Functional p53 chimeras containing the Epstein-Barr virus Gly-Ala repeat are protected from Mdm2- and HPV-E6-induced proteolysis.
Functional inactivation of the tumor suppressor protein p53 by accelerated ubiquitin/proteasome-dependent proteolysis is a common event in tumor progression. Proteasomal degradation is inhibited by the Gly-Ala repeat (GAr) of the Epstein-Barr virus nuclear antigen-1, which acts as a transferable element on a variety of proteasomal substrates. We demonstrate that p53 chimeras containing GAr domains of different lengths and positions within the protein are protected from proteolysis induced by the ubiquitin ligases murine double minute 2 and E6-associated protein but are still ubiquitinated and retain the capacity to interact with the S5a ubiquitin-binding subunit of the proteasome. The GAr chimeras transactivate p53 target genes, induce cell cycle arrest and apoptosis, and exhibit improved growth inhibitory activity in tumor cells with impaired endogenous p53 activity.
Heessen
Stijn
S
Microbiology and Tumor Biology Center, and Cancer Center Karolinska, Karolinska Institute, S-17177 Stockholm, Sweden.
Leonchiks
Ainars
A
Issaeva
Natalia
N
Sharipo
Anatoly
A
Selivanova
Galina
G
Masucci
Maria G
MG
Dantuma
Nico P
NP
D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division; D003546:Cysteine Endopeptidases / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004151:Dipeptides / Q000737:chemistry*; D016158:Genes, p53; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames; D012516:Osteosarcoma; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins; D020449:Repetitive Sequences, Amino Acid; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; D004151:Dipeptides; C052603:E6 protein, Human papillomavirus type 18; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C065992:N-glycylalanine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex