate in a novel selective form of autophagy, called zymophagy, mediated by VMP1-USP9x-p62 pathway during acute pancreatitis.

Implicated in

Entity Pancreatic cancer
Disease Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies with a 2-3% 5-year survival rate. This is due to both the aggressive nature of the disease and the lack of specific symptoms and early-detection tools. It is relatively refractory to traditional cytotoxic agents and radiotherapy. Gemcitabine, the standard chemotherapy agent for the treatment of pancreatic cancer, induces autophagy of cancer cells and that this process mediates the cell death-promoting activity of this compound. Early induction of autophagy by gemcitabine leads to cancer cell death and this cellular process is mediated by the activation of VMP1 expression. In PANC-1 and MIAPaCa-2 cells the inhibition of autophagy significantly reduced the percentage of dead cells in response to gemcitabine. In addition, gemcitabine promoted early VMP1 expression, and downregulation of VMP1 expression significantly reduced cell death.
  
Entity Acute pancreatitis
Disease VMP1 was characterized because is not constitutively expressed in pancreatic acinar cells and it is highly activated early during experimental acute pancreatitis in acinar cells. VMP1 is an autophagy-related membrane protein involved in the initial steps of the mammalian cell autophagic process. VMP1 is a transmembrane protein that co-localizes with LC3, a marker of the autophagosomes, in pancreas tissue undergoing pancreatitis-induced autophagy. VMP1 interacts with with Beclin1, a mammalian autophagy initiator, to start autophagosome formation. We developed the ElaI-VMP1 mouse in which acinar cell-specific constitutive expression of a VMP1-EGFP chimera induces the formation of autophagosomes. Upon CCK-R hyperstimulation, wild type mice developed acute pancreatitis with high amylase and lipase serum levels. On the contrary, enzymatic levels in cerulein-treated ElaI-VMP1 mice were significantly lower compared to wild type mice. Consistently, ElaI-VMP1 mouse pancreata showed remarkably less macroscopic evidence of acute pancreatitis compared to wild type animals, which showed marked edema and hemorrhage. Histological analyses displayed a high degree of necrosis as well as infiltration in wild type pancreata with acute pancreatitis. In contrast, neither necrosis nor significant inflammation was seen in cerulein-treated ElaI-VMP1 mice. ElaIVMP1 mice showed secretory granules with normal ultrastructural characteristics CCK-R hyperstimulation in wild type animals induced a markedly altered distribution pattern of the secretory granules. Acinar cells lose their polarity, which results in the relocation of zymogen granules to the basolateral membrane. These alterations in vesicular traffic are known to occur in acinar cells during acute pancreatitis and upon hyperstimulation of their CCK-R with cerulein. ElaI-VMP1 mice subjected to CCK-R hyperstimulation revealed that acinar cells preserve their structure and polarity with negligible or no alteration in vesicular transport. Surprisingly, in pancreata from cerulein-treated ElaI-VMP1 mice, we observed autophagosomes containing zymogen granules displaying a distinct localization to the apical area of the acinar cell. VMP1, the ubiquitin-protease USP9x, and the ubiquitin-binding protein p62 mediate this process. Moreover, VMP1 interacts with USP9x, indicating that there is a close cooperation between the autophagy pathway and the ubiquitin recognition machinery required for selective autophagosome formation. We have coined the term "zymophagy" to refer to this process. Zymophagy is activated by experimental pancreatitis and by acute pancreatitis in humans. Furthermore, zymophagy has pathophysiological relevance by controlling pancreatitis-induced intracellular zymogen activation and helping to prevent cell death. This new selective autophagy is activated in pancreatic acinar cells during pancreatitis-induced vesicular transport alteration to sequester and degrade potentially deleterious activated zymogen granules.
 
Confocal microscopy of AR42J cell transfected with pEGFP-VMP1.
  
Entity Diabetes
Disease Experimental diabetes activates VMP1 expression and autophagy in pancreas beta cells as a direct response to streptozotocin (STZ). VMP1 mRNA expression is activated after STZ treatment by islet beta cells. Electron microscopy shows chromatin aggregation and autophagy morphology that was confirmed by LC3 expression and LC3-VMP1 co-localization. Apoptotic cell death and the reduction of beta cell pool are evident after 24h treatment, while VMP1 is still expressed in the remaining cells. VMP1-Beclin1 colocalization in pancreas tissue from STZ-treated rats suggests that VMP1-Beclin1 interaction is involved in the autophagic process activation during experimental diabetes. Pancreas beta cells trigger VMP1 expression and autophagy during the early cellular events in response to experimental diabetes.
  

