PDCD4 (Programmed Cell Death 4)

Identity

Other names	TIS
	H731
	DUG
	MA3
Hugo	PDCD4
Location	10q24

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
Hugo	PDCD4
GDB	PDCD4
Entrez_Gene	PDCD4  27250  programmed cell death 4 (neoplastic transformation inhibitor)
	Cards
Atlas	PDCD4ID41675ch10q24
GeneCards	PDCD4
Ensembl	PDCD4 [Search_View]   ENSG00000150593 [Gene_View]
Genatlas	PDCD4
GeneLynx	PDCD4
eGenome	PDCD4
euGene	27250
	Genomic and cartography
GoldenPath	PDCD4  -  10q24   chr10:112621586-112649753 +  10q24   [Description]    (hg18-Mar_2006)
Ensembl	PDCD4 - 10q24 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	PDCD4
	Gene and transcription
Genbank	AK223623 [ ENTREZ ]
Genbank	AL049932 [ ENTREZ ]
Genbank	BC015036 [ ENTREZ ]
Genbank	BC026104 [ ENTREZ ]
Genbank	BC031049 [ ENTREZ ]
RefSeq	NM_014456 [ SRS ]    NM_014456 [ ENTREZ ]
RefSeq	NM_145341 [ SRS ]    NM_145341 [ ENTREZ ]
RefSeq	AC_000053 [ SRS ]    AC_000053 [ ENTREZ ]
RefSeq	NC_000010 [ SRS ]    NC_000010 [ ENTREZ ]
RefSeq	NT_030059 [ SRS ]    NT_030059 [ ENTREZ ]
RefSeq	NW_924884 [ SRS ]    NW_924884 [ ENTREZ ]
AceView	PDCD4 AceView - NCBI
Unigene	Hs.232543 [ SRS ]    Hs.232543 [ NCBI ]     HS232543 [ spliceNest ]
Fast-db	16753 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q53EL6 [ SRS]    Q53EL6 [ EXPASY ]     Q53EL6 [ INTERPRO ]
Interpro	IPR003891 IF_eIF4G_MA3 [ SRS ]    IPR003891 IF_eIF4G_MA3 [ EBI ]
CluSTr	Q53EL6
Pfam	PF02847 MA3 [ SRS ]    PF02847 MA3 [ Sanger ]    pfam02847 [ NCBI-CDD ]
Smart	SM00544 MA3 [EMBL]
Blocks	Q53EL6
PDB	2GGF [ SRS ]    2GGF [ PdbSum ],   2GGF [ IMB ]   2GGF [ RSDB ]
HPRD	10549
	Protein Interaction databases
DIP	Q53EL6
IntAct	Q53EL6
	Polymorphism : SNP, mutations, diseases
OMIM	608610    [ map ]
GENECLINICS	608610
SNP	PDCD4 [dbSNP-NCBI]
SNP	NM_014456 [SNP-NCI]
SNP	NM_145341 [SNP-NCI]
SNP	PDCD4 [GeneSNPs - Utah]  PDCD4] [HGBASE - SRS]
HAPMAP	PDCD4 [HAPMAP]
COSMIC	PDCD4 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	PDCD4
	General knowledge
Family Browser	PDCD4 [UCSC Family Browser]
SOURCE	NM_014456
SOURCE	NM_145341
SMD	Hs.232543
SAGE	Hs.232543
GO	RNA binding [Amigo]  RNA binding
GO	protein binding [Amigo]  protein binding
GO	nucleus [Amigo]  nucleus
GO	nucleus [Amigo]  nucleus
GO	cytoplasm [Amigo]  cytoplasm
GO	cytosol [Amigo]  cytosol
GO	apoptosis [Amigo]  apoptosis
GO	cell cycle [Amigo]  cell cycle
GO	cell aging [Amigo]  cell aging
GO	negative regulation of transcription [Amigo]  negative regulation of transcription
GO	negative regulation of transcription [Amigo]  negative regulation of transcription
GO	negative regulation of JNK activity [Amigo]  negative regulation of JNK activity
GO	negative regulation of cell cycle [Amigo]  negative regulation of cell cycle
PubGene	PDCD4
TreeFam	PDCD4
CTD	27250 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	PDCD4 Related clones (RZPD - Berlin)
	PubMed
PubMed	26 Pubmed reference(s) in LocusLink

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.

B��hm 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, Kn��sel 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, G��ke 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, B��hm M, Schmedt T, Choong PT, Muskett FW, Klempnauer KH, Carr MD

Oncogene. 2007 ; 26 (34) : 4941-4950.

PMID 17310995

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Last year publications	automatic search in PubMed

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Contributor(s)

Written	08-2007	Nancy 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. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PDCD4ID41675ch10q24.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:25:55 2008