title: Malnutrition suppresses cell cycle progression of hematopoietic progenitor cells in mice via cyclin D1 down-regulation.
abstract: OBJECTIVE
  Protein malnutrition (PM) often is associated with changes in bone marrow (BM) microenvironment leading to an impaired hematopoiesis; however, the mechanism involved is poorly understood. The aim of this study was to compare the cell cycle progression of hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) and evaluate the cell cycle signaling in malnourished mice to assess the mechanism of cell cycle arrest.
  
  
  METHODS
  C57Bl/6J mice were randomly assigned in control and malnourished groups receiving normoproteic and hypoproteic diets (12% and 2% protein, respectively) over a 5-wk period. Nutritional and hematologic parameters were assessed and BM immunophenotypic analysis was performed. Cell cycle of HPC (Lin(-)) and HSC (Lin(-)Sca-1(+)c-Kit(+)) were evaluated after 6 h of in vivo 5-bromo-2'-deoxyuridine (BrDU) incorporation. Cell cycle regulatory protein expression of HPC was assessed by Western blot.
  
  
  RESULTS
  Malnourished mice showed lower levels of serum protein, albumin, glucose, insulin-like growth factor-1, insulin, and higher levels of serum corticosterone. PM also caused a reduction of BM myeloid compartment resulting in anemia and leukopenia. After 6 h of BrDU incorporation, malnourished mice showed G0-G1 arrest of HPC without changes of HSC proliferation kinetics. HPC of malnourished mice showed reduced expression of proteins that induce cell cycle (cyclin D1, cyclin E, pRb, PCNA, Cdc25a, Cdk2, and Cdk4) and increased expression of inhibitory proteins (p21 and p27) with no significant difference in p53 expression.
  
  
  CONCLUSIONS
  PM suppressed cell cycle progression mainly of HPC. This occurred via cyclin D1 down-regulation and p21/p27 overexpression attesting that BM microenvironment commitment observed in PM is affecting cell interactions compromising cell proliferation.
authors.affiliation: Experimental Hematology Laboratory, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: knakajima@usp.br.
authors.forename: Karina
authors.initials: K
authors.lastname: Nakajima
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Crisma
authors.forename: Graziela B
authors.initials: GB
authors.lastname: Silva
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Rogero
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Fock
authors.forename: Primavera
authors.initials: P
authors.lastname: Borelli
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D002149:Energy Intake; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009752:Nutritional Status; D011502:Protein-Energy Malnutrition / Q000378:metabolism*; D015398:Signal Transduction; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
chemical_list: C530105:Ccnd1 protein, mouse; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases
keywords: Cell cycle; Cyclin D1; Hematopoietic progenitor cells; Hematopoietic stem cells; Malnutrition