External links

Nomenclature
HGNC (Hugo)VMP1   29559
Cards
AtlasVMP1ID50079ch17q23
Entrez_Gene (NCBI)VMP1  81671  vacuole membrane protein 1
GeneCards (Weizmann)VMP1
Ensembl (Hinxton)ENSG00000062716 [Gene_View]  chr17:57784863-57917952 [Contig_View]  VMP1 [Vega]
ICGC DataPortalENSG00000062716
cBioPortalVMP1
AceView (NCBI)VMP1
Genatlas (Paris)VMP1
WikiGenes81671
SOURCE (Princeton)NM_030938
Genomic and cartography
GoldenPath (UCSC)VMP1  -  17q23.1   chr17:57784863-57917952 +  17q23.2   [Description]    (hg19-Feb_2009)
EnsemblVMP1 - 17q23.2 [CytoView]
Mapping of homologs : NCBIVMP1 [Mapview]
OMIM611753   
Gene and transcription
Genbank (Entrez)AB047551 AF161410 AF214006 AK024969 AK025987
RefSeq transcript (Entrez)NM_030938
RefSeq genomic (Entrez)AC_000149 NC_000017 NC_018928 NT_010783 NW_001838449 NW_004929407
Consensus coding sequences : CCDS (NCBI)VMP1
Cluster EST : UnigeneHs.708260 [ NCBI ]
CGAP (NCI)Hs.708260
Alternative Splicing : Fast-db (Paris)GSHG0012699
Alternative Splicing GalleryENSG00000062716
Gene ExpressionVMP1 [ NCBI-GEO ]     VMP1 [ SEEK ]   VMP1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96GC9 (Uniprot)
NextProtQ96GC9  [Medical]
With graphics : InterProQ96GC9
Splice isoforms : SwissVarQ96GC9 (Swissvar)
Related proteins : CluSTrQ96GC9
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
DMDM Disease mutations81671
Blocks (Seattle)Q96GC9
Human Protein AtlasENSG00000062716 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ96GC9
HPRD15649
IPIIPI01015255   IPI01015169   IPI01013905   IPI00792839   IPI01014766   IPI00742911   
Protein Interaction databases
DIP (DOE-UCLA)Q96GC9
IntAct (EBI)Q96GC9
FunCoupENSG00000062716
BioGRIDVMP1
InParanoidQ96GC9
Interologous Interaction database Q96GC9
IntegromeDBVMP1
STRING (EMBL)VMP1
Ontologies - Pathways
Ontology : AmiGOpre-autophagosomal structure  autophagic vacuole membrane  protein binding  endoplasmic reticulum  plasma membrane  autophagy  embryo implantation  regulation of autophagy  integral component of membrane  single organismal cell-cell adhesion  endoplasmic reticulum-Golgi intermediate compartment membrane  cell junction assembly  
Ontology : EGO-EBIpre-autophagosomal structure  autophagic vacuole membrane  protein binding  endoplasmic reticulum  plasma membrane  autophagy  embryo implantation  regulation of autophagy  integral component of membrane  single organismal cell-cell adhesion  endoplasmic reticulum-Golgi intermediate compartment membrane  cell junction assembly  
Protein Interaction DatabaseVMP1
Wikipedia pathwaysVMP1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)VMP1
snp3D : Map Gene to Disease81671
SNP (GeneSNP Utah)VMP1
SNP : HGBaseVMP1
Genetic variants : HAPMAPVMP1
Exome VariantVMP1
1000_GenomesVMP1 
ICGC programENSG00000062716 
Somatic Mutations in Cancer : COSMICVMP1 
CONAN: Copy Number AnalysisVMP1 
Mutations and Diseases : HGMDVMP1
Genomic VariantsVMP1  VMP1 [DGVbeta]
dbVarVMP1
ClinVarVMP1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM611753   
MedgenVMP1
GENETestsVMP1
Disease Genetic AssociationVMP1
Huge Navigator VMP1 [HugePedia]  VMP1 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneVMP1
Homology/Alignments : Family Browser (UCSC)VMP1
Phylogenetic Trees/Animal Genes : TreeFamVMP1
Chemical/Protein Interactions : CTD81671
Chemical/Pharm GKB GenePA142670765
Clinical trialVMP1
Cancer Resource (Charite)ENSG00000062716
Other databases
Other databaseThe Pancreapedia
Probes
Litterature
PubMed31 Pubmed reference(s) in Entrez
CoreMineVMP1
iHOPVMP1
OncoSearchVMP1

