Use of the stress-inducible grp78/BiP promoter in targeting high level gene expression in fibrosarcoma in vivo.
Current advances in human gene therapy open up new frontiers for molecular therapies of cancer. However, one major limitation in cancer gene therapy is the lack of a general tumor-specific promoter which allows stringent and high level expression of the therapeutic reagent in malignantly transformed but not normal tissues. Hallmark features of solid tumors such as glucose deprivation, chronic anoxia, and acidic pH induce the glucose-regulated proteins, in particular, GRP78/BiP, a M(r) 78,000 endoplasmic reticulum-localized protein with chaperone and calcium-binding properties. We report here that a truncated rat grp78 promoter with most of the distal basal elements removed can be utilized as a potent internal promoter in a retroviral vector to drive high level expression of a reporter gene in a murine fibrosarcoma model system. The stress-inducible grp78 promoter offers a novel approach for gene delivery systems targeting transcription in tumorigenic cells.
Gazit
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Department of Biochemistry, University of Southern California School of Medicine, Los Angeles 90033-0800, USA.
Kane
S E
SE
Nichols
P
P
Lee
A S
AS
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005354:Fibrosarcoma / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones / Q000096:biosynthesis* / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D012190:Retroviridae; D013312:Stress, Physiological; D014162:Transfection
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones