Atlas of Genetics and Cytogenetics in Oncology and Haematology
PDCD6 (programmed cell death 6)
| Identity |
| Other names | ALG-2 |
| MGC111017 | |
| MGC119050 | |
| MGC9123 | |
| PEF1B | |
| HGNC (Hugo) | PDCD6 |
| Location | 5p15.33 |
| Location_base_pair | Starts at 324736 and ends at 368089 bp from pter ( according to hg18-Mar_2006) [Mapping] |
| 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 |
| 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. |
| External links |
| Bibliography |
| Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. |
| Vito P, LacanˆƯ 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, Mˆ½ller 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, Lacanˆ° 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. |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 01-2008 | Martin W Berchtold |
| Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark |
| Citation |
| This paper should be referenced as such : |
| Berchtold MW . PDCD6 (programmed cell death 6). Atlas Genet Cytogenet Oncol Haematol. January 2008 . URL : http://AtlasGeneticsOncology.org/Genes/PDCD6ID43402ch5p15.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Sat Feb 6 13:44:08 CET 2010 |
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