title: TNF-α response of vascular endothelial and vascular smooth muscle cells involve differential utilization of ASK1 kinase and p73.
abstract: Atherosclerosis involves a specialized inflammatory process regulated by an intricate network of cytokine and chemokine signaling. Atherosclerotic lesions lead to the release of cytokines that can have multiple affects on various vascular cell functions either promoting lesion expansion or alternatively retard progression. Tumor necrosis factor-α (TNF-α) is one such cytokine that can activate both cell survival and cell death mechanisms simultaneously. Here we show that TNF-α induces apoptosis in human aortic endothelial cells (HAECs), while it promotes the proliferation of vascular smooth muscle cells (VSMCs). Both events involved the activation of the Rb-E2F1 transcriptional regulatory pathway. Stimulation of HAECs with TNF-α led to an increased expression of p73 protein and a reduction in the levels of p53. This involved apoptosis signal-regulating kinase 1 (ASK1)- mediated inactivation of Rb and its dissociation from the p73 promoter. In contrast, TNF-α stimulation of VSMCs enhanced the association of E2F1 with proliferative promoters like thymidylate synthase and cdc25A, while Rb was dissociated. ASK1 kinase has a critical role in the apoptotic process, as its depletion or dissociation from Rb reduced TNF-α-induced apoptosis. These results show that the cytokine TNF-α can elicit diametrically opposite responses in vascular endothelial cells and VSMCs, utilizing the Rb-E2F pathway.
authors: Department of Tumor Biology, H Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
authors: S
authors: S
authors: Rastogi
authors: W
authors: W
authors: Rizwani
authors: B
authors: B
authors: Joshi
authors: S
authors: S
authors: Kunigal
authors: S P
authors: SP
authors: Chellappan
mesh_terms: D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000166:cytology*; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C000606460:TP73 protein, human; D014409:Tumor Necrosis Factor-alpha; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D048848:MAP Kinase Kinase Kinase 5