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PDCD4 (Programmed Cell Death 4)

Identity

Other namesTIS
H731
DUG
MA3
HGNC (Hugo) PDCD4
LocusID (NCBI) 27250
Location 10q25.2
Location_base_pair Starts at 112631553 and ends at 112659764 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description Single gene of 11 exons spanning 21 Kbp.
Transcription 2.4 Kb mRNA; PDCD4 mRNA levels modulated by apoptosis inducers, retinoids, and other extracellular signals.
Pseudogene None.

Protein

 
Description 469 amino acids; 52 kDa predicted; found to be 50-64 kDa in mouse and human tissues and cell lines; contains two highly conserved helical MA3 domains each about 130 amino acids long; contains two Akt/S6K phosphorylation sites, one N-terminal and one C-terminal; contains two nuclear export signals.
Expression PDCD4 expressed in all tissues tested. Shows inverse expression with proliferation marker PCNA, higher expression in differentiated areas. Protein expression is regulated by PI3K/Akt/S6K and MEK/ERK signaling that programs PDCD4 for ubiquitylation and proteasome degradation.
Localisation Nuclear and cytoplasmic. Inhibits translation in cytoplasm.
Function PDCD4 inhibits translation initiation mRNA-specifically by interacting with translation initiation factor eIF4A and competing with eIF4Gc for binding to eIF4A. As a consequence of inhibiting translation initiation, inhibits AP-1 dependent transcription via targeting Jun kinase signaling. Found to be a tumor suppressor in PDCD4 transgenic and deficient mice.
Homology Conserved MA3 domain also found in translation initiation factor eIF4G, a scaffold protein; death associated protein DAP5; and NOM 1, a nucleolar protein.

Mutations

Note No evidence for mutational inactivation in cancer.

Implicated in

Entity Human tumors
Disease PDCD4 expression attenuated with progression in human tumors of the lung, colon, prostate and breast; diagnostic and prognostic for colon cancer staging with decreased expression in adenomas and a further decrease in stage 1 adenocarcinomas. Transgenic PDCD4 expression attenuates skin tumorigenesis and tumor progression in transgenic mice; PDCD4 deficiency increases tumor multiplicity and tumor incidence.
  

