title: Tumor necrosis factor-alpha inhibits hTERT gene expression in human myeloid normal and leukemic cells.
abstract: Telomerase catalytic subunit (hTERT) has been shown to play a critical role not only in telomere homeostasis but also in cellular survival, DNA repair, and genetic stability. In a previous study, we described that tumor necrosis factor-xalpha (TNFxalpha) induced in the leukemic KG1 cells a senescence state characterized by decreased hTERT activity followed by prolonged growth arrest, increasedx beta-galactosidase activity, telomere shortening, and major chromosomal instability. Interestingly, granulocyte-macrophage colony-stimulating factor (GM-CSF) abrogated all these events. In the present study, we show for the first time that TNFxalpha acts by inhibiting the hTERT gene in both normal CD34x+ cells and fresh leukemic cells. Using KG1 cells as a representative cellular model, we show that TNFxalpha induced sphingomyelin hydrolysis, ceramide production, and c-Jun N-terminal kinase (JNK) activation, all of which are critical components of TNFxalpha signaling, resulting in hTERT gene inhibition. Moreover, we provide evidence that the protective effect of GM-CSF is related to its capacity to interfere with both ceramide generation and ceramide signaling. Negative regulation of the hTERT gene may represent one mechanism by which TNFxalpha interferes with normal hemopoiesis.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) U563, Centre Hospitalier et Universitaire (CHU) Purpan, Toulouse, France.
authors: Odile
authors: O
authors: Beyne-Rauzy
authors: Naïs
authors: N
authors: Prade-Houdellier
authors: Cécile
authors: C
authors: Demur
authors: Christian
authors: C
authors: Recher
authors: Jacques
authors: J
authors: Ayel
authors: Guy
authors: G
authors: Laurent
authors: Véronique
authors: V
authors: Mansat-De Mas
mesh_terms: D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects* / Q000201:enzymology*; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
chemical_list: D002518:Ceramides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D019098:Telomerase