Bibliography

Cloning and expression of the rat vacuole membrane protein 1 (VMP1), a new gene activated in pancreas with acute pancreatitis, which promotes vacuole formation.
Dusetti NJ, Jiang Y, Vaccaro MI, Tomasini R, Azizi Samir A, Calvo EL, Ropolo A, Fiedler F, Mallo GV, Dagorn JC, Iovanna JL.
Biochem Biophys Res Commun. 2002 Jan 18;290(2):641-9.
PMID 11785947
 
VMP1 expression correlates with acinar cell cytoplasmic vacuolization in arginine-induced acute pancreatitis.
Vaccaro MI, Grasso D, Ropolo A, Iovanna JL, Cerquetti MC.
Pancreatology. 2003;3(1):69-74.
PMID 12649568
 
Expression of vacuole membrane protein 1 (VMP1) in spontaneous chronic pancreatitis in the WBN/Kob rat.
Jiang PH, Motoo Y, Vaccaro MI, Iovanna JL, Okada G, Sawabu N.
Pancreas. 2004 Oct;29(3):225-30.
PMID 15367889
 
The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells.
Ropolo A, Grasso D, Pardo R, Sacchetti ML, Archange C, Lo Re A, Seux M, Nowak J, Gonzalez CD, Iovanna JL, Vaccaro MI.
J Biol Chem. 2007 Dec 21;282(51):37124-33. Epub 2007 Oct 16.
PMID 17940279
 
Autophagy and pancreas disease.
Vaccaro MI.
Pancreatology. 2008;8(4-5):425-9. Epub 2008 Aug 20. (REVIEW)
PMID 18714176
 
A novel mammalian trans-membrane protein reveals an alternative initiation pathway for autophagy.
Vaccaro MI, Ropolo A, Grasso D, Iovanna JL.
Autophagy. 2008 Apr;4(3):388-90. Epub 2008 Jan 30.
PMID 18253086
 
Autophagy and VMP1 expression are early cellular events in experimental diabetes.
Grasso D, Sacchetti ML, Bruno L, Lo Re A, Iovanna JL, Gonzalez CD, Vaccaro MI.
Pancreatology. 2009;9(1-2):81-8. Epub 2008 May 5.
PMID 19077458
 
Gemcitabine induces the VMP1-mediated autophagy pathway to promote apoptotic death in human pancreatic cancer cells.
Pardo R, Lo Re A, Archange C, Ropolo A, Papademetrio DL, Gonzalez CD, Alvarez EM, Iovanna JL, Vaccaro MI.
Pancreatology. 2010;10(1):19-26. Epub 2010 Mar 19.
PMID 20299819
 
Zymophagy, a novel selective autophagy pathway mediated by VMP1-USP9x-p62, prevents pancreatic cell death.
Grasso D, Ropolo A, Lo Re A, Boggio V, Molejon MI, Iovanna JL, Gonzalez CD, Urrutia R, Vaccaro MI.
J Biol Chem. 2011 Mar 11;286(10):8308-24. Epub 2010 Dec 20.
PMID 21173155
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written11-2011Alejandro Ropolo, Andrea Lo Ré, María Inés Vaccaro
Molecular Pathophysiology Lab, School of Pharmacie and Biochemistry, University of Buenos Aires, Argentina

Citation

This paper should be referenced as such :
Ropolo A, Lo Ré A, Vaccaro MI
VMP1 (vacuole membrane protein 1);
Atlas Genet Cytogenet Oncol Haematol. November 2011
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/VMP1ID50079ch17q23.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Jul 30 16:57:18 CEST 2014

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