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PDCD6 (programmed cell death 6)

Written2008-01Martin W Berchtold
Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark

(Note : for Links provided by Atlas : click)

Identity

Other namesALG-2
MGC111017
MGC119050
MGC9123
PEF1B
HGNC (Hugo) PDCD6
LocusID (NCBI) 10016
Atlas_Id 43402
Location 5p15.33  [Link to chromosome band 5p15]
Location_base_pair Starts at 271736 and ends at 315089 bp from pter ( according to hg19-Feb_2009)  [Mapping PDCD6.png]
Fusion genes
(updated 2016)
CLPTM1L (5p15.33) / PDCD6 (5p15.33)PDCD6 (5p15.33) / CCDC127 (5p15.33)PDCD6 (5p15.33) / PDCD6 (5p15.33)
PDCD6 (5p15.33) / TERT (5p15.33)PDCD6 (5p15.33) / ZNF605 (12q24.33)

DNA/RNA

 
  Map of the PDCD gene at 5pt-15.2, black boxes indicate exons, red boxes indicate untranslated exons.
Description The PDCD6 gene contains 43351 bp. The coding sequence extends from 324738 nt to 368089 nt and contains 6 exons. The initiation codon is located at position 101 in exon 1. Exon 3 sequence is identical with AHRR (HGNC symbol Synonyms: AHH, AHHR, KIAA1234) position 357291-357336 at the same locus.
Transcription is in a telomere to centromere direction. There is one alternative splice site (validated by ESTs and RNAse protection analysis) at the 5' of exon 4 creating a 6 bp shorter exon corresponding of a protein lacking GF121/122.
Pseudogene Q7Z6L2_HUMAN, lOC728613, p15.33, NC-000005.8, 1650672 - 1705673 in a centromere to telomere direction.

Protein

 
  Protein structure: 3-dimensional structure of the PDCD6 dimer: EF1, EF3, EF5 are the functional calcium binding domains (blue). In green are the calcium ions, in yellow is the N-terminal peptide modeled on the protein, in cyan an red are G121 and F122 missing in the known splice form.
Description 191 amino acids, 21.7 kDa, member of the penta EF hand protein family.
Expression Ubiquitously expressed, higher abundance in some tumor tissues.
Localisation Cytoplasmic, nuclear and unidentified structures in the cytoplasm.
Function PDCD6 (product of the apoptosis-linked gene 2) is a calcium binding protein with 5 EF hand motifs originally identified as a proapoptotic protein in a genetic screen. A knock out mouse with deleted PDCD6 gene showed no obvious phenotype. Newer results indicate that inhibition of PDCD6 expression reduces cellular viability. Several target proteins, which interact with PDCD6 in a calcium dependent fashion have been found. Most prominent are AIP1/Alix, an adaptor protein involved in apoptosis, endocytosis, adhesion and cytokinesis as well as TSG101, a tumor suppressor gene product, which is a component of the ESRT-1 (endosomal sorting complex required for transport I) and Sec31A, a component of the COPII, ER to Golgi transport vesicles. As all these proteins are linked to intracellular trafficking PDCD6 may connect calcium signaling to trafficking processes through these target proteins or yet to be identified novel PDCD6 targets and thereby regulates cell viability. As a commercial anti PDCD6 antibody, which turned out to be directed against the cochaperone protein p23 and not against PDCD6 was used to confirm interaction of PDCD6 with target proteins some of the early reports on PDCD6 have to be treated with caution.
Homology PEF (Penta EF-hand) family proteins sorcin, grancalcin, calpain light and heavy chain, peflin.

