Abstract 3941: The Egr1 transcription factor contributes to radiation-induced apoptosis in the mouse hippocampus and intestinal crypts

Abstract

Although radiation therapy is a mainstay of cancer treatments, it can have deleterious effects on normal tissues, leading to poor quality of life for cancer survivors. Stem cells in normal tissues are particularly sensitive to radiation. It is believed that they are depleted after radiation, resulting in late sequelae such as low IQ, cognitive disorders, intestinal malabsorption, infertility, and skin injuries. Our laboratory has found that normal tissue stem cells express high levels of Early Growth Response 1 (Egr1) protein and mRNA. Egr1 is a zinc-finger transcription factor that initiates early signaling events in response to ionizing radiation. Radiation enhances Egr1 expression and the Egr1 protein subsequently activates the transcription of genes involved in cell death. Therefore, we hypothesized that Egr1 could contribute to the sensitivity of stem cells to ionizing radiation. Using mouse models, we investigated the effect of Egr1 status on cell death in two clinically important stem cell niches-the dentate gyrus of the hippocampus and crypts of the intestine. Egr1 null mice had significantly less cell death in the dentate gyrus and small intestinal crypts following irradiation, as compared to their wild-type littermates. To elucidate the molecular basis underlying the resistance of Egr1 null hippocampi to radiation-induced cell death, we performed immunoblotting on ex vivo protein lysates made from Egr1 wild-type and knockout hippocampi. Protein lysates from Egr1 wild-type hippocampi showed that radiation treatment induced Egr1, as well as its known targets–p53 and regulators of the mitochondrial pathway of apoptosis, Bim and Bax. In contrast, the induction of these pro-apoptotic proteins by radiation was attenuated in Egr1 null hippocampal lysates. These results suggest that Egr1 is involved in the apoptosis mode of cell death in the irradiated hippocampus. The mechanism may involve Egr1 induction by ionizing radiation, followed by direct binding of Egr1 to the promoters of p53, Bim, and Bax to allow for transcription. We further conducted studies using mouse embryonic stem cell models and showed that knockdown of Egr1 using siRNA decreased cell death after radiation treatment. This finding supports our in vivo data that the hippocampal and gastrointestinal stem cell niches are radioprotected in Egr1 null mice. Thus, this study establishes an important role for Egr1 in radiation-induced apoptosis of hippocampal and intestinal tissues. Egr1 could be a potential molecular target to minimize the normal tissue complications associated with radiation therapy. Citation Format: Diana Y. Zhao, Keith M. Jacobs, Rowan M. Karvas, Jarrett L. Joubert, Dennis E. Hallahan, Dinesh Thotala. The Egr1 transcription factor contributes to radiation-induced apoptosis in the mouse hippocampus and intestinal crypts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3941. doi:10.1158/1538-7445.AM2014-3941

Skin-Derived Precursors against UVB-Induced Apoptosis via Bcl-2 and Nrf2 Upregulation

“…These findings implied that SKPs were not only resistant to UVB-induced apoptosis and DNA damage, but also greatly proliferated after UVB irradiation in this experiment, which were to some extent inconsistent with other reports. In general, it is considered that cells after UVB radiation or IR would become versiform, injured, aged, reductive, and even apoptotic [ 13 – 15 , 28 , 29 ]. This phenomenon indeed occurred in FBs in our study, indicating the obvious reduction and deformation of FBs after a certain dose of UVB radiation.…”

“…After exposure to UV, Nrf2 translocates into the nucleus and its signaling pathway is provoked, which further activates downstream cytoprotective genes and upregulates antioxidant enzyme heme oxygenase-1 (HO-1) to resist UVB-mediated cellular injury and eventually sustains cells survival [ 11 ]. Generally, apoptosis prevails in DNA or cell damage induced by UV radiation or ionization, which leads to gH2AX phosphorylation (pH2AX, an important biomarker of DNA damage) presence, cells reduction, senescence, and death [ 12 – 15 ]. However, some reports indicated that after hair-follicle-bulge stem cells (SCs) or embryonic stem (ES) cells were exposed to a certain dose of ionizing radiation (IR), cells biological activity and viability were rarely affected, let alone their differentiation or senescence, the mechanism of which was associated with Bcl-2 upregulation [ 16 , 17 ].…”