Ionizing Radiation-inducible Apoptosis in the Absence of p53 Linked to Transcription Factor EGR-1

Abstract

The tumor suppressor protein p53 is a pivotal regulator of apoptosis, and prostate cancer cells that lack p53 protein are moderately resistant to apoptotic death by ionizing radiation. Genes encoding the transcription factor early growth response-1 (EGR-1) and cytokine tumor necrosis factor-␣ (TNF-␣) were induced upon irradiation of prostate cancer cells, and inhibition of EGR-1 function resulted in abrogation of both TNF-␣ induction and apoptosis. Induction of the TNF-␣ gene by ionizing radiation and EGR-1 was mediated via a GC-rich EGR-1-binding motif in the TNF-␣ promoter. Because TNF-␣ induces apoptosis in prostate cancer cells, these findings suggest that, in the absence of p53, ionizing radiation-inducible apoptosis is mediated by EGR-1 via TNF-␣ transactivation.

MyD genes in negative growth control

“…Both Egr-1 and TNFa are induced upon irradiation induced apoptosis of prostate cancer cells that lack p53 (Ahmed et al, 1997). Inhibition of Egr-1 was observed to abrogate both TNFa induction and apoptosis.…”

EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells

“…On the contrary, EGR-1 can suppress growth when overexpressed or re-expressed in transformed cells. EGR-1 can induce apoptosis either by stimulating p53 activity or by IR (Ahmed et al, 1996(Ahmed et al, , 1997, or PTEN expression (Virolle et al, 2001). Thus, it appears that EGR-1 can act as a tumor suppressor in some cells and as a growth stimulator in other cell types.…”

“…In this study, we selected the Egr-1 gene to understand its role in radiation resistance, because (a) upon orchiectomy Egr-1 was rapidly induced, leading to apoptosis of androgen-dependent prostate cells (Buttyan et al, 1988;Day et al, 1993); (b) IR upregulates EGR-1 expression (Datta et al, 1992); and (c) EGR-1 protein upregulates pro-apoptotic gene expression (Ahmed et al, 1997;Nair et al, 1997;Das et al, 2001).…”

“…Expression of dominant-negative EGR-1 mutant (dnEGR-1) in melanoma cells (wt p53) caused radio resistance (Ahmed et al, 1996). Despite the absence of p53 protein, the cells overexpressing EGR-1 protein were sensitive to IR, which was associated with upregulation of tumor necrosis factor-a protein through EGR-1-mediated transactivation (Ahmed et al, 1997). In addition, Egr-1 À/À mouse embryonic fibroblast cells were highly radioresistant as compared with Egr-1 þ /À mouse embryonic fibroblast cells, where the radiationinduced pro-apoptotic function of EGR-1 was solely mediated by the target genes such as p53 and retinoblastoma (Das et al, 2001).…”

Novel targets for CNS gene therapy

“…Such a bimodal therapeutic design could theoretically allow for lower radiation burdens because radiation inducible promoters can be activated at smaller doses than is generally given when a primary therapy. 8 Success with radiation inducible preclinical gene therapy for neoplastic disease supports the application of this approach to AVM. 9 Although technical issues relating to the adequacy of gene transfer to the endothelium of the AVM will be formidable, existing methods for vessel microcatheterization may be applicable with modification.…”