The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract.
Both DR4 and DR5 have recently been identified as membrane death receptors that are activated by their ligand TRAIL to engage the intracellular apoptotic machinery. TRID (also named as TRAIL-R3) is an antagonist decoy receptor and lacks the cytoplasmic death domain. TRID protects from TRAIL-induced apoptosis by competing with DR4 and DR5 for binding to TRAIL. TRID has been shown to be overexpressed in normal human tissues but not in malignantly transformed cell lines. DR5 is a p53-regulated gene and we have recently reported that DR5 expression is induced in response to genotoxic stress in both a p53-dependent and independent manner (Sheikh et al., 1998). In the current study, we demonstrate that TRID gene expression is also induced by the genotoxic agents ionizing radiation and methyl methanesulfonate (MMS) in predominantly p53 wild-type cells, whereas UV-irradiation does not induce TRID gene expression. Consistent with these results, exogenous wild-type p53 also upregulates the expression of endogenous TRID in p53-null cells. Thus, TRID appears to be a p53 target gene that is regulated by genotoxic stress in a p53-dependent manner. Using primary gastrointestinal tract (GIT) tumors and their matching normal tissue, we also demonstrate for the first time that TRID expression is enhanced in primary tumors of the GIT. It is, therefore, possible that TRID overexpressing GIT tumors may gain a selective growth advantage by escaping from TRAIL-induced apoptosis.
Sheikh
M S
MS
Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Huang
Y
Y
Fernandez-Salas
E A
EA
El-Deiry
W S
WS
Friess
H
H
Amundson
S
S
Yin
J
J
Meltzer
S J
SJ
Holbrook
N J
NJ
Fornace
A J
AJ
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins; D005720:Gamma Rays; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D016158:Genes, p53; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008875:Middle Aged; D009153:Mutagens / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D009928:Organ Specificity; D011487:Protein Conformation; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013312:Stress, Physiological / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand; D013696:Temperature; D014407:Tumor Cells, Cultured; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D014466:Ultraviolet Rays
D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009153:Mutagens; D009363:Neoplasm Proteins; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D008741:Methyl Methanesulfonate