Down-regulation of MDM2 and activation of p53 in human cancer cells by antisense 9-aminoacridine-PNA (peptide nucleic acid) conjugates

Nucleic Acids Research
Takehiko Shiraishi, P E Nielsen

Abstract

A series of peptide nucleic acid (PNA) oligomers targeting the mdm2 oncogene mRNA has been tested for the ability to inhibit the growth of JAR cells. The effect of these PNAs on the cells was also reflected in reduced levels of the MDM2 protein and increased levels of the p53 tumor suppressor protein, which is negatively regulated by MDM2. Initially, PNA oligomers were delivered as DNA complexes with lipofectamine, but it was discovered that PNA conjugated to the DNA intercalator 9-aminoacridine (Acr) (Acr-PNA) could be effectively delivered to JAR cells (as well as to HeLa pLuc705 cells) even in the absence of a DNA carrier. Using such lipofectamine-delivered Acr-PNA conjugates, one PNA targeting a cryptic AUG initiation site was identified that at a concentration of 2 microM caused a reduction of MDM2 levels to approximately 20% (but no reduction in mdm2 mRNA levels) and a 3-fold increase in p53 levels, whereas a 2-base mismatch control had no such effects. Furthermore, transcriptional activation by p53 was also increased (6-fold), and cell viability was reduced to 80%. Finally, this PNA acted cooperatively with camptothecin treatment both with regard to p53 activity induction as well as cell viability. Using this novel cell ...Continue Reading

References

Jul 1, 1993·Genes & Development·X WuA J Levine
May 1, 1995·Journal of Peptide Science : an Official Publication of the European Peptide Society·L ChristensenR H Berg
Feb 21, 1998·Proceedings of the National Academy of Sciences of the United States of America·L ChenJ Chen
Jul 22, 1998·Nucleic Acids Research·J MomandJ Niland
Jun 22, 1999·Chemistry & Biology·S E HamiltonD R Corey
Nov 24, 1999·Bioconjugate Chemistry·T LjungstrømP E Nielsen
Jun 7, 2000·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·I LebedevaM Vilenchik
Nov 10, 2000·International Journal of Cancer. Journal International Du Cancer·G TortoraF Ciardiello
Apr 3, 2001·Nature Biotechnology·L GoodP E Nielsen
Jul 5, 2002·Journal of Molecular Biology·Nathalie DiasTula Ester Saison-Behmoaras
Jun 6, 2003·Journal of the American Chemical Society·Thomas Bentin, Peter E Nielsen

❮ Previous
Next ❯

Citations

Jan 28, 2006·Nucleosides, Nucleotides & Nucleic Acids·Vladimir A EfimovEric Wickstrom
Apr 6, 2006·Oligonucleotides·Frank Winther RasmussenUffe Koppelhus
May 4, 2006·Nucleic Acids Research·Vladimir A EfimovOksana G Chakhmakhcheva
Jun 1, 2007·Nucleic Acids Research·Fatima Boutimah-HamoudiTula Ester Saison-Behmoaras
Feb 16, 2006·Molecular and Cellular Biology·Yi DingDuen-Hwa Yan
Mar 20, 2008·Virology Journal·Weilin WuFatah Kashanchi
Apr 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yana K ReshetnyakDonald M Engelman
Jan 11, 2014·Expert Opinion on Therapeutic Patents·Roberto Gambari
Oct 26, 2005·Growth Factors·Yaara Levav-CohenYgal Haupt
Aug 21, 2007·Expert Opinion on Biological Therapy·Soccorsa PensatoAlessandra Romanelli
Sep 8, 2009·Expert Opinion on Biological Therapy·William ColeyFatah Kashanchi
Mar 18, 2008·Bioorganic & Medicinal Chemistry Letters·Anna AviñóRamon Eritja
Jun 1, 2006·Advances in Genetics·Karin E LundinC I Edvard Smith
Oct 22, 2013·Molecular Immunology·Lakshmi T SunkaraGuolong Zhang
Jan 5, 2019·Advanced Pharmaceutical Bulletin·Soheila MontazersahebHojjatollah Nozad Charoudeh
Feb 15, 2011·Bioorganicheskaia khimiia·V A EfimovO G Chakhmakhcheva
Feb 8, 2019·Current Pharmaceutical Biotechnology·Soheila MontazersahebMohammad S Hejazi
Dec 14, 2016·Molecular Medicine Reports·Ning ZhouZhongzhou Si
Aug 25, 2021·Applied Microbiology and Biotechnology·Vinay G JoshiSatish Kumar
Jan 19, 2006·Bioconjugate Chemistry·Takehiko ShiraishiPeter E Nielsen

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.