title: Upregulation of p21(WAF1/Cip1) precedes tumor necrosis factor-induced necrosis-like cell death.
abstract: The molecular mechanisms mediating death receptor-induced caspase-independent necrotic cell death are still largely unknown. We have previously reported that NIH3T3 cells are sensitized by caspase inhibition to death receptor-induced cytotoxicity leading to a necrosis-like cell death. In addition, we have identified an important role of cell cycle progression for this sensitization effect. Here, we report that tumor necrosis factor-induced necrotic death is preceded by an upregulation of the cyclin-dependent kinase inhibitor p21(WAF1/Cip1). Increased expression of p21(WAF1/Cip1) occurs prior to cell death in the nucleus, where it binds to a cyclin-dependent kinase indicating its functionality. The use of specific pharmacological inhibitors revealed a partial involvement of p38 mitogen-activated protein kinase in the upregulation of p21(WAF1/Cip1). Inhibition of p21(WAF1/Cip1) upregulation prevents a previously observed delay of the cells in the G2/M phase of the cell cycle thereby augmenting, not inhibiting cell death.
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität Kiel, Michaelisstrasse 5, Kiel D-24105, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ussat
authors.forename: Ulf-Eike
authors.initials: UE
authors.lastname: Werner
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Kruse
authors.forename: Silke
authors.initials: S
authors.lastname: Lüschen
authors.forename: Gudrun
authors.initials: G
authors.lastname: Scherer
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Sabine
authors.initials: S
authors.lastname: Adam-Klages
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009336:Necrosis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D014409:Tumor Necrosis Factor-alpha