Regulation of radiation-induced apoptosis by early growth response-1 gene in solid tumors

Ionizing radiation exposure is associated with activation of certain immediate-early genes that function as transcription factors. These include members of jun or fos and early growth response (EGR) gene families. In particular, the functional role of EGR-1 in radiation-induced signaling is pivotal since the promoter of EGR-1 contains radiation inducible CArG DNA sequences. The Egr-1 gene belongs to a family of Egr genes that includes EGR-1, EGR-2, EGR-3, EGR-4, EGR-alpha and the tumor suppressor, Wilms' tumor gene product, WT1. The Egr-1 gene product, EGR-1, is a nuclear protein that contains three zinc fingers of the C(2)H(2) subtype. The EGR-1 GC-rich consensus target sequence, 5'-GCGT/GGGGCG-3' or 5'-TCCT/ACCTCCTCC-3', has been identified in the promoter regions of transcription factors, growth factors, receptors, cell cycle regulators and proapoptotic genes. The gene targets mediated by Egr-1 in response to ionizing radiation include TNF-alpha, p53, Rb and Bax, all these are effectors of apoptosis. Based on these targets, Egr-1 is a pivotal gene that initiates early signal transduction events in response to ionizing radiation leading to either growth arrest or cell death in tumor cells. There are two potential application of Egr-1 gene in therapy of cancer. First, the Egr-1 promoter contains information for appropriate spatial and temporal expression in-vivo that can be regulated by ionizing radiation to control transcription of genes that have pro-apoptotic and suicidal function. Secondly, EGR-1 protein can eliminate "induced-radiation resistance" by inhibiting the functions of radiation-induced pro-survival genes (NFkappaB activity and bcl-2 expression) and activate proapoptotic genes (such as bax) to confer a significant radio-sensitizing effect. Together, the review of reported findings demonstrate clearly that EGR-1 is an early central gene that confers radiation sensitivity and its pro-apoptotic functions are synergized by abrogation of induced radiation resistance.