Mutations

Note not known

Implicated in

Note
Entity Various cancers
Note PDCD6 has been reported to be downregulated in atherosclerotic plaques as shown by Western array anaysis. However, it was found later that the cochaperone p23 and not PDCD6 was downregulated due to the use of a nonspecific antibody.
Oncogenesis PDCD6 downregulation has been implicated in ocular melanoma, possibly giving cancer cells a growth advantage.
PDCD6 has been shown to be significantly upregulated in rat hepatomas and human small lung cancer as well as in non small lung cancer cells analyzed in specimens of 263 patients. In a tissue microarray analysis with ca 8000 samples of normal and tumor tissues strong PDCD6 signals were detected in urothelium (benign), adeno dysplasia, thymoma and neuroendocrine tumors with over 35 % of the samples to give a moderate or strong staining. Brenner, carcinoid and cribriform tumors gave the strongest signals. In normal tissues cells of the urothelium of the kidney and urinary bladder, islet cells of the pancreas, columnar ductal cells of the seminal vesicle, tall columnar cells of the epididymus and ciliated as well as secretory cells of the fallopian tube were stained for PDCD6 with strongest intensity but below the one found in strongly staining tumor cells. PDCD6 downregulation with siRNA inhibited growth of HeLa cells. PDCD6 might therefore play a role as a cellular viability factor. However, no correlation between PDCD6 staining intensity and survival of patients with lung cancer, colon cancer or breast cancer was found.
  

Bibliography

Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3.
Vito P, Lacanà E, D'Adamio L
Science (New York, N.Y.). 1996 ; 271 (5248) : 521-525.
PMID 8560270
 
Calcium-induced exposure of a hydrophobic surface of mouse ALG-2, which is a member of the penta-EF-hand protein family.
Maki M, Yamaguchi K, Kitaura Y, Satoh H, Hitomi K
Journal of biochemistry. 1998 ; 124 (6) : 1170-1177.
PMID 9832622
 
Alix, a novel mouse protein undergoing calcium-dependent interaction with the apoptosis-linked-gene 2 (ALG-2) protein.
Missotten M, Nichols A, Rieger K, Sadoul R
Cell death and differentiation. 1999 ; 6 (2) : 124-129.
PMID 10200558
 
Cloning of AIP1, a novel protein that associates with the apoptosis-linked gene ALG-2 in a Ca2+-dependent reaction.
Vito P, Pellegrini L, Guiet C, D'Adamio L
The Journal of biological chemistry. 1999 ; 274 (3) : 1533-1540.
PMID 9880530
 
Two forms of the apoptosis-linked protein ALG-2 with different Ca(2+) affinities and target recognition.
Tarabykina S, M&oring;ller AL, Durussel I, Cox J, Berchtold MW
The Journal of biological chemistry. 2000 ; 275 (14) : 10514-10518.
PMID 10744743
 
Structure of apoptosis-linked protein ALG-2: insights into Ca2+-induced changes in penta-EF-hand proteins.
Jia J, Tarabykina S, Hansen C, Berchtold M, Cygler M
Structure (London, England : 1993). 2001 ; 9 (4) : 267-275.
PMID 11525164
 
Peflin and ALG-2, members of the penta-EF-hand protein family, form a heterodimer that dissociates in a Ca2+-dependent manner.
Kitaura Y, Matsumoto S, Satoh H, Hitomi K, Maki M
The Journal of biological chemistry. 2001 ; 276 (17) : 14053-14058.
PMID 11278427
 
Apoptosis-linked gene 2-deficient mice exhibit normal T-cell development and function.
Jang IK, Hu R, Lacan´ E, D'Adamio L, Gu H
Molecular and cellular biology. 2002 ; 22 (12) : 4094-4100.
PMID 12024023
 
Structures, functions and molecular evolution of the penta-EF-hand Ca2+-binding proteins.
Maki M, Kitaura Y, Satoh H, Ohkouchi S, Shibata H
Biochimica et biophysica acta. 2002 ; 1600 (1-2) : 51-60.
PMID 12445459
 
Up-regulation of ALG-2 in hepatomas and lung cancer tissue.
la Cour JM, Mollerup J, Winding P, Tarabykina S, Sehested M, Berchtold MW
The American journal of pathology. 2003 ; 163 (1) : 81-89.
PMID 12819013
 
Properties of the co-chaperone protein p23 erroneously attributed to ALG-2 (apoptosis-linked gene 2).
Mollerup J, Krogh TN, Nielsen PF, Berchtold MW
FEBS letters. 2003 ; 555 (3) : 478-482.
PMID 14675759
 
Cytosolic prostaglandin E2 synthase/p23 but not apoptosis-linked gene 2 is downregulated in human atherosclerotic plaques.
Martinet W, Schrijvers DM, De Meyer GR, Herman AG, Kockx MM
Cardiovascular research. 2004 ; 61 (2) : 360-361.
PMID 14736553
 
ALG-2, a multifunctional calcium binding protein?
Tarabykina S, Mollerup J, Winding P, Berchtold MW
Frontiers in bioscience : a journal and virtual library. 2004 ; 9 : 1817-1832.
PMID 14977589
 
Ca2+ binding to EF hands 1 and 3 is essential for the interaction of apoptosis-linked gene-2 with Alix/AIP1 in ocular melanoma.
Subramanian L, Crabb JW, Cox J, Durussel I, Walker TM, van Ginkel PR, Bhattacharya S, Dellaria JM, Palczewski K, Polans AS
Biochemistry. 2004 ; 43 (35) : 11175-11186.
PMID 15366927
 
The penta-EF-hand protein ALG-2 interacts directly with the ESCRT-I component TSG101, and Ca2+-dependently co-localizes to aberrant endosomes with dominant-negative AAA ATPase SKD1/Vps4B.
Katoh K, Suzuki H, Terasawa Y, Mizuno T, Yasuda J, Shibata H, Maki M
The Biochemical journal. 2005 ; 391 (Pt 3) : 677-685.
PMID 16004603
 
Do Alix and ALG-2 really control endosomes for better or for worse?
Sadoul R
Biology of the cell / under the auspices of the European Cell Biology Organization. 2006 ; 98 (1) : 69-77.
PMID 16354163
 
The Ca2+-binding protein ALG-2 is recruited to endoplasmic reticulum exit sites by Sec31A and stabilizes the localization of Sec31A.
Yamasaki A, Tani K, Yamamoto A, Kitamura N, Komada M
Molecular biology of the cell. 2006 ; 17 (11) : 4876-4887.
PMID 16957052
 
ALG-2 directly binds Sec31A and localizes at endoplasmic reticulum exit sites in a Ca2+-dependent manner.
Shibata H, Suzuki H, Yoshida H, Maki M
Biochemical and biophysical research communications. 2007 ; 353 (3) : 756-763.
PMID 17196169
 
ALG-2 oscillates in subcellular localization, unitemporally with calcium oscillations.
la Cour JM, Mollerup J, Berchtold MW
Biochemical and biophysical research communications. 2007 ; 353 (4) : 1063-1067.
PMID 17214967
 
The apoptosis linked gene ALG-2 is dysregulated in tumors of various origin and contributes to cancer cell viability.
La Cour JM, Hoj BR, Mollerup J, Simon R, Sauter G, Berchtold MW
Molecular Oncology (. 2008.
 

Citation

This paper should be referenced as such :
Berchtold, M
PDCD6 (programmed cell death 6)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(5):379-381.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PDCD6ID43402ch5p15.html


