Protein kinase C mediates x-ray inducibility of nuclear signal transducers EGR1 and JUN.

Abstract

The cellular response to ionizing radiation includes growth arrest and DNA repair followed by proliferation. Induction of immediate early response genes may participate in signal transduction preceding these phenotypic responses. We analyzed mRNA expression for different classes of immediate early genes (JUN, EGRI, and FOS) after cellular x-irradiation. Increased expression ofthe EGRI andJUN genes was observed within 0.5-3 hr following x-ray exposure. Preincubation with cycloheximide was associated with superinduction of JUN and EGRI in x-irradiated cells. Inhibition of protein kinase C activity by prolonged stimulation with phorbol 12-myristate 13-acetate or the protein kinase inhibitor H7 prior to irradiation attenuated the increase in EGRI and JUN transcripts. FOS expression was not coregulated with that of EGRI following x-irradiation, suggesting a distinct regulatory pathway of this gene as compared with its regulation following serum and phorbol ester. These data implicate the EGR1 and JUN proteins as signal transducers during the cellular response to radiation injury and suggest that this effect is mediated in part by a protein kinase C-dependent pathway.Exposure to ionizing radiation results in pleiotropic biological responses such as cell cycle-specific growth arrest and repair of damaged DNA. Proliferation subsequent to irradiation results in repopulation of injured tissues and tumors (1, 2). In addition, certain cells produce growth factors or cytokines in response to x-rays (3, 4). To effect these delayed responses to injury, x-rays may induce nuclear signaltransducer genes whose products couple early biochemical second-messenger signals to long-term phenotypic changes. Several of these genes encode transcription factors that initiate a cascade of molecular events. Immediate early response genes that encode transcription factors include the JUN family (JUN, JUNB, and JUND; refs. 5-9), the EGR family (EGRI,and 4;, and the FOS family (FOS, FRAI, and FOSB) (13-16). JUN tTo whom reprint requests should be addressed. 2156The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Intratracheal injection of manganese superoxide dismutase (MnSOD) plasmid/liposomes protects normal lung but not orthotopic tumors from irradiation

“…[1][2][3] Irradiation-induced increases in VEGF and other cytokines, 18-21 and inflammatory response genes have been reported. 19 Previously, we demonstrated that mice injected 24 h before irradiation with MnSOD-PL complex had decreased cytokine mRNA levels for IL-1 and TGF-␤ at 24 h, and TNF-␣ increase at 48 h compared with irradiated control. [1][2][3] In the present study we detected at 24 h after irradiation, increases in TGF-␤3, IL-1␤, MIF and IL-1R␣ in normal lung and these levels were reduced by C57BL/6J mice were IT-injected with 5 × 10 5 3LL-LacZ cells.…”

A potential role of heat shock proteins and nicotinamide N‐methyl transferase in predicting response to radiation in bladder cancer

“…This interval was chosen since previous studies suggested that the induction of some early response genes activated by ionising radiation occurred within 0.5-3 hr postexposure to radiation. 8,9 Twenty of 234 genes (12%) blotted on the array filter showed a difference in between S40b and MGH-U1 in at least 1 of the 2 independent experiments (Table II). It was of some concern that the differential gene expression pattern appeared to be inconsistent for some genes in the repeat experiments (e.g., NM23-H1).…”

Development of synthetic promoters for radiation-mediated gene therapy

“…5,6,14 The radio-responsive enhancer, containing four 'CArG' elements, has been identified in the 5Ј distal region of the Egr1 promoter. 9,10 In the current study, this Egr1 enhancer (in the plasmid pNGFP) was found to induce a 1.67-fold increase in reporter gene expression in MCF-7 cells after a single radiation dose of 5 Gy (Figure 1).…”

“…[1][2][3][4][5][6][7] These genes include those encoding the human tissue-type plasminogen activator, tumour necrosis factor alpha (TNF-␣) and early growth response protein 1 (Egr1). 8,9 Transcriptional activation of the Egr1 gene by ionising radiation appears to be a direct consequence of the production of reactive oxygen intermediates.…”