Reovirus has potent activity against human malignant gliomas in vitro, in vivo, and ex vivo. Oncolysis with reovirus may be a potentially useful treatment for a broad range of human cancers.
affects the degree of physical association between proliferating cell nuclear antigen (PCNA) and p300, an association that has been proposed to link DNA repair to chromatin remodeling. Together with the finding that human ING1 proteins bind PCNA in a DNA damagedependent manner, these data suggest that ING1 proteins provide a direct linkage between DNA repair, apoptosis, and chromatin remodeling via multiple HAT⅐ING1⅐PCNA protein complexes.
A novel method has been developed for modulating the expression of an endogenous chromosomal gene in a higher eukaryote, by competitive inhibition at the level of gene transcription. The gene studied was the hsp70 gene, which encodes a 72-kilodalton (kD) heat shock protein that is synthesized after thermal stress. The 5' control region of the hsp70 gene was inserted on a plasmid containing the eukaryotic gene for dihydrofolate reductase. The hybrid plasmid was then introduced into a Chinese hamster ovary cell line and elevated in copy number approximately 20,000-fold by selection of cells with methotrexate. Heat-inducible expression from the intact hsp70 gene was reduced by at least 90% in the modified cells when compared with the induction in control cells, and the modified cells also displayed elevated thermosensitivity. The change in heat shock protein synthesis is presumably caused by competition among the increased number of binding sites for the heat-shock transcription factor, leading to altered expression from the native heat shock gene. These results support a role for heat shock protein in the recovery of mammalian cells from acute thermal stress.
The ING1 candidate tumor suppressor is downregulated in a variety of primary tumors and established cancer cell lines. Blocking its expression experimentally promotes unregulated growth in vitro and in vivo, using cell and animal models. Alternative splicing products encode proteins that localize to the nucleus, inhibit cell cycle progression and affect apoptosis in different model systems. Here we show that ING1 proteins translocate to the nucleolus 12-48 h after UV-induced DNA damage. When a small 50 amino acid portion of ING1 was fused to green fluorescent protein, the fusion protein was efficiently targeted to the nucleolus, indicating that ING1 possesses an intrinsic nucleolar targeting sequence (NTS). We mapped this activity to two distinct 4 amino acid regions, which individually direct fused heterologous proteins to the nucleolus. Overexpression of ING1 induced apoptosis of primary fibroblasts in the presence and absence of UV exposure. In contrast, NTS mutants of ING1 that were not targeted to the nucleolus did not efficiently induce apoptosis when overexpressed and instead protected cells from UV-induced apoptosis. Taken together, these results indicate that UV induces ING1 to translocate to the nucleolus and that this translocation may facilitate apoptosis.
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