Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16
Medulloblastoma, one of the most malignant pediatric brain tumors, is believed to arise from the undifferentiated external granule-layer cells in the cerebellum. It is a heterogeneous cancer, and the mechanism of tumorigenesis for the majority of types is unknown. Repressor element-1 silencing trans...
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| Veröffentlicht in: | Molecular cancer therapeutics 2005-03, Vol.4 (3), p.343-349 |
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| creator | Fuller, Gregory N Su, Xiaohua Price, Roger E Cohen, Zvi R Lang, Frederick F Sawaya, Raymond Majumder, Sadhan |
| description | Medulloblastoma, one of the most malignant pediatric brain tumors, is believed to arise from the undifferentiated external
granule-layer cells in the cerebellum. It is a heterogeneous cancer, and the mechanism of tumorigenesis for the majority of
types is unknown. Repressor element-1 silencing transcription/neuron-restrictive silencer factor (REST/NRSF) is a transcriptional
repressor that can block transcription of a battery of neuronal differentiation genes by binding to a specific consensus DNA
sequence present in their regulatory region. Previously, we found that some medulloblastoma cell lines express REST/NRSF at
high levels compared with either neuronal progenitor cells or fully differentiated neurons. However, it is not known if REST/NRSF
is indeed overexpressed in human medulloblastoma tumor specimens and in what frequency. Here, we did an immunohistochemical
analysis of such tumor specimens using an anti-REST antibody. We show that among 21 human medulloblastoma tumors, 17 expressed
REST/NRSF (6 strongly and 11 weakly). In contrast, adjacent normal cerebellum tissue sections and four of the tumor specimens
did not express REST/NRSF, indicating that abnormal expression of REST/NRSF is observed in the majority of human medulloblastoma
tumors. To determine whether countering REST/NRSF activity blocks tumorigenicity of medulloblastoma cells, especially in the
intracranial (i.c.) environment, we found that adenovirus-mediated expression of REST-VP16, a recombinant transcription factor
that can compete with REST/NRSF and activate REST/NRSF target genes instead of repressing them, blocked the i.c. tumorigenic
potential of medulloblastoma cells and inhibited growth of established tumors in nude mice, suggesting that REST/NRSF may
serve as a therapeutic target for medulloblastoma and that forced expression of neuronal differentiation genes in medulloblastoma
cells through agents, such as REST-VP16, can interfere with their tumorigenicity. |
| doi_str_mv | 10.1158/1535-7163.MCT-04-0228 |
| format | Article |
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granule-layer cells in the cerebellum. It is a heterogeneous cancer, and the mechanism of tumorigenesis for the majority of
types is unknown. Repressor element-1 silencing transcription/neuron-restrictive silencer factor (REST/NRSF) is a transcriptional
repressor that can block transcription of a battery of neuronal differentiation genes by binding to a specific consensus DNA
sequence present in their regulatory region. Previously, we found that some medulloblastoma cell lines express REST/NRSF at
high levels compared with either neuronal progenitor cells or fully differentiated neurons. However, it is not known if REST/NRSF
is indeed overexpressed in human medulloblastoma tumor specimens and in what frequency. Here, we did an immunohistochemical
analysis of such tumor specimens using an anti-REST antibody. We show that among 21 human medulloblastoma tumors, 17 expressed
REST/NRSF (6 strongly and 11 weakly). In contrast, adjacent normal cerebellum tissue sections and four of the tumor specimens
did not express REST/NRSF, indicating that abnormal expression of REST/NRSF is observed in the majority of human medulloblastoma
tumors. To determine whether countering REST/NRSF activity blocks tumorigenicity of medulloblastoma cells, especially in the
intracranial (i.c.) environment, we found that adenovirus-mediated expression of REST-VP16, a recombinant transcription factor
that can compete with REST/NRSF and activate REST/NRSF target genes instead of repressing them, blocked the i.c. tumorigenic
potential of medulloblastoma cells and inhibited growth of established tumors in nude mice, suggesting that REST/NRSF may
serve as a therapeutic target for medulloblastoma and that forced expression of neuronal differentiation genes in medulloblastoma
