The TRAIL Decoy Receptor TRUNDD (DcR2, TRAIL-R4) Is Induced by Adenovirus-p53 Overexpression and Can Delay TRAIL-, p53-, and KILLER/DR5-Dependent Colon Cancer Apoptosis
The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL-R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induced by the cytotoxic ligand TRAIL in part because of their absent or truncated cytoplasmic death domains, respectively. We previously identified the dea...
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| Veröffentlicht in: | Molecular therapy 2000-02, Vol.1 (2), p.130-144 |
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| description | The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL-R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induced by the cytotoxic ligand TRAIL in part because of their absent or truncated cytoplasmic death domains, respectively. We previously identified the death domain containing proapoptotic TRAIL death receptor KILLER/DR5 (TRAIL-R2) as an upregulated transcript following exposure of cancer cells, with wild-type but not with mutant or degraded p53 proteins, to a cytotoxic dose of adriamycin. In the present studies we provide evidence that expression of the TRAIL decoy receptors TRUNDD and TRID increases following infection of cancer cells with p53-expressing adenovirus (Ad-p53), in a manner similar to other p53 target genes such as KILLER/DR5 and p21WAF1/CIP1. Subsequent overexpression of TRUNDD in colon cancer cell lines caused a significant delay in killing induced by TRAIL. Furthermore, cotransfection of TRUNDD with either p53 or KILLER/DR5 (at a 4:1 DNA ratio) in colon cancer cells decreased cell death caused by either gene. This protective effect of TRUNDD was not dependent on the presence of TRAIL, and overexpression of TRUNDD did not alter the protein levels of either p53 or KILLER/DR5. Further deletion studies showed that whereas protection by TRUNDD against TRAIL-mediated apoptosis did not require an intact intracellular domain (ICD), the first 43 amino acids of the ICD of TRUNDD were needed for protection against cell death induced by p53 or KILLER/DR5. Our results suggest a model in which the TRAIL decoy receptors may be induced by p53, thereby attenuating an apoptotic response that appears to involve KILLER/DR5. Therefore, the p53-dependent induction of TRUNDD may provide a mechanism to transiently favor cell survival over cell death, and overexpression of TRUNDD may be another mechanism of escape from p53-mediated apoptosis in gene therapy experiments. |
| doi_str_mv | 10.1006/mthe.2000.0025 |
| format | Article |
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Robert ; Sheikh, M. Saeed ; Fornace, Albert J. ; El-Deiry, Wafik S.</creator><creatorcontrib>Meng, Raymond D. ; McDonald, E. Robert ; Sheikh, M. Saeed ; Fornace, Albert J. ; El-Deiry, Wafik S.</creatorcontrib><description>The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL-R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induced by the cytotoxic ligand TRAIL in part because of their absent or truncated cytoplasmic death domains, respectively. We previously identified the death domain containing proapoptotic TRAIL death receptor KILLER/DR5 (TRAIL-R2) as an upregulated transcript following exposure of cancer cells, with wild-type but not with mutant or degraded p53 proteins, to a cytotoxic dose of adriamycin. In the present studies we provide evidence that expression of the TRAIL decoy receptors TRUNDD and TRID increases following infection of cancer cells with p53-expressing adenovirus (Ad-p53), in a manner similar to other p53 target genes such as KILLER/DR5 and p21WAF1/CIP1. Subsequent overexpression of TRUNDD in colon cancer cell lines caused a significant delay in killing induced by TRAIL. Furthermore, cotransfection of TRUNDD with either p53 or KILLER/DR5 (at a 4:1 DNA ratio) in colon cancer cells decreased cell death caused by either gene. This protective effect of TRUNDD was not dependent on the presence of TRAIL, and overexpression of TRUNDD did not alter the protein levels of either p53 or KILLER/DR5. Further deletion studies showed that whereas protection by TRUNDD against TRAIL-mediated apoptosis did not require an intact intracellular domain (ICD), the first 43 amino acids of the ICD of TRUNDD were needed for protection against cell death induced by p53 or KILLER/DR5. Our results suggest a model in which the TRAIL decoy receptors may be induced by p53, thereby attenuating an apoptotic response that appears to involve KILLER/DR5. Therefore, the p53-dependent induction of TRUNDD may provide a mechanism to transiently favor cell survival over cell death, and overexpression of TRUNDD may be another mechanism of escape from p53-mediated apoptosis in gene therapy experiments.