PDCD6 (programmed cell death 6)

2008-01-01   Martin W Berchtold 

Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark

Identity

HGNC
LOCATION
5p15.33
LOCUSID
ALIAS
ALG-2,ALG2,PEF1B
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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

Entity name
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

Pubmed IDLast YearTitleAuthors
120240232002Apoptosis-linked gene 2-deficient mice exhibit normal T-cell development and function.Jang IK et al
115251642001Structure of apoptosis-linked protein ALG-2: insights into Ca2+-induced changes in penta-EF-hand proteins.Jia J et al
160046032005The 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 et al
112784272001Peflin and ALG-2, members of the penta-EF-hand protein family, form a heterodimer that dissociates in a Ca2+-dependent manner.Kitaura Y et al
124454592002Structures, functions and molecular evolution of the penta-EF-hand Ca2+-binding proteins.Maki M et al
98326221998Calcium-induced exposure of a hydrophobic surface of mouse ALG-2, which is a member of the penta-EF-hand protein family.Maki M et al
147365532004Cytosolic prostaglandin E2 synthase/p23 but not apoptosis-linked gene 2 is downregulated in human atherosclerotic plaques.Martinet W et al
102005581999Alix, a novel mouse protein undergoing calcium-dependent interaction with the apoptosis-linked-gene 2 (ALG-2) protein.Missotten M et al
146757592003Properties of the co-chaperone protein p23 erroneously attributed to ALG-2 (apoptosis-linked gene 2).Mollerup J et al
163541632006Do Alix and ALG-2 really control endosomes for better or for worse?Sadoul R et al
171961692007ALG-2 directly binds Sec31A and localizes at endoplasmic reticulum exit sites in a Ca2+-dependent manner.Shibata H et al
153669272004Ca2+ 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 et al
149775892004ALG-2, a multifunctional calcium binding protein?Tarabykina S et al
85602701996Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3.Vito P et al
98805301999Cloning of AIP1, a novel protein that associates with the apoptosis-linked gene ALG-2 in a Ca2+-dependent reaction.Vito P et al
169570522006The Ca2+-binding protein ALG-2 is recruited to endoplasmic reticulum exit sites by Sec31A and stabilizes the localization of Sec31A.Yamasaki A et al
172149672007ALG-2 oscillates in subcellular localization, unitemporally with calcium oscillations.la Cour JM et al

Other Information

Locus ID:

NCBI: 10016
MIM: 601057
HGNC: 8765
Ensembl: ENSG00000249915

Variants:

dbSNP: 10016
ClinVar: 10016
TCGA: ENSG00000249915
COSMIC: PDCD6

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000249915ENST00000264933O75340
ENSG00000249915ENST00000505221O75340
ENSG00000249915ENST00000505526D6RA21
ENSG00000249915ENST00000507473H0Y9X3
ENSG00000249915ENST00000507528O75340
ENSG00000249915ENST00000509581Q86W51
ENSG00000249915ENST00000614778A0A024QZ42
ENSG00000249915ENST00000618970A0A087WZ38
ENSG00000249915ENST00000628729D6RA21

Expression (GTEx)

0
10
20
30
40
50
60
70

References

Pubmed IDYearTitleCitations
255343482014Mechanism of Ca²⁺-triggered ESCRT assembly and regulation of cell membrane repair.59
169570522006The Ca2+-binding protein ALG-2 is recruited to endoplasmic reticulum exit sites by Sec31A and stabilizes the localization of Sec31A.36
198644162009Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent interactor of mucolipin-1.36
171961692007ALG-2 directly binds Sec31A and localizes at endoplasmic reticulum exit sites in a Ca2+-dependent manner.30
189570602008Identification of prognostic biomarkers in gastric cancer using endoscopic biopsy samples.29
128190132003Up-regulation of ALG-2 in hepatomas and lung cancer tissue.25
189361012008Alix and ALG-2 are involved in tumor necrosis factor receptor 1-induced cell death.24
189406112008Structural basis for Ca2+ -dependent formation of ALG-2/Alix peptide complex: Ca2+/EF3-driven arginine switch mechanism.22
116060592001Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells.21
118839392002ALG-2 interacts with the amino-terminal domain of annexin XI in a Ca(2+)-dependent manner.21

Citation

Martin W Berchtold

PDCD6 (programmed cell death 6)

Atlas Genet Cytogenet Oncol Haematol. 2008-01-01

Online version: http://atlasgeneticsoncology.org/gene/43402/pdcd6