Potential molecular mechanism for rodent tumorigenesis: mutational generation of Progression Elevated Gene-3 (PEG-3)

Su, Zao-zhong; Emdad, Luni; Sarkar, Devanand; Randolph, Aaron; Valerie, K.; Yacoub, Adly; Dent, Paul; Fisher, Paul B.

doi:10.1038/sj.onc.1208420

Cited by 24 publications

(28 citation statements)

References 31 publications

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“…PEG-3 is a C-terminally truncated mutant form of the rat GADD-34 (8,9). We have recently documented that mutation in the GADD34 gene resulting in PEG-3-like C-terminally truncated molecules is a frequent event during rodent tumorigenesis in multiple tissues, and PEG-3 functions as a dominant negative inhibitor of the apoptosis-inducing and growth-suppressing prop- erties of both human and rat GADD34 (9).…”

Section: Discussionmentioning

confidence: 99%

“…E11-NMT is a clone of E11 that has been selected for aggressiveness by passage through a nude mouse and that forms rapidly growing, highly aggressive tumors (5). Subtraction hybridization of an E11 cDNA library from an E11-NMT cDNA library identified PEG-3 (7), which has recently been determined to be a C-terminal truncated mutant form of the rat-growth-arrest and DNA-damageinducible gene-34 (GADD-34) (8,9). Elevated PEG-3 expression has been documented in E11-NMT cells in comparison with E11 cells and also in normal cloned rat embryo fibroblast (CREF) cells displaying a transformed͞tumorigenic phenotype as a consequence of the expression of diversely acting oncogenes, including Ha-ras, v-src, human papilloma virus type-18-transforming genes, and a specific mutant of adenovirus (Ad) 5 (H5hr1), relative to parental CREF cells (7).…”

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confidence: 99%

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

Sarkar

Emdad

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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104

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Sarkar

Emdad

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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104

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“…77,78 PEG-3: (i) displays elevated expression as a function of oncogenic transformation (by diverse oncogenes), during cancer progression and after DNA damage (γ irradiation); 77,78 and (ii) induces an aggressive cancer phenotype and enhanced angiogenesis and genomic instability when ectopically expressed in rodent and human tumors, without promoting transformation when expressed in normal cells. [77][78][79][80] Additionally, the PEG-3 gene promoter (PEG-Prom) has been isolated and shown to display elevated expression in both rodent and human tumors, with negligible expression in normal cells. [81][82][83] Infection of cancer and normal cells with adenovirus vectors expressing a transgene (such as GFP or luciferase) under the control of the PEG-Prom documented high GFP or luciferase expression in cancer cells, with little to no expression in normal cells.…”

Section: Peg-3 Promoter: Novel Cancer-specific Promotermentioning

confidence: 99%

Unique Conditionally Replication Competent Bipartite Adenoviruses—Cancer Terminator Viruses (CTV): Efficacious Reagents for Cancer Gene Therapy

Sarkar¹,

Su²,

Fisher³

2006

Cell Cycle

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The frequent resistance of aggressive cancers to currently available therapies, such as radiotherapy and chemotherapy, mandates development of targeted, nontoxic and more efficacious treatment protocols. Conditionally replication competent adenoviruses (CRCAs) that induce oncolysis by cancer-specific replication are currently being evaluated in clinical trials. However, a single modality approach may not be sufficient to completely eradicate cancer in a patient, because most cancers arise from abnormalities in multiple genetic and signal transduction pathways. The promoter region of rodent progression elevated gene-3 (PEG-3), cloned and characterized in our laboratory, embodies the unique property of increased activity in a broad range of tumor cells, both rodent and human, when compared to normal counterparts. Bipartite adenoviruses were engineered to express the E1A gene, necessary for viral replication, under control of the PEG-3 promoter (PEG-Prom) and simultaneously express a second transgene in the E3 region that encodes an apoptosis-inducing and immunomodulatory cytokine, either immune interferon (IFN-γ) or melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). These conditionally replication competent bipartite adenoviruses, referred to as cancer terminator viruses (CTVs), facilitated cancer-selective adenovirus replication, robust transgene expression and apoptosis induction with complete eradication of both primary and distant (metastatic) human cancers xenotransplanted in athymic nude mice. These findings suggest that CTVs might prove efficacious for the therapy of primary and advanced neoplastic diseases.

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“…PEG-3 was cloned as an up-regulated transcript from a transformation progression rodent cancer model, and attractively, the activity of its promoter (PEG-Prom) was found to be significantly and often markedly higher not only in rodent but also in human cancer cells of diverse origin when compared with normal cells (12)(13)(14)(15). The cancer cell specificity of the PEG-Prom is governed by two transcription factors, AP-1 and PEA-3, which are overexpressed, either singly or in combination, in virtually all types of cancers (16)(17)(18)(19).…”

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confidence: 99%

Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice

Sarkar

Vozhilla

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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117

185

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Limitations of current viral-based gene therapies for malignant tumors include lack of cancer-specific targeting and insufficient tumor delivery. To ameliorate these problems and develop a truly effective adenovirus gene-based therapy for cancer, we constructed a conditionally replication competent adenovirus (CRCA) manifesting the unique properties of tumor-specific virus replication in combination with production of a cancer-selective cytotoxic cytokine, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), which embodies potent bystander antitumor activity. Cancer cell selective tropism was ensured by engineering the expression of the adenoviral E1A protein, necessary for viral replication, under the control of a minimal promoter region of progression elevated gene-3 (PEG-3), which functions selectively in diverse cancer cells with minimal activity in normal cells. In the E3 region of this CRCA, we introduced the mda-7/IL-24 gene, thereby mediating robust production of this cytokine as a function of adenovirus replication. Infection of this CRCA (designated Ad.PEG-E1A-mda-7) in normal mammary epithelial cells and breast cancer cells confirmed cancer cell selective adenoviral replication, mda-7/ IL-24 expression, growth inhibition, and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 into human breast cancer xenografts in athymic nude mice completely eradicated not only the primary tumor but also distant tumors (established on the opposite flank of the animal) thereby implementing a cure. This dual cancer-specific targeting strategy provides an effective approach for treating breast and other human neoplasms with the potential for eradicating both primary tumors and metastatic disease. Additionally, these studies support the potential use of mda-7/IL-24 in the therapy of malignant cancers.bystander antitumor activity ͉ conditionally replication competent adenovirus ͉ PEG-Prom ͉ mda-7͞IL-24 ͉ in vivo tumorigenesis

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Potential molecular mechanism for rodent tumorigenesis: mutational generation of Progression Elevated Gene-3 (PEG-3)

Cited by 24 publications

References 31 publications

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

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

Unique Conditionally Replication Competent Bipartite Adenoviruses—Cancer Terminator Viruses (CTV): Efficacious Reagents for Cancer Gene Therapy

Dual cancer-specific targeting strategy cures primary and distant breast carcinomas in nude mice

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