External links

Nomenclature
HGNC (Hugo)PDCD6   8765
Cards
AtlasPDCD6ID43402ch5p15
Entrez_Gene (NCBI)PDCD6  10016  programmed cell death 6
AliasesALG-2; ALG2; PEF1B
GeneCards (Weizmann)PDCD6
Ensembl hg19 (Hinxton)ENSG00000249915 [Gene_View]  chr5:271736-315089 [Contig_View]  PDCD6 [Vega]
Ensembl hg38 (Hinxton)ENSG00000249915 [Gene_View]  chr5:271736-315089 [Contig_View]  PDCD6 [Vega]
ICGC DataPortalENSG00000249915
TCGA cBioPortalPDCD6
AceView (NCBI)PDCD6
Genatlas (Paris)PDCD6
WikiGenes10016
SOURCE (Princeton)PDCD6
Genomic and cartography
GoldenPath hg19 (UCSC)PDCD6  -     chr5:271736-315089 +  5p15.33   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PDCD6  -     5p15.33   [Description]    (hg38-Dec_2013)
EnsemblPDCD6 - 5p15.33 [CytoView hg19]  PDCD6 - 5p15.33 [CytoView hg38]
Mapping of homologs : NCBIPDCD6 [Mapview hg19]  PDCD6 [Mapview hg38]
OMIM601057   
Gene and transcription
Genbank (Entrez)AF035606 AK001917 AK024175 AK124302 AK128087
RefSeq transcript (Entrez)NM_001267556 NM_001267557 NM_001267558 NM_001267559 NM_013232
RefSeq genomic (Entrez)NC_000005 NC_018916 NT_006576 NW_004929321
Consensus coding sequences : CCDS (NCBI)PDCD6
Cluster EST : UnigeneHs.50823 [ NCBI ]
CGAP (NCI)Hs.50823
Alternative Splicing GalleryENSG00000249915
Gene ExpressionPDCD6 [ NCBI-GEO ]   PDCD6 [ EBI - ARRAY_EXPRESS ]   PDCD6 [ SEEK ]   PDCD6 [ MEM ]
Gene Expression Viewer (FireBrowse)PDCD6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)10016
GTEX Portal (Tissue expression)PDCD6
Protein : pattern, domain, 3D structure
UniProt/SwissProtO75340 (Uniprot)
NextProtO75340  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO75340
Splice isoforms : SwissVarO75340 (Swissvar)
PhosPhoSitePlusO75340
Domaine pattern : Prosite (Expaxy)EF_HAND_1 (PS00018)    EF_HAND_2 (PS50222)   
Domains : Interpro (EBI)EF-hand-dom_pair    EF_Hand_1_Ca_BS    EF_hand_dom   
Domain families : Pfam (Sanger)EF-hand_7 (PF13499)    EF-hand_8 (PF13833)   
Domain families : Pfam (NCBI)pfam13499    pfam13833   
Domain families : Smart (EMBL)EFh (SM00054)  
DMDM Disease mutations10016
Blocks (Seattle)PDCD6
PDB (SRS)2ZN8    2ZN9    2ZND    2ZNE    2ZRS    2ZRT    3AAJ    3AAK    3WXA   
PDB (PDBSum)2ZN8    2ZN9    2ZND    2ZNE    2ZRS    2ZRT    3AAJ    3AAK    3WXA   
PDB (IMB)2ZN8    2ZN9    2ZND    2ZNE    2ZRS    2ZRT    3AAJ    3AAK    3WXA   
PDB (RSDB)2ZN8    2ZN9    2ZND    2ZNE    2ZRS    2ZRT    3AAJ    3AAK    3WXA   
Structural Biology KnowledgeBase2ZN8    2ZN9    2ZND    2ZNE    2ZRS    2ZRT    3AAJ    3AAK    3WXA   
SCOP (Structural Classification of Proteins)2ZN8    2ZN9    2ZND    2ZNE    2ZRS    2ZRT    3AAJ    3AAK    3WXA   
CATH (Classification of proteins structures)2ZN8    2ZN9    2ZND    2ZNE    2ZRS    2ZRT    3AAJ    3AAK    3WXA   
SuperfamilyO75340
Human Protein AtlasENSG00000249915
Peptide AtlasO75340
HPRD03035
IPIIPI00025277   IPI00930304   IPI00443967   IPI00966787   IPI00967516   IPI00930049   IPI00966206   IPI00967847   IPI00965447   
Protein Interaction databases
DIP (DOE-UCLA)O75340
IntAct (EBI)O75340
FunCoupENSG00000249915
BioGRIDPDCD6
STRING (EMBL)PDCD6
ZODIACPDCD6
Ontologies - Pathways
QuickGOO75340
