30][“G Molecule”

In mammals, HSF corresponds to the ubiquitous stressresponsive activator, whereas HSF, although widely expressed, is developmentally regulated and important for neuronal specification, and HSF is highly cell typespecific associated with expression of crystallines. The activity of HSF is induced by a variety of stress signals, including a wide range of acute and chronic perturbations of physiological states and disease. Induction of the heatshock response corresponds to a stepwise process that involves activation of HSF monomers to nuclearlocalized trimers, binding to DNA, and attenuation of transcription with subsequent conversion back to the monomer. The principal targets for HSF are heatshock elements. The signals that induce the heatshock response and HSF have not been thoroughly elucidated.Much of the data is consistent with the primary signal being associated with a flux of intermediates that are detected as misfolded and Vagistat damaged proteins. The appearance of excess nonnative protein shifts the chaperone equilibrium, thus derepressing HSF to undergo a conformational transformation to an active state.Association of chaperones with HSF suppresses transcription. The combination of these posttranslational modifications and chaperone interactions thus affords HSF with multiple forms and levels of control and feedback loops to precisely regulate chaperone levels in the cell.The heatshock response has often been portrayed as a universal molecular response to various stress stimuli. While this is generally correct, the exceptions are instructive.There are numerous observations in the literature in which the heatshock response is poorly or incompletely activated.These include early development or exposure of intact organisms to wholebody stress. Of particular interest have been studies on the heatshock response in the brain and during aging. Achieving a stress condition in whole mammals is challenging and has required anesthetics to prevent temperatureinduced seizures.Restricted expression of HS genes has been observed in different regions of the brain, consistent with the selective expression of HS genes in cultured neuronal cells.In intact primary hippocampal neurons from neonatal rat embryos, only HSF but not HSF is expressed until later stages of development. Consequently, the heatshock response of primary hippocampal neurons is deficient, whereas astro GENES DEVELOPMENT cytes that express both HSF and HSF have a robust stress response.Similar observations have been made in primary motor neurons that exhibit a deficient heatshock response thought to be due to a defect in activation of HSF. The regulation of the heatshock response and HSF activity by small molecules has provided valuable tools to elucidate the mechanism of HSF regulation.NSAIDS including sodium salicylate have multiple properties; at higher concentrations they partially L-GLUCOSE activate HSF and at lower concentrations they synergize with other stress conditions to induce the heatshock response. Salicylatetreated cells, however, are sensitized to stress and readily activate HS genes upon exposure to other mild stress conditions.Of the inflammatory modulators, arachidonic acid, and the cyclopentenone prostaglandins, including PGA, PGA, and PGJ, all induce the full complement of HSF activities. Chaperones, together with the autophagy and ubiquitin proteasome system, are abundantly expressed, yet there is evidence to suggest that limitations and malfunction of the clearance machinery are risk factors in diseases of protein conformation.

Leave a Reply