External links

Nomenclature
HGNC (Hugo)PDCD4   8763
Cards
AtlasPDCD4ID41675ch10q24
Entrez_Gene (NCBI)PDCD4  27250  programmed cell death 4 (neoplastic transformation inhibitor)
GeneCards (Weizmann)PDCD4
Ensembl (Hinxton)ENSG00000150593 [Gene_View]  chr10:112631553-112659764 [Contig_View]  PDCD4 [Vega]
ICGC DataPortalENSG00000150593
AceView (NCBI)PDCD4
Genatlas (Paris)PDCD4
WikiGenes27250
SOURCE (Princeton)NM_001199492 NM_014456 NM_145341
Genomic and cartography
GoldenPath (UCSC)PDCD4  -  10q25.2   chr10:112631553-112659764 +  10q24   [Description]    (hg19-Feb_2009)
EnsemblPDCD4 - 10q24 [CytoView]
Mapping of homologs : NCBIPDCD4 [Mapview]
OMIM608610   
Gene and transcription
Genbank (Entrez)AK223623 AK296753 AK312540 AK315295 AL049932
RefSeq transcript (Entrez)NM_001199492 NM_014456 NM_145341
RefSeq genomic (Entrez)AC_000142 NC_000010 NC_018921 NT_030059 NW_001838006 NW_004929376
Consensus coding sequences : CCDS (NCBI)PDCD4
Cluster EST : UnigeneHs.711490 [ NCBI ]
CGAP (NCI)Hs.711490
Alternative Splicing : Fast-db (Paris)GSHG0003681
Alternative Splicing GalleryENSG00000150593
Gene ExpressionPDCD4 [ NCBI-GEO ]     PDCD4 [ SEEK ]   PDCD4 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ53EL6 (Uniprot)
NextProtQ53EL6  [Medical]
With graphics : InterProQ53EL6
Splice isoforms : SwissVarQ53EL6 (Swissvar)
Domaine pattern : Prosite (Expaxy)MI (PS51366)   
Domains : Interpro (EBI)ARM-type_fold    Initiation_fac_eIF4g_MI    MIF4-like_typ_1/2/3   
Related proteins : CluSTrQ53EL6
Domain families : Pfam (Sanger)MA3 (PF02847)   
Domain families : Pfam (NCBI)pfam02847   
Domain families : Smart (EMBL)MA3 (SM00544)  
DMDM Disease mutations27250
Blocks (Seattle)Q53EL6
PDB (SRS)2GGF    2KZT    2RG8    2ZU6    3EIJ   
PDB (PDBSum)2GGF    2KZT    2RG8    2ZU6    3EIJ   
PDB (IMB)2GGF    2KZT    2RG8    2ZU6    3EIJ   
PDB (RSDB)2GGF    2KZT    2RG8    2ZU6    3EIJ   
Human Protein AtlasENSG00000150593
Peptide AtlasQ53EL6
HPRD10549
IPIIPI00290110   IPI00647084   IPI00240675   
Protein Interaction databases
DIP (DOE-UCLA)Q53EL6
IntAct (EBI)Q53EL6
FunCoupENSG00000150593
BioGRIDPDCD4
IntegromeDBPDCD4
STRING (EMBL)PDCD4
Ontologies - Pathways
QuickGOQ53EL6
Ontology : AmiGORNA binding  protein binding  nucleus  nucleus  nucleus  nucleolus  cytoplasm  cytosol  apoptotic process  cell aging  negative regulation of JUN kinase activity  negative regulation of cell cycle  negative regulation of transcription, DNA-templated  negative regulation of transcription, DNA-templated  
Ontology : EGO-EBIRNA binding  protein binding  nucleus  nucleus  nucleus  nucleolus  cytoplasm  cytosol  apoptotic process  cell aging  negative regulation of JUN kinase activity  negative regulation of cell cycle  negative regulation of transcription, DNA-templated  negative regulation of transcription, DNA-templated  
Pathways : KEGGProteoglycans in cancer    MicroRNAs in cancer   
Protein Interaction DatabasePDCD4
Wikipedia pathwaysPDCD4
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)PDCD4
SNP (GeneSNP Utah)PDCD4
SNP : HGBasePDCD4
Genetic variants : HAPMAPPDCD4
1000_GenomesPDCD4 
ICGC programENSG00000150593 
CONAN: Copy Number AnalysisPDCD4 
Somatic Mutations in Cancer : COSMICPDCD4 
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
DECIPHER (Syndromes)10:112631553-112659764
Mutations and Diseases : HGMDPDCD4
OMIM608610   
MedgenPDCD4
GENETestsPDCD4
Disease Genetic AssociationPDCD4
Huge Navigator PDCD4 [HugePedia]  PDCD4 [HugeCancerGEM]
Genomic VariantsPDCD4  PDCD4 [DGVbeta]
Exome VariantPDCD4
dbVarPDCD4
ClinVarPDCD4
snp3D : Map Gene to Disease27250
General knowledge
Homologs : HomoloGenePDCD4
Homology/Alignments : Family Browser (UCSC)PDCD4
Phylogenetic Trees/Animal Genes : TreeFamPDCD4
Chemical/Protein Interactions : CTD27250
Chemical/Pharm GKB GenePA33113
Clinical trialPDCD4
Cancer Resource (Charite)ENSG00000150593
Other databases
Probes
Litterature
PubMed152 Pubmed reference(s) in Entrez
CoreMinePDCD4
GoPubMedPDCD4
iHOPPDCD4

Bibliography

Differential transcriptional regulation of CD161 and a novel gene, 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells.
Azzoni L, Zatsepina O, Abebe B, Bennett IM, Kanakaraj P, Perussia B
Journal of immunology (Baltimore, Md. : 1950). 1998 ; 161 (7) : 3493-3500.
PMID 9759869
 
Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation.
Cmarik JL, Min H, Hegamyer G, Zhan S, Kulesz-Martin M, Yoshinaga H, Matsuhashi S, Colburn NH
Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (24) : 14037-14042.
PMID 10570194
 
The chicken Pdcd4 gene is regulated by v-Myb.
Schlichter U, Burk O, Worpenberg S, Klempnauer KH
Oncogene. 2001 ; 20 (2) : 231-239.
PMID 11313950
 
A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-kappaB or ODC transactivation.
Yang HS, Jansen AP, Nair R, Shibahara K, Verma AK, Cmarik JL, Colburn NH
Oncogene. 2001 ; 20 (6) : 669-676.
PMID 11314000
 
Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor.
Zhang Z, DuBois RN
Oncogene. 2001 ; 20 (33) : 4450-4456.
PMID 11494140
 
Targeted disruption of c-myb in the chicken pre B-cell line DT40.
Appl H, Klempnauer KH
Oncogene. 2002 ; 21 (19) : 3076-3081.
PMID 12082539
 
The transformation suppressor protein Pdcd4 shuttles between nucleus and cytoplasm and binds RNA.
Bhm M, Sawicka K, Siebrasse JP, Brehmer-Fastnacht A, Peters R, Klempnauer KH
Oncogene. 2003 ; 22 (31) : 4905-4910.
PMID 12894233
 
Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis.
Chen Y, Knsel T, Kristiansen G, Pietas A, Garber ME, Matsuhashi S, Ozaki I, Petersen I
The Journal of pathology. 2003 ; 200 (5) : 640-646.
PMID 12898601
 