cells through agents, such as REST-VP16, can interfere with their tumorigenicity.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-04-0228</identifier><identifier>PMID: 15767543</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Adenoviridae - genetics ; Animals ; Apoptosis ; Brain - metabolism ; Brain - pathology ; Brain Neoplasms - metabolism ; Cell Differentiation ; Cell Line, Tumor ; Etoposide - pharmacology ; Green Fluorescent Proteins - metabolism ; Humans ; Immunohistochemistry ; Magnetic Resonance Imaging ; Medulloblastoma - metabolism ; Mice ; Mice, Nude ; Models, Biological ; Neoplasm Transplantation ; Neurons - metabolism ; Repressor Proteins - biosynthesis ; Stem Cells - metabolism ; Time Factors ; Transcription Factors - biosynthesis ; Transcription, Genetic</subject><ispartof>Molecular cancer therapeutics, 2005-03, Vol.4 (3), p.343-349</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c369t-b12e09d7154697d71708296f50cf9f3fcdcf87185f7fc9fc617f7f8ab6b5aef3</citedby><cites>FETCH-LOGICAL-c369t-b12e09d7154697d71708296f50cf9f3fcdcf87185f7fc9fc617f7f8ab6b5aef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15767543$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fuller, Gregory N</creatorcontrib><creatorcontrib>Su, Xiaohua</creatorcontrib><creatorcontrib>Price, Roger E</creatorcontrib><creatorcontrib>Cohen, Zvi R</creatorcontrib><creatorcontrib>Lang, Frederick F</creatorcontrib><creatorcontrib>Sawaya, Raymond</creatorcontrib><creatorcontrib>Majumder, Sadhan</creatorcontrib><title>Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Medulloblastoma, one of the most malignant pediatric brain tumors, is believed to arise from the undifferentiated external
granule-layer cells in the cerebellum. It is a heterogeneous cancer, and the mechanism of tumorigenesis for the majority of
types is unknown. Repressor element-1 silencing transcription/neuron-restrictive silencer factor (REST/NRSF) is a transcriptional
repressor that can block transcription of a battery of neuronal differentiation genes by binding to a specific consensus DNA
sequence present in their regulatory region. Previously, we found that some medulloblastoma cell lines express REST/NRSF at
high levels compared with either neuronal progenitor cells or fully differentiated neurons. However, it is not known if REST/NRSF
is indeed overexpressed in human medulloblastoma tumor specimens and in what frequency. Here, we did an immunohistochemical
analysis of such tumor specimens using an anti-REST antibody. We show that among 21 human medulloblastoma tumors, 17 expressed
REST/NRSF (6 strongly and 11 weakly). In contrast, adjacent normal cerebellum tissue sections and four of the tumor specimens
did not express REST/NRSF, indicating that abnormal expression of REST/NRSF is observed in the majority of human medulloblastoma
tumors. To determine whether countering REST/NRSF activity blocks tumorigenicity of medulloblastoma cells, especially in the
intracranial (i.c.) environment, we found that adenovirus-mediated expression of REST-VP16, a recombinant transcription factor
that can compete with REST/NRSF and activate REST/NRSF target genes instead of repressing them, blocked the i.c. tumorigenic
potential of medulloblastoma cells and inhibited growth of established tumors in nude mice, suggesting that REST/NRSF may
serve as a therapeutic target for medulloblastoma and that forced expression of neuronal differentiation genes in medulloblastoma
cells through agents, such as REST-VP16, can interfere with their tumorigenicity.</description><subject>Adenoviridae - genetics</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Brain Neoplasms - metabolism</subject><subject>Cell Differentiation</subject><subject>Cell Line, Tumor</subject><subject>Etoposide - pharmacology</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Magnetic Resonance Imaging</subject><subject>Medulloblastoma - metabolism</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Models, Biological</subject><subject>Neoplasm Transplantation</subject><subject>Neurons - metabolism</subject><subject>Repressor Proteins - biosynthesis</subject><subject>Stem Cells - metabolism</subject><subject>Time Factors</subject><subject>Transcription Factors - biosynthesis</subject><subject>Transcription, Genetic</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFu1DAQhiNERUvhEUA-IZBwayexnRyrVYFKrYpgxdVyvOPGyLEX22nZB-P96nRX6pHTjKz_nxn_X1W9o-SMUtadU9YwLChvzm5Wa0xaTOq6e1GdlPcOd4y2L5_6vea4ep3Sb0Jo19f0VXVMmeCCtc1J9e9G-R0a50l5NMFmdi4MTqUcJoXyPIWYULiHCH-3EVJCEZ5qiAgcTOAzpihZB15bf4dyVD7paLfZBo8-_rj8uf507mGOweNiy9HqbO_h4ICIjNI5xM_oYbR6RLrcMAAys9fLAOXcDukw-1z2b9CwQ8tA_Os75W-qI6NcgreHelqtv1yuV9_w9e3Xq9XFNdYN7zMeaA2k3wjKWt6LUgXp6p4bRrTpTWP0RptO0I4ZYXRvNKeidJ0a-MAUmOa0-rAfu43hz1w-ICebNDinPIQ5yZIhrTkT_xXSXnDSsq4I2V6oY0gpgpHbaCcVd5ISuXCVCzO5MJOFqyStXLgW3_vDgnkomJ5dB5DPF4z2bnywEWRJs0RcYgcV9Shb2cimCB8Bs9axAg</recordid><startdate>20050301</startdate><enddate>20050301</enddate><creator>Fuller, Gregory N</creator><creator>Su, Xiaohua</creator><creator>Price, Roger E</creator><creator>Cohen, Zvi R</creator><creator>Lang, Frederick F</creator><creator>Sawaya, Raymond</creator><creator>Majumder, Sadhan</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20050301</creationdate><title>Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16</title><author>Fuller, Gregory