Activation of Egr-1 Expression in Astrocytes by HIV-1 Tat: New Insights into Astrocyte-Mediated Tat Neurotoxicity

Human immunodeficiency virus type 1 (HIV-1) Tat plays an important role in HIV-associated neuropathogenesis; the underlying mechanisms are still evolving. We have recently shown that HIV-1 Tat induces expression of glial fibrillary acidic protein (GFAP), a characteristic of HIV-1 infection of the central nervous system. We have also shown that the Tat-induced GFAP expression in astrocytes is regulated by p300 and that deletion of the early growth response 1 (Egr-1) cis-transacting element within the p300 promoter abolishes Tat-induced GFAP expression. In this study, we further examined the relationship between Tat and Egr-1 in astrocytes. We found increased Egr-1 protein expression in Tat-expressing human astrocytoma cells and mouse primary astrocytes. Using the Egr-1 promoter-driven firefly luciferase reporter gene assay and the site-directed mutagenesis, we demonstrated that Tat increased Egr-1 expression by transactivating the Egr-1 promoter and involving specific serum response elements within the promoter. Consistent with these data, we showed that Tat transactivation of the Egr-1 promoter was abrogated when astrocytes were cultured in serum-reduced media. Taken together, these results reveal that Tat directly transactivates Egr-1 expression and suggest that Tat interaction with Egr-1 is probably one of the very upstream molecular events that initiate Tat-induced astrocyte dysfunction and subsequent Tat neurotoxicity.     

Stress signaling from irradiated to non-irradiated cells

Evidence accumulated over the past two decades has indicated that exposure of cell populations to ionizing radiation results in significant biological effects occurring in both the irradiated and non-irradiated cells in the population. This phenomenon, termed the "bystander response", has been shown to occur both in vitro and in vivo. Experiments have indicated that genetic alterations, changes in gene expression and lethality occur in bystander cells that neighbor directly irradiated cells. Furthermore, cells recipient of growth medium harvested from irradiated cultures exhibit responses similar to those of the irradiated cells. Several mechanisms involving secreted soluble factors, gap-junction intercellular communication and oxidative metabolism have been proposed to regulate the radiation-induced bystander effect. In this review, our current knowledge of this phenomenon and its potential impact both on the estimation of risks of exposure to low doses/low fluences of ionizing radiation and on radiotherapy is discussed.     

Origin of the linearity no threshold (LNT) dose–response concept

This paper identifies the origin of the linearity at low-dose concept [i.e., linear no threshold (LNT)] for ionizing radiation-induced mutation. After the discovery of X-ray-induced mutations, Olson and Lewis (Nature 121(3052):673–674, 1928) proposed that cosmic/terrestrial radiation-induced mutations provide the principal mechanism for the induction of heritable traits, providing the driving force for evolution. For this concept to be general, a LNT dose relationship was assumed, with genetic damage proportional to the energy absorbed. Subsequent studies suggested a linear dose response for ionizing radiation-induced mutations (Hanson and Heys in Am Nat 63(686):201–213, 1929; Oliver in Science 71:44–46, 1930), supporting the evolutionary hypothesis. Based on an evaluation of spontaneous and ionizing radiation-induced mutation with Drosophila, Muller argued that background radiation had a negligible impact on spontaneous mutation, discrediting the ionizing radiation-based evolutionary hypothesis. Nonetheless, an expanded set of mutation dose–response observations provided a basis for collaboration between theoretical physicists (Max Delbruck and Gunter Zimmer) and the radiation geneticist Nicolai Timoféeff-Ressovsky. They developed interrelated physical science-based genetics perspectives including a biophysical model of the gene, a radiation-induced gene mutation target theory and the single-hit hypothesis of radiation-induced mutation, which, when integrated, provided the theoretical mechanism and mathematical basis for the LNT model. The LNT concept became accepted by radiation geneticists and recommended by national/international advisory committees for risk assessment of ionizing radiation-induced mutational damage/cancer from the mid-1950s to the present. The LNT concept was later generalized to chemical carcinogen risk assessment and used by public health and regulatory agencies worldwide.     

The radiation-induced bystander effect: evidence and significance

A multitude of biological effects observed over the past two decades in various in vivo and in vitro cell culture experiments have indicated that low dose/low fluence ionizing radiation has significantly different biological responses than high dose radiation. Exposure of cell populations to very low fluences of alpha-particles or incorporated radionuclides results in significant biological effects occurring in both the irradiated and nonirradiated cells in the population. Cells recipient of growth medium from irradiated cultures can also respond to the radiation exposure. This phenomenon, termed the 'bystander response', has been postulated to impact both the estimation of risks of exposure to ionizing radiation and radiotherapy. Amplification of radiation-induced cytotoxic and genotoxic effects by the bystander effect is in contrast to the observations of adaptive responses, which are generally induced following exposure to low dose, low linear energy transfer radiation and which tend to attenuate radiation-induced damage. In this article, the evidence for existence of radiation-induced bystander effects and our current knowledge of the biochemical and molecular events involved in mediating these effects are described. Potential similarities between factors that mediate the radiation-induced bystander and adaptive responses are highlighted.