title: CD99 drives terminal differentiation of osteosarcoma cells by acting as a spatial regulator of ERK 1/2.
abstract: Differentiation therapy is an attractive treatment for osteosarcoma (OS). CD99 is a cell surface molecule expressed in mesenchymal stem cells and osteoblasts that is maintained during osteoblast differentiation while lost in OS. Herein, we show that whenever OS cells regain CD99, they become prone to reactivate the terminal differentiation program. In differentiating conditions, CD99-transfected OS cells express osteocyte markers, halt proliferation, and largely die by apoptosis, resembling the fate of mature osteoblasts. CD99 induces ERK activation, increasing its membrane-bound/cytoplasmic form rather than affecting its nuclear localization. Through cytoplasmic ERK, CD99 promotes activity of the main osteogenic transcriptional factors AP1 and RUNX2, which in turn enhance osteocalcin and p21(WAF1/CIP1) , leading to G0 /G1 arrest. These data underscore the alternative positions of active ERK into distinct subcellular compartments as key events for determining OS fate.
authors.affiliation: CRS Development of Biomolecular Therapies, Laboratory of Experimental Oncology, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Sciandra
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Marino
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Manara
authors.forename: Clara
authors.initials: C
authors.lastname: Guerzoni
authors.forename: Maria
authors.initials: M
authors.lastname: Grano
authors.forename: Angela
authors.initials: A
authors.lastname: Oranger
authors.forename: Enrico
authors.initials: E
authors.lastname: Lucarelli
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Lollini
authors.forename: Barbara
authors.initials: B
authors.lastname: Dozza
authors.forename: Loredana
authors.initials: L
authors.lastname: Pratelli
authors.forename: Maria Flavia Di
authors.initials: MF
authors.lastname: Renzo
authors.forename: Mario Paolo
authors.initials: MP
authors.lastname: Colombo
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.forename: Katia
authors.initials: K
authors.lastname: Scotlandi
mesh_terms: D000071443:12E7 Antigen; D015703:Antigens, CD; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
chemical_list: D000071443:12E7 Antigen; D015703:Antigens, CD; C061828:CD99 protein, human; C493956:CDKN1A protein, human; D015815:Cell Adhesion Molecules; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009363:Neoplasm Proteins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: CD99; MAPK SIGNALING; OSTEOBLAST DIFFERENTIATION; OSTEOSARCOMA; RUNX2