Ontology : AmiGOangiogenesis  positive regulation of endothelial cell proliferation  calcium-dependent cysteine-type endopeptidase activity  calcium ion binding  protein binding  nucleus  cytoplasm  endosome  endoplasmic reticulum  endoplasmic reticulum membrane  intracellular protein transport  activation of cysteine-type endopeptidase activity involved in apoptotic process  positive regulation of endothelial cell migration  negative regulation of vascular endothelial growth factor receptor signaling pathway  cytoplasmic vesicle  nuclear membrane  negative regulation of TOR signaling  cellular response to heat  vascular endothelial growth factor receptor-2 signaling pathway  identical protein binding  protein homodimerization activity  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  protein anchor  positive regulation of angiogenesis  protein dimerization activity  calcium-dependent protein binding  response to calcium ion  negative regulation of protein kinase B signaling  binding, bridging  extracellular exosome  endoplasmic reticulum exit site  apoptotic signaling pathway  
Ontology : EGO-EBIangiogenesis  positive regulation of endothelial cell proliferation  calcium-dependent cysteine-type endopeptidase activity  calcium ion binding  protein binding  nucleus  cytoplasm  endosome  endoplasmic reticulum  endoplasmic reticulum membrane  intracellular protein transport  activation of cysteine-type endopeptidase activity involved in apoptotic process  positive regulation of endothelial cell migration  negative regulation of vascular endothelial growth factor receptor signaling pathway  cytoplasmic vesicle  nuclear membrane  negative regulation of TOR signaling  cellular response to heat  vascular endothelial growth factor receptor-2 signaling pathway  identical protein binding  protein homodimerization activity  positive regulation of cysteine-type endopeptidase activity involved in apoptotic process  protein anchor  positive regulation of angiogenesis  protein dimerization activity  calcium-dependent protein binding  response to calcium ion  negative regulation of protein kinase B signaling  binding, bridging  extracellular exosome  endoplasmic reticulum exit site  apoptotic signaling pathway  
NDEx Network
Atlas of Cancer Signalling NetworkPDCD6
Wikipedia pathwaysPDCD6
Orthology - Evolution
OrthoDB10016
GeneTree (enSembl)ENSG00000249915
Phylogenetic Trees/Animal Genes : TreeFamPDCD6
Homologs : HomoloGenePDCD6
Homology/Alignments : Family Browser (UCSC)PDCD6
Gene fusions - Rearrangements
Fusion : MitelmanCLPTM1L/PDCD6 [5p15.33/5p15.33]  [t(5;5)(p15;p15)]  
Fusion : MitelmanPDCD6/TERT [5p15.33/5p15.33]  [t(5;5)(p15;p15)]  
Fusion: TCGACLPTM1L 5p15.33 PDCD6 5p15.33 KIRC
Fusion: TCGAPDCD6 5p15.33 TERT 5p15.33 KIRC
Polymorphisms : SNP, variants
NCBI Variation ViewerPDCD6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PDCD6
dbVarPDCD6
ClinVarPDCD6
1000_GenomesPDCD6 
Exome Variant ServerPDCD6
ExAC (Exome Aggregation Consortium)PDCD6 (select the gene name)
Genetic variants : HAPMAP10016
Genomic Variants (DGV)PDCD6 [DGVbeta]
Mutations
ICGC Data PortalPDCD6 
TCGA Data PortalPDCD6 
Broad Tumor PortalPDCD6
OASIS PortalPDCD6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPDCD6 
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 PDCD6
DgiDB (Drug Gene Interaction Database)PDCD6
DoCM (Curated mutations)PDCD6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PDCD6 (select a term)
intoGenPDCD6
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)5:271736-315089  ENSG00000249915
CONAN: Copy Number AnalysisPDCD6 
Mutations and Diseases : HGMDPDCD6
OMIM601057   
MedgenPDCD6
Genetic Testing Registry PDCD6
NextProtO75340 [Medical]
TSGene10016
GENETestsPDCD6
Huge Navigator PDCD6 [HugePedia]
snp3D : Map Gene to Disease10016
BioCentury BCIQPDCD6
ClinGenPDCD6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD10016
Chemical/Pharm GKB GenePA33115
Clinical trialPDCD6
Miscellaneous
canSAR (ICR)PDCD6 (select the gene name)
Probes
Litterature
PubMed80 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePDCD6
EVEXPDCD6
GoPubMedPDCD6
iHOPPDCD6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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