Protective role of stress genes.

Some 3,000 million years ago, when the first living cell evolved on the surface of the earth, it had to struggle hard to survive in the face of seemingly insurmountable environmental odds. It traversed a long and arduous path to become a more organized form able to cope with adverse circumstances. Manipulations of genomic organization were required to adapt to the changing circumstances. The result was the evolution of more organized life forms-from photosynthetic bacteria to man. In the evolutionary pathway, more than 99% of all species of living organisms that existed at one time or the other are now extinct, and they have no present day descendants. The surviving species were better equipped to transform into nonlethal mutants as a result of chemically and physically induced changes in the genomic sequences. Thus, it was possible to select the best suited to survive the contemporary environmental conditions of life. The result was the evolution of stress response genes, which appear to be one of the most highly conserved and abundant genomic sequences found in nature. A large volume of published literature suggests that there are unique genomic sequences which impart high efficiency for survival of the organism. They are conserved in the genome even across species barriers. These genes appear to be activated to cope with certain stressful events, such as heat shock, metabolic stress exposure to microgravity, hydration, genotoxic stress, oxidative stress, osmotic stress, radiation stress, and chemical and carcinogenic stress. We know that there is an intrinsic urge in any organism to adjust itself to the prevalent conditions, adjust itself to come back to a normal or steady state conducive for perpetuation of life. All organisms are continuously being exposed to environmental, toxic, physiological, and metabolic stressors. But they are not always harmed because they possess the intrinsic capabilities to withstand divergent types of stresses. Those inherent mechanisms of stress resistance are, therefore, our evolutionary gains. It is only logical to assume that a large number of genes may have organized themselves together in the form of a superfamily. Such genes act and function in harmony as per the needs of the organism. Although the nature of the stressors used may be different, the reactions they induce may be similar in nature (1). Sometimes a particular type of stressor may induce a large array of reactions that protect the host from altogether different types of physical, chemical, and biological stressors and from a wide variety of toxic or carcinogenic chemicals (2-9). These observations provide us with the understanding that by using a specific inducer one may be able to activate a large number of gene sequences involved in providing resistance against a host of stressors. As a result of such activation, a large number of biomolecules are produced to abrogate the harmful effects of different stress inducing substances. This appears to be true in case of both biological and chemical stressors (4,5). While attempting to withstand the onslaughts of the stressful conditions, the organisms may activate specific genes to produce specific proteins, each responsible for counteracting specific or nonspecific stress-induced abnormalities (3-9). Such proteins may have a variety of functions: as enzymes to catalyze biotransformation and detoxification reactions, hormones to potentiate cell proliferation, structural proteins to repair tissue damage, antibodies, cytokines, and growth factors, carrier proteins and enzymes, signal proteins, transcription factors, differentiation factors, etc. Studies carried out on heat shock proteins (hsps) (1) and various other stress-induced proteins U (1-10) have yielded a wealth of information. Genes dealing with the resistance mechanisms in microorganisms against the immune attack of the host, in addition to those which induce immunity against them in the host (3,4,6,8) also provided important information regarding the existence of stress response genes. The evolutionary dogma of survival of the fittest therefore lies in the ability of the organisms to perpetuate the stress response genes vis-a-vis the stress resistance genes. Several immunomodulators that can be considered as stress inducers, such as Bacille bilie de Calmette-Guerin vaccine, Staphyloccus aureus, Streptococcus faecalis, Corynebacterium parvum, Coley's toxin, various viruses, bacterial lipopolysaccharides, lipid A, and protein A, not only potentiate nonspecific immune responses against a variety of bacteria and viruses but also cause regression of various tumors (11). The tumor is a major stress inducer. One of the major outcomes of progressive growth of a tumor is depression of the immune system, which gives rise to total anergy (11). It has been well established that sensitizing the host with small amount of various types of stressors helps activate the host resistance mechanism to fight tumor growth (11). Induction of stress by calorie restriction provides the host with an increased ability to fight toxic or carcinogenic chemical stress (9). Lipopolysaccharide-induced induction of minor oxidative stress stimulates antioxidant mechanisms such that reperfusioninduced cardiac damage could be lessened (5). It is now well established that the resistance of the myocardium to ischemia can be enhanced both by preconditioning the host and by up regulating the cytoprotective proteins, particularly hsps. An association between heat stress proteins and myocardial protection has been indicated (10). When body temperature in rats increased, both cardiac hsps and catalase activity were increased such that hearts became resistant to ischemia/reperfusion injury. Of greater pathological relevance was the observation that ischaemia itself could induce evolution of hsps and involution of cardiac stress (12) by simultaneously increasing a stress protein and a myocardial antioxidant enzyme, superoxide dismutase (10). Protein A of S. aureus has been shown to induce antitoxic (3-5), anticarcinogenic (13,14), and antitumor (15) responses, rendering protection to the host against a wide variety of chemical and biological stressors, such as cyclophosphamide, carbon tetrachloride, benzene, dimethyl benzanthracene, Salmonella endotoxin and aflatoxin. Significant protection against the toxic, carcinogenic, and