The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation.
Yang HS, Jansen AP, Komar AA, Zheng X, Merrick WC, Costes S, Lockett SJ, Sonenberg N, Colburn NH
Molecular and cellular biology. 2003 ; 23 (1) : 26-37.
PMID 12482958
 
Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation.
Yang HS, Knies JL, Stark C, Colburn NH
Oncogene. 2003 ; 22 (24) : 3712-3720.
PMID 12802278
 
Promising molecular targets for cancer prevention: AP-1, NF-kappa B and Pdcd4.
Young MR, Yang HS, Colburn NH
Trends in molecular medicine. 2003 ; 9 (1) : 36-41.
PMID 12524209
 
Characterization of programmed cell death 4 in multiple human cancers reveals a novel enhancer of drug sensitivity.
Jansen AP, Camalier CE, Stark C, Colburn NH
Molecular cancer therapeutics. 2004 ; 3 (2) : 103-110.
PMID 14985450
 
A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A.
Yang HS, Cho MH, Zakowicz H, Hegamyer G, Sonenberg N, Colburn NH
Molecular and cellular biology. 2004 ; 24 (9) : 3894-3906.
PMID 15082783
 
Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis.
Jansen AP, Camalier CE, Colburn NH
Cancer research. 2005 ; 65 (14) : 6034-6041.
PMID 16024603
 
Akt phosphorylates and regulates Pdcd4 tumor suppressor protein.
Palamarchuk A, Efanov A, Maximov V, Aqeilan RI, Croce CM, Pekarsky Y
Cancer research. 2005 ; 65 (24) : 11282-11286.
PMID 16357133
 
S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth.
Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M
Science (New York, N.Y.). 2006 ; 314 (5798) : 467-471.
PMID 17053147
 
Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4.
Hilliard A, Hilliard B, Zheng SJ, Sun H, Miwa T, Song W, Gke R, Chen YH
Journal of immunology (Baltimore, Md. : 1950). 2006 ; 177 (11) : 8095-8102.
PMID 17114484
 
Aerosol delivery of urocanic acid-modified chitosan/programmed cell death 4 complex regulated apoptosis, cell cycle, and angiogenesis in lungs of K-ras null mice.
Jin H, Kim TH, Hwang SK, Chang SH, Kim HW, Anderson HK, Lee HW, Lee KH, Colburn NH, Yang HS, Cho MH, Cho CS
Molecular cancer therapeutics. 2006 ; 5 (4) : 1041-1049.
PMID 16648576
 
Signal transduction. Protein synthesis and oncogenesis meet again.
Sonenberg N, Pause A
Science (New York, N.Y.). 2006 ; 314 (5798) : 428-429.
PMID 17053135
 
Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion.
Yang HS, Matthews CP, Clair T, Wang Q, Baker AR, Li CC, Tan TH, Colburn NH
Molecular and cellular biology. 2006 ; 26 (4) : 1297-1306.
PMID 16449643
 
Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma.
Zhang H, Ozaki I, Mizuta T, Hamajima H, Yasutake T, Eguchi Y, Ideguchi H, Yamamoto K, Matsuhashi S
Oncogene. 2006 ; 25 (45) : 6101-6112.
PMID 16682950
 
Structural basis for inhibition of translation by the tumor suppressor Pdcd4.
LaRonde-LeBlanc N, Santhanam AN, Baker AR, Wlodawer A, Colburn NH
Molecular and cellular biology. 2007 ; 27 (1) : 147-156.
PMID 17060447
 
Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors.
Leupold JH, Yang HS, Colburn NH, Asangani I, Post S, Allgayer H
Oncogene. 2007 ; 26 (31) : 4550-4562.
PMID 17297470
 
Programmed cell death-4 tumor suppressor protein contributes to retinoic acid-induced terminal granulocytic differentiation of human myeloid leukemia cells.
Ozpolat B, Akar U, Steiner M, Zorrilla-Calancha I, Tirado-Gomez M, Colburn N, Danilenko M, Kornblau S, Berestein GL
Molecular cancer research : MCR. 2007 ; 5 (1) : 95-108.
PMID 17259349
 
Structure of the C-terminal MA-3 domain of the tumour suppressor protein Pdcd4 and characterization of its interaction with eIF4A.
Waters LC, Veverka V, Bhm M, Schmedt T, Choong PT, Muskett FW, Klempnauer KH, Carr MD
Oncogene. 2007 ; 26 (34) : 4941-4950.
PMID 17310995
 
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Contributor(s)

Written08-2007Nancy H Colburn
Laboratory of Cancer Prevention, National Cancer Institute, Bldg. 576, Rm. 101, Frederick, MD 21702-1201, USA

Citation

This paper should be referenced as such :
Colburn, NH
PDCD4 (programmed cell death 4)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):125-126.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/PDCD4ID41675ch10q24.html

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indexed on : Sat Nov 8 16:24:16 CET 2014

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