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PMID: 9419352 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 1 ·1998-01-06 ·Pages 195-200

Chen L, Agrawal S, Zhou W, Zhang R, Chen J

Abstract

The MDM2 oncogene encodes an inhibitor of the p53 tumor suppressor protein that regulates p53 in a negative feedback loop. MDM2 gene amplification and overexpression occur in several types of tumors and are often associated with poor prognosis. An MDM2 antisense phosphorothioate oligodeoxynucleotide has been identified that effectively inhibits MDM2 expression in tumor cells containing MDM2 gene amplifications. Antisense inhibition of MDM2 is associated with a decrease in MDM2-p53 complex formation, increase in p53-inducible gene expression, increase in p53 transcriptional activity, and apoptosis. Significantly, inhibition of MDM2 expression enhances the activation of p53 by a DNA-damaging cancer chemotherapy agent in a synergistic fashion. Therefore, the MDM2 negative feedback pathway is an important limiting factor in DNA damage-induced p53 activation. MDM2 antisense oligonucleotides may be useful as antitumor agents alone or as enhancers of other conventional DNA-damaging drugs.

MeSH Terms
Apoptosis Cell Line DNA Damage Gene Amplification Humans Neoplasm Proteins/biosynthesis,genetics Nuclear Proteins Oligonucleotides, Antisense/pharmacology Proto-Oncogene Proteins/biosynthesis,genetics Proto-Oncogene Proteins c-mdm2 Tumor Cells, Cultured Tumor Suppressor Protein p53/metabolism
Chemicals
Neoplasm Proteins Nuclear Proteins Oligonucleotides, Antisense Proto-Oncogene Proteins Tumor Suppressor Protein p53 MDM2 protein, human Proto-Oncogene Proteins c-mdm2
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Chen L
Department of Microbiology, Louisiana State University Medical Center, Stanley S. Scott Cancer Center, New Orleans, LA 70112, USA.
Agrawal S
Zhou W
Zhang R
Chen J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.1.195
Published
1998-01-06
Pages
195-200
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC18173
Subset
IM
Grants
NCI NIH HHS · CA72915 · United States
External Links
PubMed source DOI: 10.1073/pnas.95.1.195 PMC Full Text View journal details
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