Efficient replication of adenovirus despite the overexpression of active and nondegradable p53.
The adenoviral oncoproteins E1B-55 kDa and E4orf6 inactivate and destabilize the tumor suppressor protein p53, thereby contributing to malignant transformation. However, it is unclear whether the elimination of p53 also contributes to the efficiency of viral replication. Furthermore, it is controversial whether adenoviruses with a deletion in the E1B-55 kDa-coding region might selectively replicate in cells with a mutation or deletion of the p53 gene and, therefore, represent a tool in cancer therapy. To address the role of p53 in virus replication, amino acid substitutions were introduced into the NH(2)-terminal portion of p53, replacing residues 24-28 with the corresponding sequence of the human p53-homologue p73. This replacement leaves p53 transcriptionally active but renders the modified protein, termed p53mt24-28, completely resistant to inhibition and degradation by adenoviral oncoproteins. Surprisingly, even strong overexpression of p53 or p53mt24-28 allowed the virus to replicate as efficiently as in the absence of p53 proteins, both in tumor cells and in primary endothelial cells. Also, p53 or p53mt24-28 did not reduce the amount of virus released from infected cells. These observations were made in primary cells or in cell lines that were capable of expressing the p53-agonist p14ARF. Thus, active p53 does not inhibit the growth of adenovirus. Alternative strategies should be used to improve the utility of adenoviruses in cancer therapy.
Koch
P
P
Institut für Virologie, Philipps-Universität Marburg, Robert Koch Str. 17, 35037 Marburg, Germany.
Gatfield
J
J
Löber
C
C
Hobom
U
U
Lenz-Stöppler
C
C
Roth
J
J
Dobbelstein
M
M
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017501:Adenovirus E1B Proteins / Q000502:physiology; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D014176:Protein Biosynthesis; D011993:Recombinant Fusion Proteins; D014162:Transfection; D000072160:Tumor Protein p73; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D014779:Virus Replication
D017501:Adenovirus E1B Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins