Ubiquitination-resistant p53 protein transduction therapy facilitates anti-cancer effect on the growth of human malignant glioma cells.
Protein transduction therapy using poly-arginine can deliver the bioactive p53 protein into cancer cells and inhibits the proliferation of the cells. However, one disadvantage of such therapy is the short intracellular half-life of the delivered protein. Here, we generated mutant proteins in which multiple lysine residues in the C-terminal were substituted by arginines. The mutant proteins were effectively delivered in glioma cells and were resistant to Mdm2-mediated ubiquitination. Moreover, the mutant proteins displayed higher transcription regulatory activity and powerful inhibition of the proliferation of glioma cells. These results suggest that ubiquitination-resistant p53 protein therapy may become a new effective cancer therapy.
Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Hiroyuki
H
Michiue
Kazuhito
K
Tomizawa
Masayuki
M
Matsushita
Takashi
T
Tamiya
Yun-Fei
YF
Lu
Tomotsugu
T
Ichikawa
Isao
I
Date
Hideki
H
Matsui
D000256:Adenoviridae / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter / Q000235:genetics; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000473:pathology / Q000628:therapy; D006801:Humans; D020287:In Situ Nick-End Labeling; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism
D000970:Antineoplastic Agents; D018076:DNA, Complementary; D010455:Peptides; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C015462:polyarginine