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Protein kinase C alpha-specific peptide substrate graft-type copolymer for cancer cell-specific gene regulation systems.

Abstract
We recently proposed a novel gene regulation system responding to specifically and abnormally activated intracellular enzymes in diseased cells. In the present study, we focused on protein kinase C (PKC)alpha, which is hyper-activated in most tumor cells, as a trigger for transgene regulation. We prepared cationic copolymers comprising hydrophilic and neutral polymers in main chains and cationic peptide substrates with different contents in side chains. Our copolymer with high peptide content (>3 mol%) condensed with pDNA more weakly than with poly(L-lysine) (pLL) having a similar molecular weight, but gene suppression was nearly identical to that of pLL, probably due to the steric hindrance of the main chains in our copolymer. Steric hindrance of the main chains barely affected the phosphorylation reaction of the pendant peptide. In cell and mouse experiments, higher gene expression was observed in complexes of pDNA with copolymers pended PKC alpha-specific substrate peptide than that in complexes with negative copolymers pended peptide substituted phosphorylation site of serine residues with alanine. These results indicate that our system can recognize intracellular PKC alpha as a trigger to regulate transgene expression, and may be useful for tumor gene therapy.
AuthorsRiki Toita, Jeong-Hun Kang, Jong-Hwan Kim, Tetsuro Tomiyama, Takeshi Mori, Takuro Niidome, Byungdug Jun, Yoshiki Katayama
JournalJournal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 139 Issue 2 Pg. 133-9 (Oct 15 2009) ISSN: 1873-4995 [Electronic] Netherlands
PMID19545594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Peptides
  • Polylysine
  • DNA
  • Protein Kinase C-alpha
Topics
  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • DNA (administration & dosage)
  • Gene Expression Regulation, Neoplastic
  • Genetic Therapy
  • Male
  • Melanoma (genetics, therapy)
  • Mice
  • Mice, Inbred BALB C
  • Peptides (chemistry)
  • Plasmids (administration & dosage)
  • Polylysine (chemistry)
  • Protein Kinase C-alpha (genetics, metabolism)
  • Transfection

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