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Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter.

Abstract
One impediment to effective cancer-specific gene therapy is the rarity of regulatory sequences targeting gene expression selectively in tumor cells. Although many tissue-specific promoters are recognized, few cancer-selective gene promoters are available. Progression-elevated gene-3 (PEG-3) is a rodent gene identified by subtraction hybridization that displays elevated expression as a function of transformation by diversely acting oncogenes, DNA damage, and cancer cell progression. The promoter of PEG-3, PEG-Prom, displays robust expression in a broad spectrum of human cancer cell lines with marginal expression in normal cellular counterparts. Whereas GFP expression, when under the control of a CMV promoter, is detected in both normal and cancer cells, when GFP is expressed under the control of the PEG-Prom, cancer-selective expression is evident. Mutational analysis identifies the AP-1 and PEA-3 transcription factors as primary mediators of selective, cancer-specific expression of the PEG-Prom. Synthesis of apoptosis-inducing genes, under the control of the CMV promoter, inhibits the growth of both normal and cancer cells, whereas PEG-Prom-mediated expression of these genes kills only cancer cells and spares normal cells. The efficacy of the PEG-Prom as part of a cancer gene therapeutic regimen is further documented by in vivo experiments in which PEG-Prom-controlled expression of an apoptosis-inducing gene completely inhibited prostate cancer xenograft growth in nude mice. These compelling observations indicate that the PEG-Prom, with its cancer-specific expression, provides a means of selectively delivering genes to cancer cells, thereby providing a crucial component in developing effective cancer gene therapies.
AuthorsZhao-Zhong Su, Devanand Sarkar, Luni Emdad, Gregory J Duigou, Charles S H Young, Joy Ware, Aaron Randolph, Kristoffer Valerie, Paul B Fisher
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 4 Pg. 1059-64 (Jan 25 2005) ISSN: 0027-8424 [Print] United States
PMID15647352 (Publication Type: Journal Article)
Chemical References
  • Antigens, Differentiation
  • Cell Cycle Proteins
  • Interleukins
  • Myd116 protein, rat
  • Neoplasm Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Transcription Factor AP-1
  • Transcription Factors
  • interleukin-24
  • transcription factor PEA3
  • PPP1R15A protein, human
  • Ppp1r15a protein, mouse
  • Protein Phosphatase 1
Topics
  • Animals
  • Antigens, Differentiation (genetics)
  • Cell Cycle Proteins
  • Genes, Tumor Suppressor
  • Genetic Therapy
  • Humans
  • Interleukins (genetics)
  • Male
  • Mice
  • Neoplasm Proteins (genetics)
  • Neoplasms (therapy)
  • Promoter Regions, Genetic
  • Protein Phosphatase 1
  • Proteins (genetics)
  • Proto-Oncogene Proteins
  • Transcription Factor AP-1 (physiology)
  • Transcription Factors (physiology)

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