Genetic reprogramming of tumor cells by zinc finger transcription factors

Cancer arises by the accumulation of genetic alterations in DNA leading to aberrant gene transcription. Expression-profiling studies have correlated genomewide expression signatures with malignancy. However, functional analysis elucidating the contribution and synergy of genes in specific cancer cel...

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Autors principals: Blancafort, Pilar, Chen, Emily I., Gonzalez, Beatriz, Bergquist, Sharon, Zijlstra, Andries, Guthy, Daniel, Brachat, Arndt, Brakenhoff, Ruud H., Quigley, James P., Erdmann, Dirk, Barbas, Carlos F.
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Idioma:English
Publicat: National Academy of Sciences 2005
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Biological Sciences
Accés en línia:https://ncbi.nlm.nih.gov/pmc/articles/PMC1187960/
https://ncbi.nlm.nih.gov/pubmed/16081541
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1073/pnas.0501162102
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spelling pubmed-11879602006-02-16 Genetic reprogramming of tumor cells by zinc finger transcription factors Blancafort, Pilar Chen, Emily I. Gonzalez, Beatriz Bergquist, Sharon Zijlstra, Andries Guthy, Daniel Brachat, Arndt Brakenhoff, Ruud H. Quigley, James P. Erdmann, Dirk Barbas, Carlos F. Proc Natl Acad Sci U S A Biological Sciences Cancer arises by the accumulation of genetic alterations in DNA leading to aberrant gene transcription. Expression-profiling studies have correlated genomewide expression signatures with malignancy. However, functional analysis elucidating the contribution and synergy of genes in specific cancer cell phenotypes remains a formidable obstacle. Herein, we describe an alternative genetic approach for identification of genes involved in tumor progression by using a library of zinc finger artificial transcription factors (ATFs) and functional screening of tumor cells as a source of genetic plasticity and clonal selection. We isolated a six-zinc finger transcriptional activator (TF 20-VP, TF 20 containing the VP64 activator domain) that acts to reprogram a drug-sensitive, poorly invasive, and nonmetastatic cell line into a cell line with a drug-resistant, highly invasive, and metastatic phenotype. Differential expression profiles of cells expressing TF 20-VP followed by functional studies, both in vitro and in animal models, revealed that invasion and metastasis requires coregulation of multiple target genes. Significantly, the E48 antigen, associated with poor metastasis-free survival in head and neck cancer, was identified as one specific target of TF 20-VP. We have shown phenotypic modulation of tumor cell behavior by E48 expression, including enhanced cell migration in vitro and tumor cell dissemination in vivo. This study demonstrates the use of ATFs to identify the group of genes that cooperate during tumor progression. By coregulating multiple targets, ATFs can be used as master genetic switches to reprogram and modulate complex neoplastic phenotypes. National Academy of Sciences 2005-08-16 2005-08-04 /pmc/articles/PMC1187960/ /pubmed/16081541 http://dx.doi.org/10.1073/pnas.0501162102 Text en Copyright © 2005, The National Academy of Sciences
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Biological Sciences
spellingShingle Biological Sciences
Blancafort, Pilar
Chen, Emily I.
Gonzalez, Beatriz
Bergquist, Sharon
Zijlstra, Andries
Guthy, Daniel
Brachat, Arndt
Brakenhoff, Ruud H.
Quigley, James P.
Erdmann, Dirk
Barbas, Carlos F.
Genetic reprogramming of tumor cells by zinc finger transcription factors
description Cancer arises by the accumulation of genetic alterations in DNA leading to aberrant gene transcription. Expression-profiling studies have correlated genomewide expression signatures with malignancy. However, functional analysis elucidating the contribution and synergy of genes in specific cancer cell phenotypes remains a formidable obstacle. Herein, we describe an alternative genetic approach for identification of genes involved in tumor progression by using a library of zinc finger artificial transcription factors (ATFs) and functional screening of tumor cells as a source of genetic plasticity and clonal selection. We isolated a six-zinc finger transcriptional activator (TF 20-VP, TF 20 containing the VP64 activator domain) that acts to reprogram a drug-sensitive, poorly invasive, and nonmetastatic cell line into a cell line with a drug-resistant, highly invasive, and metastatic phenotype. Differential expression profiles of cells expressing TF 20-VP followed by functional studies, both in vitro and in animal models, revealed that invasion and metastasis requires coregulation of multiple target genes. Significantly, the E48 antigen, associated with poor metastasis-free survival in head and neck cancer, was identified as one specific target of TF 20-VP. We have shown phenotypic modulation of tumor cell behavior by E48 expression, including enhanced cell migration in vitro and tumor cell dissemination in vivo. This study demonstrates the use of ATFs to identify the group of genes that cooperate during tumor progression. By coregulating multiple targets, ATFs can be used as master genetic switches to reprogram and modulate complex neoplastic phenotypes.
author Blancafort, Pilar
Chen, Emily I.
Gonzalez, Beatriz
Bergquist, Sharon
Zijlstra, Andries
Guthy, Daniel
Brachat, Arndt
Brakenhoff, Ruud H.
Quigley, James P.
Erdmann, Dirk
Barbas, Carlos F.
author_facet Blancafort, Pilar
Chen, Emily I.
Gonzalez, Beatriz
Bergquist, Sharon
Zijlstra, Andries
Guthy, Daniel
Brachat, Arndt
Brakenhoff, Ruud H.
Quigley, James P.
Erdmann, Dirk
Barbas, Carlos F.
author_sort Blancafort, Pilar
title Genetic reprogramming of tumor cells by zinc finger transcription factors
title_short Genetic reprogramming of tumor cells by zinc finger transcription factors
title_full Genetic reprogramming of tumor cells by zinc finger transcription factors
title_fullStr Genetic reprogramming of tumor cells by zinc finger transcription factors
title_full_unstemmed Genetic reprogramming of tumor cells by zinc finger transcription factors
title_sort genetic reprogramming of tumor cells by zinc finger transcription factors
publisher National Academy of Sciences
publisher_facet National Academy of Sciences
publishDate 2005
url https://ncbi.nlm.nih.gov/pmc/articles/PMC1187960/
https://ncbi.nlm.nih.gov/pubmed/16081541
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1073/pnas.0501162102
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