TY - JOUR
T1 - A conditionally replicating adenovirus targeted to tumor cells through activated RAS/P-MAPK-selective mRNA stabilization
AU - Ahmed, Atique
AU - Thompson, Jill
AU - Emiliusen, Lisa
AU - Murphy, Stephen
AU - Beauchamp, R. Daniel
AU - Suzuki, Kaori
AU - Alemany, Ramon
AU - Harrington, Kevin
AU - Vile, Richard G.
N1 - Funding Information:
The work in this manuscript is dedicated to the memory of Ashfaq Uddin Ahmed. We thank Toni Higgins for expert secretarial assistance. A.A., J.T. and R.V. are supported by the Mayo Foundation.
PY - 2003/7/1
Y1 - 2003/7/1
N2 - The expression of various proteins associated with rapid responses to inflammation and/or proliferation can be controlled at the level of mRNA stability. Because tumor cells continually recapitulate intracellular programs of proliferation, we have used tumor cell-selective stabilization of mRNA as a means to control therapeutic gene expression. We describe an adenoviral vector that is conditionally replication competent in which expression of the essential adenoviral early region 1A (E1A) gene is regulated by ligation to the 3′ untranslated region (UTR) of PTGS2 (also known as COX2), the gene encoding prostaglandin-endoperoxide synthase 2, allowing activated RAS/P-MAPK-specific stabilization of its mRNA. Induction of activated RAS supports replication, whereas matched cells in which activated RAS/P-MAPK is not expressed are very poor substrates for viral replication both in vitro and in vivo. Further tumor-targeting strategies will also be required to prevent viral replication at extratumoral sites where PTGS2 is normally induced. Many different genes contain 3′ UTRs that control selective mRNA stability under different physiological, pathological and tumor-associated conditions. Therefore, generating tumor selectivity at the level of mRNA stability is a strategy with broad potential applicability in vector design.
AB - The expression of various proteins associated with rapid responses to inflammation and/or proliferation can be controlled at the level of mRNA stability. Because tumor cells continually recapitulate intracellular programs of proliferation, we have used tumor cell-selective stabilization of mRNA as a means to control therapeutic gene expression. We describe an adenoviral vector that is conditionally replication competent in which expression of the essential adenoviral early region 1A (E1A) gene is regulated by ligation to the 3′ untranslated region (UTR) of PTGS2 (also known as COX2), the gene encoding prostaglandin-endoperoxide synthase 2, allowing activated RAS/P-MAPK-specific stabilization of its mRNA. Induction of activated RAS supports replication, whereas matched cells in which activated RAS/P-MAPK is not expressed are very poor substrates for viral replication both in vitro and in vivo. Further tumor-targeting strategies will also be required to prevent viral replication at extratumoral sites where PTGS2 is normally induced. Many different genes contain 3′ UTRs that control selective mRNA stability under different physiological, pathological and tumor-associated conditions. Therefore, generating tumor selectivity at the level of mRNA stability is a strategy with broad potential applicability in vector design.
UR - http://www.scopus.com/inward/record.url?scp=0038496739&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0038496739&partnerID=8YFLogxK
U2 - 10.1038/nbt835
DO - 10.1038/nbt835
M3 - Article
C2 - 12794639
AN - SCOPUS:0038496739
SN - 1087-0156
VL - 21
SP - 771
EP - 777
JO - Nature biotechnology
JF - Nature biotechnology
IS - 7
ER -