Disease relevance of PDCD6

• We found that ALG-2 was more than threefold overexpressed in rat liver hepatoma compared to normal rat liver using Western blot analysis, a result confirmed by immunohistochemical analysis [1].
• Up-regulation of ALG-2 in hepatomas and lung cancer tissue [1].

Psychiatry related information on PDCD6

• These findings suggest that ALG-2 may mediate Ca(2+)-regulated signals along the death pathway and that cell death may play a role in Alzheimer's disease [2].

High impact information on PDCD6

• Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3 [2].
• The Ca2+-binding Protein ALG-2 Is Recruited to Endoplasmic Reticulum Exit Sites by Sec31A and Stabilizes the Localization of Sec31A [3].
• These results suggest that peflin has features common to those of other PEF proteins (dimerization and translocation to membranes) and may modulate the function of ALG-2 in Ca(2+) signaling [4].
• Western blotting of the immunoprecipitates revealed that the 22-kDa protein corresponds to ALG-2 [4].
• Two forms of the apoptosis-linked protein ALG-2 with different Ca(2+) affinities and target recognition [5].

Biological context of PDCD6

• Co-transfection of PDCD6 and DAPk1 cDNA into a tumor cell line accelerated apoptosis via caspase-3 dependent pathway [6].
• To define the regulating mechanism of PDCD6 activity in the apoptotic pathway, we searched a human ovary cDNA library for a novel PDCD6 binding protein using a yeast two-hybrid system [6].
• The apoptosis-linked gene ALG-2 encodes a Ca(2+)-binding protein of the penta EF-hand family [5].
• Importantly, Raf-1 blocks the ASK1-dependent ALG-2 phosphorylation [7].
• ALG-2: a Ca2+ -binding modulator protein involved in cell proliferation and in cell death [8].

Anatomical context of PDCD6

• Gel filtration of the cytosolic fraction of Jurkat cells revealed co-elution of peflin and ALG-2 in fractions eluting earlier than recombinant ALG-2, further supporting the notion of heterodimerization of the two PEF proteins [4].
• ALG-2 and AIP1 colocalize in the cytosol and the presence of calcium is an indispensable requisite for their association [9].
• Staining of four different lung cancer tissue microarrays including specimens of 263 patients showed that ALG-2 is mainly localized to epithelial cells and significantly up-regulated in small-cell lung cancers and in non-small-cell lung cancers [1].
• ALG-2 is a 22-kDa calcium-binding protein necessary for cell death induced by different stimuli in 3DO T-cell hybridoma [9].
• The glioma-associated protein SETA interacts with AIP1/Alix and ALG-2 and modulates apoptosis in astrocytes [10].

Associations of PDCD6 with chemical compounds

• Surprisingly, peflin dissociated from ALG-2 in the presence of Ca(2+) [4].
• The mammalian adaptor protein Alix [ALG-2 (apoptosis-linked-gene-2 product)-interacting protein X] belongs to a conserved family of proteins that have in common an N-terminal Bro1 domain and a C-terminal PRD (proline-rich domain), both of which mediate partner protein interactions [11].
• In this work, we show that in the ALG-2-depleted clones the ICE/Ced-3 proteases are normally activated upon TCR, Fas, and dexamethasone stimulation, as determined by cleavage of the endogenous substrate poly(ADP-ribose) polymerase and of a fluorogenic substrate [12].
• In contrast, treatment of cells with the membrane-permeant Ca(2+) chelator BAPTA-AM led to a dispersion of ALG-2 throughout the cells and to a significant loss of Sec31A in the perinuclear region [13].
• Biochemical and immunofluorescent microscopic analyses showed that ALG-2 was enriched at the Sec31A-localizing membrane compartments upon stimulation with the Ca(2+) ionophore A23187 [13].

Physical interactions of PDCD6

• ASK1 failed to bind to an isotype of ALG-2 found in the liver, ALG-2,1, in which two amino acids (Gly-121 and Phe-122) are deleted [14].
• The ALG-2/AIP-complex, a modulator at the interface between cell proliferation and cell death? A hypothesis [15].
• Based on these results, together with the results of in vitro binding assay with mutant ALG-2 and Alix proteins, we propose a Ca(2+)/EF3-driven arginine switch mechanism for ALG-2 binding to Alix [16].

Enzymatic interactions of PDCD6

• Our further studies showed that Raf-1 phosphorylated ALG-2 in an in vitro kinase assay [7].

Other interactions of PDCD6

• In the course of identifying new substrates of Raf-1, we found that the Raf-1 kinase domain interacted with apoptosis-linked gene-2 (ALG-2) in yeast two-hybrid system [7].
• This observation supports the hypothesis, formulated on the basis of the structure of a homologous protein ALG-2 which shows significant differences in the orientation of EF4 and EF5 compared with grancalcin, that calcium is a necessary factor but not sufficient alone for inducing a significant conformational change in PEF proteins [17].
• The role of Ca(2+) as one of the key regulators of the cell is discussed with respect to two recently discovered proteins, ALG-2 and AIP, of which the former is a Ca(2+)-binding protein, and the latter is substrate to various kinases [15].
• Serial gene analysis of expression revealed the downregulation of voltage-dependent anion channels 1 and 2 genes and the upregulation of the cytochrome c oxidase and calcium binding protein genes (calpactin, calgizzarin and programmed cell death 6) [18].
• It was 85% at 1 year, 70% at 3 years, and 62% at 5 years in the ALG 2 regimen group and 87% at 1 year and 67% at 3 years in the ALG 3 regimen group [19].

Analytical, diagnostic and therapeutic context of PDCD6

• This was confirmed by Western blotting of the immunoprecipitates of epitope-tagged peflin or ALG-2 whose cDNA expression constructs were transfected to human embryonic kidney (HEK) 293 cells [4].
• The specificity of the antibody was shown by preabsorbtion experiments and on ALG-2-deficient cells using Western blot analysis and immunohistochemistry [1].
• Crystallization and preliminary crystallographic studies of an apoptosis-linked calcium-binding protein ALG-2 [20].
• Intracellular localization of the penta-EF-hand Ca(2+)-binding protein ALG-2 in HeLa cells was investigated by immunofluorescent confocal microscopy using a polyclonal antibody [13].

References