title: Over-expression of CDKIs p15INK4b, p16INK4a and p21CIP1/WAF1 genes mediate growth arrest in human osteosarcoma cell lines.
abstract: Human somatic cells cultured in vitro exhibit a limited number of divisions. In contrast immortal cells have lost their growth regulatory mechanisms and, thus, continue to divide indefinitely. Cyclin-dependent kinase inhibitors (CDKIs) represent one of the most important regulatory factors in both mortality and immortality, as they are over-expressed in senescent cells and are down-regulated in a number of human cancers. In the present study we determined the effect of CDKIs on the proliferation ability of human osteosarcoma cell lines. Transient expression of various CDKIs (p15INK4b, p16INK4a and p21CIP1/WAF1) in KHOS cells resulted in growth arrest and the cells failed to enter the S-phase of the cell cycle as shown by a DNA synthesis inhibition assay. In addition, stable transfection of p21CIP1/WAF1 and p16INK4a genes in two osteosarcoma cell lines (KHOS and U2-OS cells) showed that p21CIP1/WAF1 was able to repress the immortal phenotype in both cell lines, whereas temporary over-expression of p16INK4a reversibly inhibited the cell growth. Therefore this study indicates that CDKIs mediate growth arrest in human osteosarcoma cell lines and provides further evidence of the existence of molecular links between cellular mortality and immortality.
authors.affiliation: National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, 48 Vas. Constantinou Ave., Athens 11635, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Agiostratidou
authors.forename: A
authors.initials: A
authors.lastname: Derventzi
authors.forename: E S
authors.initials: ES
authors.lastname: Gonos
mesh_terms: D001859:Bone Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000096:biosynthesis; D019942:Genes, p16; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D012516:Osteosarcoma / Q000473:pathology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: C493956:CDKN1A protein, human; C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D018844:Cyclin-Dependent Kinases