p53-dependent and -independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor α

• Published in: Cancer research (Chicago, Ill.) Vol. 58; no. 8; pp. 1593 - 1598
• Main Authors: SAEED SHEIKH, M, BURNS, T. F, YING HUANG, GEN SHENG WU, AMUNDSON, S, BROOKS, K. S, FORNACE, A. J, EL-DEIRY, W. S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.04.1998
• Subjects: Ageing, cell death; Apoptosis; Apoptosis Regulatory Proteins; Biological and medical sciences; Blotting, Northern; Cell physiology; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - radiation effects; GPI-Linked Proteins; Humans; Immunoblotting; Membrane Glycoproteins - metabolism; Methyl Methanesulfonate - pharmacology; Molecular and cellular biology; Radiation, Ionizing; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor - metabolism; Receptors, Tumor Necrosis Factor, Member 10c; RNA, Messenger - analysis; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Transfection; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - radiation effects; Tumor Necrosis Factor Decoy Receptors; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Tumor Suppressor Protein p53 - physiology; Ultraviolet Rays; Human; Cytokine; Molecular interaction; Gene expression; Doxorubicin; In vitro; Stress; Ultraviolet radiation; Ionizing radiation; TP53 Gene; DNA; Established cell line; Anthracyclins; Lesion; Tumor cell; Tumor necrosis factor α; Apoptosis; Tumor suppressor gene; Biological receptor
• ISSN: 0008-5472; 1538-7445

The death receptor (DR) KILLER/DR5 gene has recently been identified as a doxorubicin-regulated transcript that was also induced by exogenous wild-type p53 in p53-negative cells. KILLER/DR5 gene encodes a DR containing cell surface protein that is highly homologous to DR4, another DR of the tumor necrosis factor (TNF) receptor family. Both DR4 and KILLER/DR5 independently bind to their specific ligand TRAIL and engage the caspase cascade to induce apoptosis. TRID (also known as TRAIL-R3) is an antiapoptotic decoy receptor that lacks the cytoplasmic death domain and competes with KILLER/DR5 and DR4 for binding to TRAIL. In this study, we demonstrate that the DR KILLER/DR5 gene is regulated in a p53-dependent and -independent manner during genotoxic and nongenotoxic stress-induced apoptosis. Just like other p53-regulated genes, ionizing radiation induction of KILLER/DR5 occurs in p53 wild-type cells, whereas methyl methanesulfonate regulation of KILLER/DR5 occurs in a p53-dependent and -independent manner. However, unlike other p53-regulated genes, KILLER/DR5 is not regulated following UV irradiation. TNF-alpha, a nongenotoxic cytokine, also induced the expression of KILLER/DR5 in a number of cancer cell lines, irrespective of p53 status. TNF-alpha did not alter the KILLER/DR5 mRNA stability, suggesting that the TNF-alpha regulation of KILLER/DRS expression appears transcriptional. We also provide evidence that KILLER/DR5 is regulated in a trigger and cell type-specific manner and that its induction by TNF-alpha, p53, or DNA damage is not the consequence of apoptosis induced by these agents. Unlike KILLER/DR5, none of the other KILLER/DR5 family members, including DR4, TRID, or the ligand TRAIL, displayed genotoxic stress or TNF-alpha regulation in a p53 transcription-dependent manner. Thus, KILLER/DR5 appears a bona fide downstream target of p53 that is also regulated in a cell type-specific, trigger-dependent, and p53-independent manner.