Article

A Mitochondrial Protein, Bit1, Mediates Apoptosis Regulated by Integrins and Groucho/TLE Corepressors

Cancer Research Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell (Impact Factor: 32.24). 04/2004; 116(5):751-62. DOI: 10.1016/j.cell.2005.07.022
Source: PubMed

ABSTRACT

A delicate balance of signals regulates cell survival. One set of these signals is derived from integrin-mediated cell adhesion to the extracellular matrix (ECM). Loss of cell attachment to the ECM causes apoptosis, a process known as anoikis. In searching for proteins involved in cell adhesion-dependent regulation of anoikis, we identified Bit1, a mitochondrial protein that is released into the cytoplasm during apoptosis. Cytoplasmic Bit1 forms a complex with AES, a small Groucho/transducin-like enhancer of split (TLE) protein, and induces cell death with characteristics of caspase-independent apoptosis. Cell attachment to fibronectin counteracts the apoptotic effect of Bit1 and AES. Increasing Bit1 expression enhances anoikis, while suppressing the expression reduces it. Thus, we have elucidated an integrin-controlled pathway that is, at least in part, responsible for the cell survival effects of cell-ECM interactions.

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Available from: Jan Pilch, Sep 22, 2015
    • "In contrast, in vivo experiments have shown that gene transfer of FasL inhibited the tumor growth (Arai et al. 1997). SRL down-regulated p53-inducible protein with a death domain (PIDD), scaffold protein implicated in DNA damage response and PTHR2 (Bit1), mitochondrial protein implicated in regulation of apoptosis (Jan et al. 2004) at 48h. "
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    ABSTRACT: Sclerotium rolfsii lectin (SRL) is a lectin isolated from fungus Sclerotium rolfsii and has high binding specificity towards the oncofetal Thomsen-Friedenreich carbohydrate antigen (Galβ1-3GalNAc-α-O-Ser/Thr, T or TF), which is expressed in more than 90% of human cancers. Our previous studies have shown that binding of SRL to human colon, breast and ovarian cancer cells induces cell apoptosis in vitro and suppresses tumor growth in vivo. This study investigated the SRL-mediated cell signalling in human colon cancer HT29 cells by mRNA and miRNA microarrays. It was found that SRL treatment results in altered expression of several hundred molecules including MAPK and c-JUN-associated, apoptosis-associated, and cell cycle and DNA replication-associated signaling molecules. Pathway analysis using GeneSpring 12.6.1 revealed that SRL treatment induces changes of MAPK and c-JUN -associated signalling pathways as early as 2h while changes of cell cycle, DNA replication and apoptosis pathways were significantly affected only after 24h. A significant change of cell miRNA expression was also observed after 12h treatment of the cells with SRL. These changes were further validated by qRT-PCR and immunoblotting. This study thus suggests that the presence of SRL affects multiple signalling pathways in cancer cells with early effects on cell proliferation pathways associated with MAPK and c-JUN, followed by miRNA-associated cell activity and apoptosis. This provides insight information into the molecular mechanism of the anti-cancer activity of this fungal lectin.
    No preview · Article · Sep 2015 · Glycobiology
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    • "In contrast, in vivo experiments have shown that gene transfer of FasL inhibited the tumor growth (Arai et al. 1997). SRL down-regulated p53-inducible protein with a death domain (PIDD), scaffold protein implicated in DNA damage response and PTHR2 (Bit1), mitochondrial protein implicated in regulation of apoptosis (Jan et al. 2004) at 48h. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sclerotium rolfsii lectin (SRL) is a lectin isolated from fungus Sclerotium rolfsii and has high binding specificity towards the oncofetal Thomsen-Friedenreich carbohydrate antigen (Galβ1–3GalNAc-α-O-Ser/Thr, T or TF), which is expressed in more than 90% of human cancers. Our previous studies have shown that binding of SRL to human colon, breast and ovarian cancer cells induces cell apoptosis in vitro and suppresses tumor growth in vivo. This study investigated the SRL-mediated cell signalling in human colon cancer HT29 cells by mRNA and miRNA microarrays. It was found that SRL treatment results in altered expression of several hundred molecules including MAPK and c-JUN-associated, apoptosis-associated, and cell cycle and DNA replication-associated signaling molecules. Pathway analysis using GeneSpring 12.6.1 revealed that SRL treatment induces changes of MAPK and c-JUN –associated signalling pathways as early as 2h while changes of cell cycle, DNA replication and apoptosis pathways were significantly affected only after 24h. A significant change of cell miRNA expression was also observed after 12h treatment of the cells with SRL. These changes were further validated by qRT-PCR and immunoblotting. This study thus suggests that the presence of SRL affects multiple signalling pathways in cancer cells with early effects on cell proliferation pathways associated with MAPK and c-JUN, followed by miRNA-associated cell activity and apoptosis. This provides insight information into the molecular mechanism of the anti-cancer activity of this fungal lectin. http://glycob.oxfordjournals.org/content/early/2015/09/06/glycob.cwv067.short?rss=1
    Full-text · Article · Sep 2015 · Glycobiology
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    • "Upon integrin-mediated attachment, Bit-1 expression induces Bcl- 2 transcription (Griffiths et al., 2011) and blocks the intrinsic mitochondrial apoptotic pathway. When integrins are not ligated, Bit-1 complexes with Groucho/TLE family proteins to promote apoptosis in a variety of cell types including myoblasts (Bouchentouf et al., 2007; Jan et al., 2004). Bit-1 is phosphorylated by PKD1, and Bit-1 expression impairs ERK phosphorylation (Biliran et al., 2008; Kairouz-Wahbe et al., 2008). "
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    ABSTRACT: Muscle differentiation requires a complex signaling cascade that leads to multinucleated myofibers. Genes regulating the intrinsic mitochondrial apoptotic pathway also function in controlling cell differentiation. How such signaling pathways are regulated during differentiation is not fully understood. Bit-1 mutations in humans cause infantile-onset multisystem disease with muscle weakness. We demonstrate here that Bit-1 controls skeletal myogenesis through a caspase-mediated signaling pathway. Bit-1 null mice exhibit a myopathy with hypotrophic myofibers. Bit-1 null myoblasts prematurely express muscle-specific proteins. Similarly, knockdown of Bit-1 expression in C2C12 myoblasts promotes early differentiation whereas overexpression delays differentiation. In wild type mice Bit-1 levels increase during differentiation. Bit-1 null myoblasts exhibited increased caspase 9 and caspase 3 without increased apoptosis *: . Bit-1 re-expression partially rescued differentiation. In Bit-1 null muscle, Bcl-2 is reduced suggesting Bcl-2-mediated inhibition of caspase 9 and caspase 3 is decreased. Bcl-2 re-expression rescued Bit-1-mediated early differentiation in Bit-1 null myoblasts and C2C12s with knockdown of Bit-1 expression. These results support an unanticipated yet essential role for Bit-1 in controlling myogenesis through regulation of Bcl-2.
    Full-text · Article · Mar 2015 · Development
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