SBDS-deficient cells undergo accelerated apoptosis through the Fas-pathway

Abstract

BackgroundShwachman-Diamond syndrome is an inherited multisystem disorder characterized by bone marrow and pancreatic dysfunction as well as metaphyseal dysostosis. Ninety percent of the patients have mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS). The relationship between SBDS and cell survival is unknown. In this study we investigated whether deficiency of the SBDS protein can cause increased apoptosis and, if so, what pathways are involved in this process.

38 Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome

“…Thus, the primary defect underlying SDS is distinct from the other ribosomopathies associated with hematological disease. We suggest that the diverse alternate functions proposed for SBDS in mammalian cells (Wessels et al 2006;Austin et al 2008;Rujkijyanont et al 2008;Ball et al 2009;Leung et al 2010) are downstream secondary consequences of the primary defect in 60S ribosomal subunit maturation. How do we explain the SDS phenotype?…”

“…Although cosedimentation of human SBDS with free cytoplasmic 60S ribosomal subunits in sucrose gradients (Ganapathi et al 2007) would be consistent with a conserved role for SBDS in 60S subunit maturation, the current model in mammalian cells posits that eIF6 removal is triggered following phosphorylation of Ser 235 by protein kinase C (PKC) and RACK1 (receptor for activated protein C) (Ceci et al 2003). Furthermore, diverse alternate functions for SBDS in mammalian cells have been suggested, including mitotic spindle stabilization (Austin et al 2008), chemotaxis (Wessels et al 2006), Fas ligand-induced apoptosis (Rujkijyanont et al 2008), cellular stress responses (Ball et al 2009), and Rac2-mediated monocyte migration (Leung et al 2010). Thus, despite the prior genetic studies in yeast, the mechanism of eIF6 release in mammalian cells is controversial, biochemical evidence supporting direct catalysis of eIF6 release by SBDS and EFL1 in eukaryotic cells is currently lacking, and the specific function of the SBDS protein, its mode of action, and the molecular mechanism of the cooperative interaction with EFL1 remain obscure.…”

Genetic Basis of Inherited Bone Marrow Failure Syndromes

“…(Dror and Freedman 1999) Marrow cells (Dror and Freedman 2001) as well as SBDS-knockdown HeLa cells (Rujkijyanont, Watanabe et al 2008) are characterized by accelerated apoptosis. (Dror and Freedman 2001) The accelerated apoptosis in marrow cells and SBDS-knockdown cells seems to be through the FAS pathway and not through the BAX/BCL-2/BCL-XL pathway.…”

“…(Dror and Freedman 2001) The accelerated apoptosis in marrow cells and SBDS-knockdown cells seems to be through the FAS pathway and not through the BAX/BCL-2/BCL-XL pathway. (Dror and Freedman 2001;Rujkijyanont, Watanabe et al 2008) Depletion of SBDS results in accumulation of FAS at the plasma membrane level and specific overexpression of FAS transcript 1; the main FAS transcript which contains both the transmembrane domain and the death domain.…”

“…(Balmain, Gray et al 2003) The IBMFS genes are crucial for fundamental cellular processes such as DNA repair, (Cohn and D'Andrea 2008) telomere maintenance, ribosome biogenesis (Choesmel, Bacqueville et al 2007;Ganapathi, Austin et al 2007;Menne, Goyenechea et al 2007) microtubule stabilization, (Austin, Gupta et al 2008) chemotaxis, (Wessels, Srikantha et al 2006) signaling from hematopoietic growth factor, (Ihara, Ishii et al 1999) signal transduction related to hematopoietic cell differentiation, (Song, Sullivan et al 1999;Nichols, Crispino et al 2000) granulocytic enzymes, (Dale, Person et al 2000) and cell survival. (Cumming, Lightfoot et al 2001;Miyake, Flygare et al 2005;Klein, Grudzien et al 2007;Rujkijyanont, Watanabe et al 2008;Watanabe, Ambekar et al 2009) Although rare, the study of IBMFSs genes made critical contributions to the understanding of not only the pathogenesis of the individual disorders, but also to common health problems such as cancer (Friedenson 2007;Londono-Vallejo 2008) (Fanconi 1927) It is a multisystem disorder which commonly affects the bone marrow and the development of other organs. (Auerbach, Rogatko et al 1989) Hematologically the patients suffer from aplastic anemia, which is characterized by various degrees of single or multilineage cytopenia, red blood cell macrocytosis, high fetal hemoglobin levels and reduced bone marrow cellularity.…”