Alternative titles; symbols
HGNC Approved Gene Symbol: PDCD6
Cytogenetic location: 5p15.33 Genomic coordinates (GRCh38) : 5:271,646-314,974 (from NCBI)
The normal development of multicellular organisms is dependent on the removal of 'unwanted' cells by a genetically controlled process termed programmed cell death (PCD) that is typically mediated by apoptosis. Dysregulation of this process contributes to or is suspected of contributing to the pathogenesis of several diseases, including neurodegenerative disorders (see 253300), cancer (see 151430), autoimmune disease (see FAS; 134637), congenital malformations (see 185900), and immunodeficiency. Vito et al. (1996) designed a method to select genes involved in apoptosis, using as a model PCD induced in a mouse T-cell hybridoma by T-cell receptor cross-linking. The selection system, which they named 'death trap,' is based on the assumption that a transfected cDNA library constructed in the mammalian expression vector pLTP should protect some recipient cells from death. Such inhibition may depend on inactivation of apoptotic genes by either antisense RNA or dominant-negative mutants or on overexpression of proteins with antiapoptotic activity. Using this system, they isolated 6 cDNA clones, designated apoptosis-linked genes (Alg1 to Alg6), that were able to inhibit PCR-induced cell death in a transient transfection assay. Vito et al. (1996) found that a 435-bp mouse Alg2 cDNA identified a single 1.3-kb transcript in mouse T-cell hybridoma cells and in all adult mouse tissues analyzed. The thymus and liver showed the most expression, whereas the testis and skeletal muscles showed the least. The full-length Alg2 cDNA has an open reading frame predicted to encode a protein of 191 amino acids.
Vito et al. (1996) showed that mouse Alg2 is a Ca(2+)-binding protein required for T-cell receptor-, Fas-, and glucocorticoid-induced cell death.
Using immunoblot analysis, Jung et al. (2001) showed that ALG2 is expressed as a 22-kD protein before FAS activation and thereafter as a 19-kD protein, probably due to N-terminal cleavage. Confocal microscopy and immunoprecipitation analysis demonstrated that ALG2 translocates from the cytoplasmic membrane to the cytosol during FAS-induced apoptosis and then dissociates from FAS after activation. Yeast 2-hybrid and GST pull-down analyses confirmed that ALG2 interacts with FAS.
Kitaura et al. (2001) found that ALG2 coimmunoprecipitated with peflin (PEF1; 610033) from Jurkat human T cells and from transfected HEK293 cells. Peflin dissociated from ALG2 in the presence of Ca(2+), and the N-terminal hydrophobic domain of peflin was not essential for heterodimerization. Peflin and ALG2 colocalized in the cytoplasm, but ALG2 was also detected in nuclei, as revealed by immunofluorescence staining and subcellular fractionation. Peflin was recovered in the cytosolic fraction in the absence of Ca(2+) and in the membrane/cytoskeletal fraction in the presence of Ca(2+). Kitaura et al. (2001) concluded that peflin may modulate the function of ALG2 in Ca(2+) signaling.
Jang et al. (2002) generated viable and fertile mice deficient in Alg2 by gene targeting. The mice were developmentally and immunologically normal. Analysis of apoptotic responses demonstrated that the Alg2 deficiency resulted in no block of apoptosis induced by TCR, FAS, or dexamethasone signals. Jang et al. (2002) concluded that ALG2 is physiologically dispensable in these signaling pathways and that other functionally redundant proteins might exist in mammalian cells.
Jang, I. K., Hu, R., Lacana, E., D'Adamio, L., Gu, H. Apoptosis-linked gene 2-deficient mice exhibit normal T-cell development and function. Molec. Cell. Biol. 22: 4094-4100, 2002. [PubMed: 12024023] [Full Text: https://doi.org/10.1128/MCB.22.12.4094-4100.2002]
Jung, Y.-S., Kim, K.-S., Kim, K. D., Lim, J.-S., Kim, J.-W., Kim, E. Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells. Biochem. Biophys. Res. Commun. 288: 420-426, 2001. [PubMed: 11606059] [Full Text: https://doi.org/10.1006/bbrc.2001.5769]
Kitaura, Y., Matsumoto, S., Satoh, H., Hitomi, K., Maki, M. Peflin and ALG-2, members of the penta-EF-hand protein family, form a heterodimer that dissociates in a Ca(2+)-dependent manner. J. Biol. Chem. 276: 14053-14058, 2001. [PubMed: 11278427] [Full Text: https://doi.org/10.1074/jbc.M008649200]
Vito, P., Lacana, E., D'Adamio, L. Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science 271: 521-524, 1996. [PubMed: 8560270] [Full Text: https://doi.org/10.1126/science.271.5248.521]