title: The short stature homeodomain protein SHOX induces cellular growth arrest and apoptosis and is expressed in human growth plate chondrocytes.
abstract: Mutations in the homeobox gene SHOX cause growth retardation and the skeletal abnormalities associated with Léri-Weill, Langer, and Turner syndromes. Little is known about the mechanism underlying these SHOX-related inherited disorders of bone formation. Here we demonstrate that SHOX expression in osteogenic stable cell lines, primary oral fibroblasts, and primary chondrocytes leads to cell cycle arrest and apoptosis. These events are associated with alterations in the expression of several cellular genes, including pRB, p53, and the cyclin kinase inhibitors p21(Cip1) and p27(Kip1). A SHOX mutant, such as seen in Léri-Weill syndrome patients, does not display these activities of the wild type protein. We have also shown that endogenous SHOX is mainly expressed in hypertrophic/apoptotic chondrocytes of the growth plate, strongly suggesting that the protein plays a direct role in regulating the differentiation of these cells. This study provides the first insight into the biological function of SHOX as regulator of cellular proliferation and viability and relates these cellular events to the phenotypic consequences of SHOX deficiency.
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchini
authors.forename: Tiina
authors.initials: T
authors.lastname: Marttila
authors.forename: Anja
authors.initials: A
authors.lastname: Winter
authors.forename: Sandra
authors.initials: S
authors.lastname: Caldeira
authors.forename: Ilaria
authors.initials: I
authors.lastname: Malanchi
authors.forename: Rüdiger J
authors.initials: RJ
authors.lastname: Blaschke
authors.forename: Beate
authors.initials: B
authors.lastname: Häcker
authors.forename: Ercole
authors.initials: E
authors.lastname: Rao
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Richter
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
authors.forename: Gudrun A
authors.initials: GA
authors.lastname: Rappold
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001827:Body Height; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D002469:Cell Separation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D006132:Growth Plate / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009055:Mouth / Q000378:metabolism; D009154:Mutation; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D000074122:Short Stature Homeobox Protein; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018398:Homeodomain Proteins; D016160:Retinoblastoma Protein; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001973:Bromodeoxyuridine