Apoptosis-Linked Gene 2-Deficient Mice Exhibit Normal T-Cell Development and Function

Abstract

The apoptosis-linked gene product, ALG-2, is a member of the family of intracellular Ca 2؉ -binding proteins and a part of the apoptotic machinery controlled by T-cell receptor (TCR), Fas, and glucocorticoid signals. To explore the physiologic function of ALG-2 in T-cell development and function, we generated mice harboring a null mutation in the alg-2 gene. The alg-2 null mutant mice were viable and fertile and showed neither gross developmental abnormality nor immune dysfunction. Analyses of apoptotic responses of ALG-2-deficient T cells demonstrated that ALG-2 deficiency failed to block apoptosis induced by TCR, Fas, or dexamethasone signals. These findings indicate that ALG-2 is physiologically dispensable for apoptotic responses induced by the above signaling pathways and suggest that other functionally redundant proteins might exist in mammalian cells.Apoptosis is a unique biological process of multicellular organisms and one of the driving forces underlying tissue/ organ remodeling during animal development. This process also plays an important role during immune system development and function (1). Under physiological conditions, apoptotic response of lymphocytes is elicited by specialized molecular networks comprising of multiple signaling pathways and appears to be pivotal for shaping lymphocyte repertoires and preventing autoimmune diseases (8). Although large numbers of molecules involved in such networks have been identified recently (28), regulation and coordination between these molecules during immune system development and function remain elusive.ALG-2 is a 22-kDa Ca 2ϩ -binding protein belonging to the penta-EF (PEF) hand protein family that contains the Ca 2ϩ -binding helix-loop-helix structure (14,15,25). The PEF hand protein family includes peflin, sorcin, and grancalcin, as well as the large and small subunits of calpains (2,10,15,24). ALG-2 is ubiquitously expressed in mouse tissues, with its highest level of expression detected in thymus and liver. Recent data from T-cell lines indicate that ALG-2 protein plays a critical role for T-cell receptor (TCR)-, Fas-, and glucocorticoid-induced apoptosis, because depletion of ALG-2 in these cells blocks apoptosis whereas its overexpression significantly promotes apoptosis induced by these signals (5, 25). Although it is unclear how ALG-2 affects apoptosis of lymphocytes, evidence indicates that ALG-2 becomes rapidly associated with ALG-2-interacting protein-1 (AIP-1), a proapoptotic protein in a Ca 2ϩ -dependent manner, suggesting that the regulation is likely controlled by a secondary messenger, Ca 2ϩ (17,26). Detailed biochemical analysis also places ALG-2 downstream of the ICE/Ced-3 signaling cascade activated by TCR, Fas, and dexamethasone stimulation (11).To study the function of ALG-2 under physiological conditions, we generated ALG-2-deficient mice by using the gene targeting approach. Our data indicate that the general development and survival of mutant mice, as well as their immune system development and differentiation, appear to be nor...

Structure and function of ALG-2, a penta-EF-hand calcium-dependent adaptor protein

“…Regardless of the original cloning report of ALG-2 cDNA in a screen for genes involved in cell death [11], ALG-2-deficient mice generated by the same group showed no abnormality in development and immune functions [64]. Nevertheless, ALG-2 has been suggested to work in cell death during ER stress [65].…”

Genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features

“…During FAS-induced apoptosis, PDCD6, which is a 22-kDa protein, is cleaved in its N-terminus to yield a 19-kDa protein and translocates from the cytoplasmic membrane to the cytosol (28). More recent work questioned the need of PDCD6 for apoptosis, as it may be compensated by other functionally redundant proteins (33). Immunohistochemical staining has revealed high expression of PDCD6 in primary tumors compared with normal tissues of the breast, liver, and lung (34,35).…”

Programmed cell death 6 (PDCD6) as a prognostic marker for gastric cancers

“…The best characterized target of PDCD6 is AIP1/Alix, an adaptor protein, which has been shown to bind to many growth-related signaling proteins [7]. Previous studies have reported that PDCD6 plays a critical role in T-cell receptor (TCR) -Fas/CD95 or glucocorticoid-induced apoptosis since depletion of PDCD6 in those cells blocked apoptosis [8]. In contrast, high PDCD6 expression was observed in primary tumors compared to normal tissues of the breast, liver, and lung [9,10].…”