title: Megakaryocyte polyploidy is inhibited by lysyl oxidase propeptide.
abstract: Megakaryocytes (MKs), the platelet precursors, undergo an endomitotic cell cycle that leads to polyploidy. Lysyl oxidase propeptide (LOX-PP) is generated from lysyl oxidase (LOX) pro-enzyme after proteolytical cleavage. We recently reported that LOX, a known matrix cross-linking enzyme, contributes to MK lineage expansion. In addition, LOX expression levels are ploidy-dependent, with polyploidy MKs having minimal levels. This led us to test the effects of LOX-PP on the number and ploidy of primary MKs. LOX-PP significantly decreases mouse bone marrow MK ploidy coupled with a reduction in MK size. MK number is unchanged upon LOX-PP treatment. Analysis of LOX-PP- or vehicle-treated MKs by western blotting revealed a reduction in ERK1/2 phosphorylation and in the levels of its downstream targets, cyclin D3 and cyclin E, which are known to play a central role in MK endomitosis. Pull-down assays and immunochemistry staining indicated that LOX-PP interacts with α-tubulin and the mictotubules, which can contribute to decreased MK ploidy. Thus, our findings defined a role for LOX-PP in reducing MK ploidy. This suggests that high-level expression of LOX in aberrantly proliferating MKs could play a part in inhibiting their polyploidization via LOX-PP.
authors.affiliation: Department of Biochemistry, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA USA.
authors.forename: Alexia
authors.initials: A
authors.lastname: Eliades
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papadantonakis
authors.forename: Shinobu
authors.initials: S
authors.lastname: Matsuura
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Mi
authors.forename: Manish V
authors.initials: MV
authors.lastname: Bais
authors.forename: Philip
authors.initials: P
authors.lastname: Trackman
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology; D056743:Cyclin D3 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011123:Polyploidy; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology*; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D056743:Cyclin D3; D019927:Cyclin E; D011498:Protein Precursors; D008249:Protein-Lysine 6-Oxidase
keywords: cyclin; lysyl oxidase propeptide; megakaryocyte; platelet; polyploidy