N ; Su, Xiaohua ; Price, Roger E ; Cohen, Zvi R ; Lang, Frederick F ; Sawaya, Raymond ; Majumder, Sadhan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c369t-b12e09d7154697d71708296f50cf9f3fcdcf87185f7fc9fc617f7f8ab6b5aef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Adenoviridae - genetics</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Brain Neoplasms - metabolism</topic><topic>Cell Differentiation</topic><topic>Cell Line, Tumor</topic><topic>Etoposide - pharmacology</topic><topic>Green Fluorescent Proteins - metabolism</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Magnetic Resonance Imaging</topic><topic>Medulloblastoma - metabolism</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Models, Biological</topic><topic>Neoplasm Transplantation</topic><topic>Neurons - metabolism</topic><topic>Repressor Proteins - biosynthesis</topic><topic>Stem Cells - metabolism</topic><topic>Time Factors</topic><topic>Transcription Factors - biosynthesis</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fuller, Gregory N</creatorcontrib><creatorcontrib>Su, Xiaohua</creatorcontrib><creatorcontrib>Price, Roger E</creatorcontrib><creatorcontrib>Cohen, Zvi R</creatorcontrib><creatorcontrib>Lang, Frederick F</creatorcontrib><creatorcontrib>Sawaya, Raymond</creatorcontrib><creatorcontrib>Majumder, Sadhan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fuller, Gregory N</au><au>Su, Xiaohua</au><au>Price, Roger E</au><au>Cohen, Zvi R</au><au>Lang, Frederick F</au><au>Sawaya, Raymond</au><au>Majumder, Sadhan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2005-03-01</date><risdate>2005</risdate><volume>4</volume><issue>3</issue><spage>343</spage><epage>349</epage><pages>343-349</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Medulloblastoma, one of the most malignant pediatric brain tumors, is believed to arise from the undifferentiated external
granule-layer cells in the cerebellum. It is a heterogeneous cancer, and the mechanism of tumorigenesis for the majority of
types is unknown. Repressor element-1 silencing transcription/neuron-restrictive silencer factor (REST/NRSF) is a transcriptional
repressor that can block transcription of a battery of neuronal differentiation genes by binding to a specific consensus DNA
sequence present in their regulatory region. Previously, we found that some medulloblastoma cell lines express REST/NRSF at
high levels compared with either neuronal progenitor cells or fully differentiated neurons. However, it is not known if REST/NRSF
is indeed overexpressed in human medulloblastoma tumor specimens and in what frequency. Here, we did an immunohistochemical
analysis of such tumor specimens using an anti-REST antibody. We show that among 21 human medulloblastoma tumors, 17 expressed
REST/NRSF (6 strongly and 11 weakly). In contrast, adjacent normal cerebellum tissue sections and four of the tumor specimens
did not express REST/NRSF, indicating that abnormal expression of REST/NRSF is observed in the majority of human medulloblastoma
tumors. To determine whether countering REST/NRSF activity blocks tumorigenicity of medulloblastoma cells, especially in the
intracranial (i.c.) environment, we found that adenovirus-mediated expression of REST-VP16, a recombinant transcription factor
that can compete with REST/NRSF and activate REST/NRSF target genes instead of repressing them, blocked the i.c. tumorigenic
potential of medulloblastoma cells and inhibited growth of established tumors in nude mice, suggesting that REST/NRSF may
serve as a therapeutic target for medulloblastoma and that forced expression of neuronal differentiation genes in medulloblastoma
cells through agents, such as REST-VP16, can interfere with their tumorigenicity.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>15767543</pmid><doi>10.1158/1535-7163.MCT-04-0228</doi><tpages>7</tpages></addata></record> |
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| ispartof | Molecular cancer therapeutics, 2005-03, Vol.4 (3), p.343-349 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Adenoviridae - genetics Animals Apoptosis Brain - metabolism Brain - pathology Brain Neoplasms - metabolism Cell Differentiation Cell Line, Tumor Etoposide - pharmacology Green Fluorescent Proteins - metabolism Humans Immunohistochemistry Magnetic Resonance Imaging Medulloblastoma - metabolism Mice Mice, Nude Models, Biological Neoplasm Transplantation Neurons - metabolism Repressor Proteins - biosynthesis Stem Cells - metabolism Time Factors Transcription Factors - biosynthesis Transcription, Genetic |
| title | Many human medulloblastoma tumors overexpress repressor element-1 silencing transcription (REST)/neuron-restrictive silencer factor, which can be functionally countered by REST-VP16 |
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