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1006/mthe.2000.0025</identifier><identifier>PMID: 10933923</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenoviridae - metabolism ; Adenoviruses ; Amino acids ; Apoptosis ; Blotting, Northern ; Blotting, Western ; Cancer therapies ; Cell cycle ; Cell death ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Colorectal cancer ; Cyclin-dependent kinases ; Cytotoxicity ; DNA damage ; DNA, Complementary - metabolism ; Female ; Gene therapy ; GPI-Linked Proteins ; Humans ; Infections ; KILLER/DR5 ; Kinases ; Ligands ; Medicine ; Membrane Proteins ; Models, Biological ; Mutation ; Oncology ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; p53 ; Plasmids - metabolism ; Protein Biosynthesis ; Protein Structure, Tertiary ; Proteins ; Radiation ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; Receptors, Tumor Necrosis Factor - chemistry ; Receptors, Tumor Necrosis Factor - genetics ; Receptors, Tumor Necrosis Factor - metabolism ; Receptors, Tumor Necrosis Factor, Member 10c ; RNA, Messenger - metabolism ; Time Factors ; Toxicity ; TRAIL ; Transfection ; TRID ; TRUNDD (DcR2, TRAIL-R4) ; Tumor Cells, Cultured ; Tumor Necrosis Factor Decoy Receptors ; Tumor necrosis factor-TNF ; Tumor Suppressor Protein p53 - chemistry ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>Molecular therapy, 2000-02, Vol.1 (2), p.130-144</ispartof><rights>2000 American Society for Gene Therapy</rights><rights>Copyright Nature Publishing Group Feb 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c408t-b10fb8c3f6a3f5f13f4b8d4f74b09747cbe5f7a9cdf663e87100c62dc56afc583</citedby><cites>FETCH-LOGICAL-c408t-b10fb8c3f6a3f5f13f4b8d4f74b09747cbe5f7a9cdf663e87100c62dc56afc583</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10933923$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Meng, Raymond D.</creatorcontrib><creatorcontrib>McDonald, E. Robert</creatorcontrib><creatorcontrib>Sheikh, M. Saeed</creatorcontrib><creatorcontrib>Fornace, Albert J.</creatorcontrib><creatorcontrib>El-Deiry, Wafik S.</creatorcontrib><title>The TRAIL Decoy Receptor TRUNDD (DcR2, TRAIL-R4) Is Induced by Adenovirus-p53 Overexpression and Can Delay TRAIL-, p53-, and KILLER/DR5-Dependent Colon Cancer Apoptosis</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL-R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induced by the cytotoxic ligand TRAIL in part because of their absent or truncated cytoplasmic death domains, respectively. We previously identified the death domain containing proapoptotic TRAIL death receptor KILLER/DR5 (TRAIL-R2) as an upregulated transcript following exposure of cancer cells, with wild-type but not with mutant or degraded p53 proteins, to a cytotoxic dose of adriamycin. In the present studies we provide evidence that expression of the TRAIL decoy receptors TRUNDD and TRID increases following infection of cancer cells with p53-expressing adenovirus (Ad-p53), in a manner similar to other p53 target genes such as KILLER/DR5 and p21WAF1/CIP1. Subsequent overexpression of TRUNDD in colon cancer cell lines caused a significant delay in killing induced by TRAIL. Furthermore, cotransfection of TRUNDD with either p53 or KILLER/DR5 (at a 4:1 DNA ratio) in colon cancer cells decreased cell death caused by either gene. This protective effect of TRUNDD was not dependent on the presence of TRAIL, and overexpression of TRUNDD did not alter the protein levels of either p53 or KILLER/DR5. Further deletion studies showed that whereas protection by TRUNDD against TRAIL-mediated apoptosis did not require an intact intracellular domain (ICD), the first 43 amino acids of the ICD of TRUNDD were needed for protection against cell death induced by p53 or KILLER/DR5. Our results suggest a model in which the TRAIL decoy receptors may be induced by p53, thereby attenuating an apoptotic response that appears to involve KILLER/DR5. Therefore, the p53-dependent induction of TRUNDD may provide a mechanism to transiently favor cell survival over cell death, and overexpression of TRUNDD may be another mechanism of escape from p53-mediated apoptosis in gene therapy experiments.</description><subject>Adenoviridae - metabolism</subject><subject>Adenoviruses</subject><subject>Amino acids</subject><subject>Apoptosis</subject><subject>Blotting, Northern</subject><subject>Blotting, Western</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colorectal cancer</subject><subject>Cyclin-dependent kinases</subject><subject>Cytotoxicity</subject><subject>DNA damage</subject><subject>DNA, Complementary - metabolism</subject><subject>Female</subject><subject>Gene therapy</subject><subject>GPI-Linked Proteins</subject><subject>Humans</subject><subject>Infections</subject><subject>KILLER/DR5</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Medicine</subject><subject>Membrane Proteins</subject><subject>Models, Biological</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Ovarian Neoplasms - pathology</subject><subject>p53</subject><subject>Plasmids - metabolism</subject><subject>Protein Biosynthesis</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Radiation</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand</subject><subject>Receptors, Tumor Necrosis Factor - chemistry</subject><subject>Receptors, Tumor Necrosis Factor - genetics</subject><subject>Receptors, Tumor Necrosis Factor - metabolism</subject><subject>Receptors, Tumor Necrosis Factor, Member 10c</subject><subject>RNA, Messenger - metabolism</subject><subject>Time Factors</subject><subject>Toxicity</subject><subject>TRAIL</subject><subject>Transfection</subject><subject>TRID</subject><subject>TRUNDD (DcR2, TRAIL-R4)</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Necrosis Factor Decoy Receptors</subject><subject>Tumor necrosis factor-TNF</subject><subject>Tumor Suppressor Protein p53 - chemistry</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kV-L1DAUxYMo7h999VECgihsZ5OmSdvHYbpqsbhQZp9Dm9ywXTpNTdrB-UZ-zE3pICL4klyS3zlczkHoHSUbSoi4PUyPsIkJIRtCYv4CXVIe8yjMycs_MxUX6Mr7pzBRnovX6IKSnLE8Zpfo9_4R8L7elhUuQNkTrkHBOFkXHh9-FAX-VKg6vlmRqE4-49LjctCzAo3bE95qGOyxc7OPRs7w_REc_BodeN_ZATeDxrtmCNZ9czp73OAAhnP5-15W1V19W9Q8KmCEIZhNeGf7IA0yBQ5vRxu28Z1_g16Zpvfw9nxfo4cvd_vdt6i6_1rutlWkEpJNUUuJaTPFjGiY4YYyk7SZTkyatCRPk1S1wE3a5EobIRhkaUhRiVgrLhqjeMau0cfVd3T25wx-kofOK-j7ZgA7e5nSlHHBRAA__AM-2dkNYTdJ0xAvSYWIA7VZKeWs9w6MHF13aNxJUiKXBuXSoFwalEuDQfD-bDu3B9B_4WtlAchWAEIKxw6c9KqDEJbuHKhJatv9z_sZeQCluQ</recordid><startdate>200002</startdate><enddate>200002</enddate><creator>Meng, Raymond D.</creator><creator>McDonald, E. 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Robert</au><au>Sheikh, M. Saeed</au><au>Fornace, Albert J.</au><au>El-Deiry, Wafik S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The TRAIL Decoy Receptor TRUNDD (DcR2, TRAIL-R4) Is Induced by Adenovirus-p53 Overexpression and Can Delay TRAIL-, p53-, and KILLER/DR5-Dependent Colon Cancer Apoptosis</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2000-02</date><risdate>2000</risdate><volume>1</volume><issue>2</issue><spage>130</spage><epage>144</epage><pages>130-144</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL-R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induced by the cytotoxic ligand TRAIL in part because of their absent or truncated cytoplasmic death domains, respectively. We previously identified the death domain containing proapoptotic TRAIL death receptor KILLER/DR5 (TRAIL-R2) as an upregulated transcript following exposure of cancer cells, with wild-type but not with mutant or degraded p53 proteins, to a cytotoxic dose of adriamycin. In the present studies we provide evidence that expression of the TRAIL decoy receptors TRUNDD and TRID increases following infection of cancer cells with p53-expressing adenovirus (Ad-p53), in a manner similar to other p53 target genes such as KILLER/DR5 and p21WAF1/CIP1. Subsequent overexpression of TRUNDD in colon cancer cell lines caused a significant delay in killing induced by TRAIL. Furthermore, cotransfection of TRUNDD with either p53 or KILLER/DR5 (at a 4:1 DNA ratio) in colon cancer cells decreased cell death caused by either gene. This protective effect of TRUNDD was not dependent on the presence of TRAIL, and overexpression of TRUNDD did not alter the protein levels of either p53 or KILLER/DR5. Further deletion studies showed that whereas protection by TRUNDD against TRAIL-mediated apoptosis did not require an intact intracellular domain (ICD), the first 43 amino acids of the ICD of TRUNDD were needed for protection against cell death induced by p53 or KILLER/DR5. Our results suggest a model in which the TRAIL decoy receptors may be induced by p53, thereby attenuating an apoptotic response that appears to involve KILLER/DR5. Therefore, the p53-dependent induction of TRUNDD may provide a mechanism to transiently favor cell survival over cell death, and overexpression of TRUNDD may be another mechanism of escape from p53-mediated apoptosis in gene therapy experiments.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>10933923</pmid><doi>10.1006/mthe.2000.0025</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adenoviridae - metabolism Adenoviruses Amino acids Apoptosis Blotting, Northern Blotting, Western Cancer therapies Cell cycle Cell death Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Colorectal cancer Cyclin-dependent kinases Cytotoxicity DNA damage DNA, Complementary - metabolism Female Gene therapy GPI-Linked Proteins Humans Infections KILLER/DR5 Kinases Ligands Medicine Membrane Proteins Models, Biological Mutation Oncology Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology p53 Plasmids - metabolism Protein Biosynthesis Protein Structure, Tertiary Proteins Radiation Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Tumor Necrosis Factor - chemistry Receptors, Tumor Necrosis Factor - genetics Receptors, Tumor Necrosis Factor - metabolism Receptors, Tumor Necrosis Factor, Member 10c RNA, Messenger - metabolism Time Factors Toxicity TRAIL Transfection TRID TRUNDD (DcR2, TRAIL-R4) Tumor Cells, Cultured Tumor Necrosis Factor Decoy Receptors Tumor necrosis factor-TNF Tumor Suppressor Protein p53 - chemistry Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
| title | The TRAIL Decoy Receptor TRUNDD (DcR2, TRAIL-R4) Is Induced by Adenovirus-p53 Overexpression and Can Delay TRAIL-, p53-, and KILLER/DR5-Dependent Colon Cancer Apoptosis |
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