Ultraviolet radiation triggers the ribotoxic stress response in mammalian cells.

The ribotoxic stress response, which is conserved between prokaryotes and eukaryotes, is a cellular reaction to cytotoxic interference with the function of the 3'-end of the large (23 S/28 S) ribosomal RNA. The 3'-end of the large rRNA is directly involved in the three sequential steps of translational elongation: the aminoacyl-tRNA binding, the peptidyl transfer, and the ribosomal translocation. In mammalian cells, the ribotoxic stress response involves activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase and the p38 mitogen-activated protein kinase and transcriptional induction of immediate early genes such as c-fos and c-jun. Active ribosomes are essential mediators of the ribotoxic stress response. We demonstrate here that the transcriptional response of mammalian cells to ultraviolet radiation (UV response) displays the characteristics of a ribotoxic stress response, inasmuch as (i) the activation of stress kinases and gene expression in response to UV requires the presence of active ribosomes at the moment of irradiation; (ii) UV irradiation inhibits protein synthesis; and (iii) irradiation of cells with UV causes specific damage to the 3'-end of the 28 S rRNA. In contrast, the activation of the stress kinases by hyperosmolarity, by the DNA-cross-linking agent diepoxybutane, or by growth factors and cytokines does not depend on the presence of active ribosomes. Our results identify UV as a potential ribotoxic stressor and support the notion that some of the cellular signaling cascades in response to UV might be generated in the ribosome, possibly triggered by damage to rRNA.

Ribotoxic stress response: activation of the stress-activated protein kinase JNK1 by inhibitors of the peptidyl transferase reaction and by sequence-specific RNA damage to the alpha-sarcin/ricin loop in the 28S rRNA.

Inhibition of protein synthesis per se does not potentiate the stress-activated protein kinases (SAPKs; also known as cJun NH2-terminal kinases [JNKs]). The protein synthesis inhibitor anisomycin, however, is a potent activator of SAPKs/JNKs. The mechanism of this activation is unknown. We provide evidence that in order to activate SAPK/JNK1, anisomycin requires ribosomes that are translationally active at the time of contact with the drug, suggesting a ribosomal origin of the anisomycin-induced signaling to SAPK/JNK1. In support of this notion, we have found that aminohexose pyrimidine nucleoside antibiotics, which bind to the same region in the 28S rRNA that is the target site for anisomycin, are also potent activators of SAPK/JNK1. Binding of an antibiotic to the 28S rRNA interferes with the functioning of the molecule by altering the structural interactions of critical regions. We hypothesized, therefore, that such alterations in the 28S rRNA may act as recognition signals to activate SAPK/JNK1. To test this hypothesis, we made use of two ribotoxic enzymes, ricin A chain and alpha-sarcin, both of which catalyze sequence-specific RNA damage in the 28S rRNA. Consistent with our hypothesis, ricin A chain and alpha-sarcin were strong agonists of SAPK/JNK1 and of its activator SEK1/MKK4 and induced the expression of the immediate-early genes c-fos and c-jun. As in the case of anisomycin, ribosomes that were active at the time of exposure to ricin A chain or alpha-sarcin were able to initiate signal transduction from the damaged 28S rRNA to SAPK/JNK1 while inactive ribosomes were not.

Long-term effects of flavone acetic acid on the growth of a rat tumour.

A rat tumour (MC7 sarcoma), growing subcutaneously, has been shown to be sensitive to a single application of flavone acetic acid. Thirteen rats were still alive after 50 days and 8 of these were tumour free, as compared with control rats which survived for 15.7 +/- 2.53 days. The 8 tumour free animals were rechallenged with MC7 sarcoma 40 weeks later, without further FAA treatment. The tumour grew initially but in all cases the animals became tumour free within 24 days. After a further 30 days they were rechallenged with D23 hepatoma which grew as effectively as in the controls.

Studies on the subunit structure of textilotoxin, a potent presynaptic neurotoxin from the venom of the Australian common brown snake (Pseudonaja textilis). 2. The amino acid sequence and toxicity studies of subunit D.

Textilotoxin is a presynaptic neurotoxin in the venom of the Australian common brown snake, Pseudonaja textilis. It has the highest lethality and is structurally the most complex of any known snake venom neurotoxin. Reverse-phase HPLC was used to resolve textilotoxin into subunits A, B, C and D. Subunit D consists of two identical covalently linked polypeptide chains. Its sequence is now reported. It is an acidic, slightly glycosylated polypeptide of 133 amino acid residues in each chain. Although it is not itself neurotoxic, it was found to be essential for the neurotoxicity of textilotoxin.

Organizational response to occupational injury and disease: the case of the uranium industry.

This study explores the factors associated with organizational action and inaction in the solution of an industrial health hazard. Obstructive and remedial variables are identified, measured, and tested. The research setting is the uranium mining industry, whose working population is experiencing a lung cancer epidemic due to radiation in uranium mines. The delay in actions leading to the reduction of hazardous radiation in mines is tied to national demands for uranium ore, the visibility of the hazard, and the structure of the industry. The eventual solution of the problem is shown to be affected by government pressure on uranium mining companies to purchase ventilation equipment.