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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 aliasALG-2
MGC111017
MGC119050
MGC9123
PEF1B
LocusID (NCBI) 10016
Atlas_Id 43402
Location 5p15.33  [Link to chromosome band 5p15]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
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

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
 
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
 
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
 
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
 
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.
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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 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
 

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


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  CLPTM1L/PDCD6 (5p15)
PDCD6/TERT (5p15)


External links

Nomenclature
Cards
AtlasPDCD6ID43402ch5p15.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)10016
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


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indexed on : Thu Oct 18 17:47:00 CEST 2018

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