title: The ribosome-related protein, SBDS, is critical for normal erythropoiesis.
abstract: Although anemia is common in Shwachman- Diamond syndrome (SDS), the underlying mechanism remains unclear. We asked whether SBDS, which is mutated in most SDS patients, is critical for erythroid development. We found that SBDS expression is high early during erythroid differentiation. Inhibition of SBDS in CD34(+) hematopoietic stem cells and early progenitors (HSC/Ps) and K562 cells led to slow cell expansion during erythroid differentiation. Induction of erythroid differentiation resulted in markedly accelerated apoptosis in the knockdown cells; however, proliferation was only mildly reduced. The percentage of cells entering differentiation was not reduced. Differentiation also increased the oxidative stress in SBDS-knockdown K562 cells, and antioxidants enhanced the expansion capability of differentiating SBDS-knockdown K562 cells and colony production of SDS patient HSC/Ps. Erythroid differentiation also resulted in reduction of all ribosomal subunits and global translation. Furthermore, stimulation of global translation with leucine improved the erythroid cell expansion of SBDS-knockdown cells and colony production of SDS patient HSC/Ps. Leucine did not reduce the oxidative stress in SBDS-deficient K562 cells. These results demonstrate that SBDS is critical for normal erythropoiesis. Erythropoietic failure caused by SBDS deficiency is at least in part related to elevated ROS levels and translation insufficiency because antioxidants and leucine improved cell expansion.
authors.affiliation: Cell Biology Program, Research Institute, Toronto, ON, Canada.
authors.forename: Saswati
authors.initials: S
authors.lastname: Sen
authors.forename: Hanming
authors.initials: H
authors.lastname: Wang
authors.forename: Chi Lan
authors.initials: CL
authors.lastname: Nghiem
authors.forename: Kim
authors.initials: K
authors.lastname: Zhou
authors.forename: Janice
authors.initials: J
authors.lastname: Yau
authors.forename: Chetankumar S
authors.initials: CS
authors.lastname: Tailor
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Irwin
authors.forename: Yigal
authors.initials: Y
authors.lastname: Dror
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001855:Bone Marrow Diseases / Q000188:drug therapy / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis; D010188:Exocrine Pancreatic Insufficiency / Q000188:drug therapy / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D007930:Leucine / Q000378:metabolism; D008068:Lipomatosis / Q000188:drug therapy / Q000378:metabolism; D018384:Oxidative Stress; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D000081003:Shwachman-Diamond Syndrome
chemical_list: D000975:Antioxidants; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C470521:SBDS protein, human; D007930:Leucine