Inhibition of human telomerase by a retrovirus expressing telomeric antisense RNA
Human telomerase, the RNA-dependent DNA polymerase that adds TTAGGG repeats to chromosome ends, is selectively expressed in immortalised cells and most tumours, suggesting a potential role for telomerase inhibitors in cancer therapy. Replication-deficient retroviruses were used to determine whether...
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Veröffentlicht in: | European journal of cancer (1990) 1998-07, Vol.34 (8), p.1242-1249 |
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creator | Bisoffi, M Chakerian, A.E Fore, M.L Bryant, J.E Hernandez, J.P Moyzis, R.K Griffith, J.K |
description | Human telomerase, the RNA-dependent DNA polymerase that adds TTAGGG repeats to chromosome ends, is selectively expressed in immortalised cells and most tumours, suggesting a potential role for telomerase inhibitors in cancer therapy. Replication-deficient retroviruses were used to determine whether mRNA containing UUAGGG, the complementary sequence to the template region of the hTR telomerase RNA, is sufficient to inhibit telomerase activity. Telomerase activities measured by the telomeric repeat amplification protocol (TRAP) assay in extracts prepared from immortalised mouse fibroblasts, human HeLa cells and human kidney carcinoma cells were inhibited by 75% or greater in 26 of 56 cell clones expressing UUAGGG. Telomerase activity was not inhibited by expression of mRNA containing a transposed sequence, GGGAUU. Telomerase activities
in vivo were inferred from changes in cellular morphology, proliferation capacity, growth rate and measurement of the content of telomere DNA. Giant senescent-like cells emerged shortly after cloning mouse PA317 and human HeLa cells expressing UUAGGG. The fraction of giant cells varied from 100% at the fifth population doubling (PD) in one culture to 2–6% at 50 PD in several other cultures. Giant cells were absent in all parental cells and clones expressing GGGAUU. The average cellular content of telomere DNA was independent of telomerase activity over 50 PD. The results indicate that expression of RNA complementary to the template region of hTR is sufficient to inhibit telomerase
in vitro and
in vivo, but that the effect of inhibition on individual cells is highly variable. |
doi_str_mv | 10.1016/S0959-8049(98)00049-5 |
format | Article |
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in vivo were inferred from changes in cellular morphology, proliferation capacity, growth rate and measurement of the content of telomere DNA. Giant senescent-like cells emerged shortly after cloning mouse PA317 and human HeLa cells expressing UUAGGG. The fraction of giant cells varied from 100% at the fifth population doubling (PD) in one culture to 2–6% at 50 PD in several other cultures. Giant cells were absent in all parental cells and clones expressing GGGAUU. The average cellular content of telomere DNA was independent of telomerase activity over 50 PD. The results indicate that expression of RNA complementary to the template region of hTR is sufficient to inhibit telomerase
in vitro and
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in vivo were inferred from changes in cellular morphology, proliferation capacity, growth rate and measurement of the content of telomere DNA. Giant senescent-like cells emerged shortly after cloning mouse PA317 and human HeLa cells expressing UUAGGG. The fraction of giant cells varied from 100% at the fifth population doubling (PD) in one culture to 2–6% at 50 PD in several other cultures. Giant cells were absent in all parental cells and clones expressing GGGAUU. The average cellular content of telomere DNA was independent of telomerase activity over 50 PD. The results indicate that expression of RNA complementary to the template region of hTR is sufficient to inhibit telomerase
in vitro and
in vivo, but that the effect of inhibition on individual cells is highly variable.</description><subject>Animals</subject><subject>antisense RNA</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>cancer</subject><subject>Humans</subject><subject>Kidney Neoplasms - enzymology</subject><subject>Kidney Neoplasms - virology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Other treatments</subject><subject>Retroviridae - genetics</subject><subject>retrovirus</subject><subject>RNA, Antisense</subject><subject>RNA, Messenger - genetics</subject><subject>Telomerase - antagonists & inhibitors</subject><subject>Telomerase - genetics</subject><subject>telomerase activity</subject><subject>telomerase inhibition</subject><subject>telomerase RNA</subject><subject>Telomere</subject><subject>telomere content</subject><subject>Treatment. 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General aspects</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bisoffi, M</creatorcontrib><creatorcontrib>Chakerian, A.E</creatorcontrib><creatorcontrib>Fore, M.L</creatorcontrib><creatorcontrib>Bryant, J.E</creatorcontrib><creatorcontrib>Hernandez, J.P</creatorcontrib><creatorcontrib>Moyzis, R.K</creatorcontrib><creatorcontrib>Griffith, J.K</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of cancer (1990)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bisoffi, M</au><au>Chakerian, A.E</au><au>Fore, M.L</au><au>Bryant, J.E</au><au>Hernandez, J.P</au><au>Moyzis, R.K</au><au>Griffith, J.K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of human telomerase by a retrovirus expressing telomeric antisense RNA</atitle><jtitle>European journal of cancer (1990)</jtitle><addtitle>Eur J Cancer</addtitle><date>1998-07-01</date><risdate>1998</risdate><volume>34</volume><issue>8</issue><spage>1242</spage><epage>1249</epage><pages>1242-1249</pages><issn>0959-8049</issn><eissn>1879-0852</eissn><abstract>Human telomerase, the RNA-dependent DNA polymerase that adds TTAGGG repeats to chromosome ends, is selectively expressed in immortalised cells and most tumours, suggesting a potential role for telomerase inhibitors in cancer therapy. Replication-deficient retroviruses were used to determine whether mRNA containing UUAGGG, the complementary sequence to the template region of the hTR telomerase RNA, is sufficient to inhibit telomerase activity. Telomerase activities measured by the telomeric repeat amplification protocol (TRAP) assay in extracts prepared from immortalised mouse fibroblasts, human HeLa cells and human kidney carcinoma cells were inhibited by 75% or greater in 26 of 56 cell clones expressing UUAGGG. Telomerase activity was not inhibited by expression of mRNA containing a transposed sequence, GGGAUU. Telomerase activities
in vivo were inferred from changes in cellular morphology, proliferation capacity, growth rate and measurement of the content of telomere DNA. Giant senescent-like cells emerged shortly after cloning mouse PA317 and human HeLa cells expressing UUAGGG. The fraction of giant cells varied from 100% at the fifth population doubling (PD) in one culture to 2–6% at 50 PD in several other cultures. Giant cells were absent in all parental cells and clones expressing GGGAUU. The average cellular content of telomere DNA was independent of telomerase activity over 50 PD. The results indicate that expression of RNA complementary to the template region of hTR is sufficient to inhibit telomerase
in vitro and
in vivo, but that the effect of inhibition on individual cells is highly variable.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>9849487</pmid><doi>10.1016/S0959-8049(98)00049-5</doi><tpages>8</tpages></addata></record> |
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subjects | Animals antisense RNA Base Sequence Biological and medical sciences cancer Humans Kidney Neoplasms - enzymology Kidney Neoplasms - virology Medical sciences Mice Molecular Sequence Data Other treatments Retroviridae - genetics retrovirus RNA, Antisense RNA, Messenger - genetics Telomerase - antagonists & inhibitors Telomerase - genetics telomerase activity telomerase inhibition telomerase RNA Telomere telomere content Treatment. General aspects Tumor Cells, Cultured Tumors |
title | Inhibition of human telomerase by a retrovirus expressing telomeric antisense RNA |
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