Cells respond to the accumulation of unfolded proteins by activating signal transduction cascades that improve protein folding. One example of such a cascade is the unfolded protein response (UPR), which senses protein folding stress in the endoplasmic reticulum (ER) and leads to improvement in the protein folding and processing capacity of the organelle. A central paradox of the UPR, and indeed of all such stress pathways, is that the response is designed to facilitate both adaptation to stress and apoptosis, depending upon the nature and severity of the stressor. Understanding how the UPR can allow for adaptation, instead of apoptosis, is of tremendous physiological importance. Recent advances have improved our understanding of ER stress and the vertebrate UPR, which suggest possible mechanisms by which cells adapt to chronic stress.
The pursuit for drugs that inhibit cyclin-dependent kinases (CDKs) has been an intense area of research for more than 15 years. The first-generation inhibitors, Flavopiridol and CY-202, are in late-stage clinical trials, but so far have demonstrated only modest activity. Several second-generation inhibitors are now in clinical trials. Future approaches to determine clinical benefit need to incorporate both the lessons learned from these early compounds and information recently obtained from the genetic analysis of CDKs in preclinical models. Here we discuss key concepts that should be considered when validating the clinical utility of CDK inhibitors in cancer therapy.
Cdc48 (p97), a conserved chaperone-like ATPase of eukaryotic cells, has attracted attention recently because of its wide range of cellular functions. Cdc48 is intimately linked to the ubiquitin pathway because its primary action is to segregate ubiquitinated substrates from unmodified partners. This ‘segregase’ activity is crucial for certain proteasomal degradation pathways and for some nonproteolytic functions of ubiquitin. Cdc48 associates not only with different ‘substrate-recruiting cofactors’ but also with distinct ‘substrate-processing cofactors’. The latter proteins control the degree of ubiquitination of bound substrates by shifting the polyubiquitination reaction into ‘forward’, ‘neutral’ or ‘reverse’. We discuss how Cdc48 might use this ‘gearbox activity’ to control protein fate and propose a similar mode of action for the 19S cap of the proteasome.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level by either degradation or translational repression of a target mRNA. More than 400 miRNAs have been identified in the human genome, but the relevance of most of them to physiological and pathological processes remains unclear. Although downregulation of the miRNA-processing enzymes Dicer and Drosha is known to impair angiogenesis, only a few specific miRNAs targeting endothelial cell function and angiogenesis have been identified. miR-221 and miR-222 block endothelial cell migration, proliferation and angiogenesis in vitro by targeting the stem cell factor receptor c-Kit and indirectly regulating expression of endothelial nitric oxide synthase. A pro-angiogenic function has been established for the miR-17-92 cluster, which promotes tumor angiogenesis in vivo . Expression of let7-f and miR-27b contributes to in vitro angiogenesis. We review recent studies on the involvement of miRNA in angiogenesis and discuss their implications for miRNA-based therapeutic strategies targeting this process in disease.
It is not clear how contracting skeletal muscles mediate the numerous and diverse metabolic and physiological effects that are beneficial for health. Researchers have searched for a muscle-contraction-induced factor – an ‘exercise factor’ – that mediates some of the exercise effects in other tissues such as the liver and adipose tissue. In our search for such a factor, we encountered the cytokine interleukin (IL)-6, which is produced by contracting muscles and released into the blood. We propose that muscle-derived IL-6 meets the criteria of an exercise factor and that such classes of cytokine should be named ‘myokines’. The discovery of contracting muscle as a cytokine-producing organ creates a new paradigm: skeletal muscle as an endocrine organ. By contracting, it stimulates the production and release of myokines that can influence metabolism in tissue and organs. Newly identified myokines and their receptors could serve as targets in the treatment of metabolic disorders and other diseases.
Multiple neurochemical pathways are involved in mediating craving and relapse to alcohol. Opioidergic and glutamatergic systems have a key role in alcoholism, as demonstrated by the clinically effective compounds naltrexone and acamprosate acting through these systems. The dopaminergic system has long featured in alcoholism research; hitherto disappointing results from clinical studies could improve following the discovery that dopamine D3 receptor antagonism produces consistent and robust results in preclinical studies. Corticotropin-releasing factor signalling and the endocannabinoid system integrate stress-related events and thereby mediate relapse behaviour. Overall, these new targets have yielded several compounds that are undergoing clinical testing. However, the heterogeneity in treatment response makes it necessary to characterize genetic and protein markers and endophenotypes for individualized pharmacotherapy.
The development of antibody therapies for cancer is increasing rapidly, primarily owing to their specificity. Antibody distribution in tumors is often extremely uneven, however, leading to some malignant cells being exposed to saturating concentrations of antibody, whereas others are completely untargeted. This is detrimental because large regions of cells escape therapy, whereas other regions might be exposed to suboptimal concentrations that promote a selection of resistant mutants. The distribution of antibody depends on a variety of factors, including dose, affinity, antigens per cell and molecular size. Because these parameters are often known or easily estimated, a quick calculation based on simple modeling considerations can predict the uniformity of targeting within a tumor. Such analyses should enable experimental researchers to identify in a straightforward way the limitations in achieving evenly distributed antibody, and design and test improved antibody therapeutics more rationally.
In recent years, dopamine has emerged as a key neurotransmitter that is crucially involved in incentive motivation and reinforcement learning. Dopamine release is evoked by rewards. The extensive divergence of outputs from a small number of dopaminergic neurons suggests a spatially nonselective action of dopamine, but it reinforces the specific actions that led to reward. How is this achieved? We propose that the selectivity of dopamine effects is achieved by the timing of dopamine release in relation to the activity of glutamatergic synapses, rather than by spatial localization of the dopamine signal to specific synaptic contacts. The synaptic mechanisms of these actions are unknown but reduced levels of dopamine, for example in Parkinson's disease, leads to a paucity of behavioural output, whereas its excess production has been associated with psychiatric problems. Clearly, there are therapeutic imperatives that require a better understanding of how dopamine functions at a synaptic level.
In addition to high temperature, other stresses and clinical conditions such as cancer and diabetes can lead to the alteration of heat-shock protein (HSP) levels in cells. Moreover, HSPs can associate with either specific lipids or with areas of special membrane topology (such as lipid rafts), and changes in the physical state of cellular membranes can alter gene expression. We propose that membrane microheterogeneity is important for regulating the HSP response. In support of this hypothesis, when particular membrane intercalating compounds are used to alter membrane properties, the simultaneous normalization of dysregulated expression of HSPs causes beneficial responses to disease states. Therefore, these compounds (such as hydroxylamine derivatives) have the potential to become a new class of pharmaceuticals for use in ‘membrane-lipid therapy’.
Cerebral vasospasm is an important syndrome that afflicts 30% of patients in the aftermath of, and secondary to, subarachnoid hemorrhage. Starting approximately one week after the hemorrhage, the condition worsens the prognosis of the hemorrhage significantly. Apart from general supportive care, no treatment exists for cerebral vasospasm. During the past 50 years, it was thought that the ischemia that signifies poor outcome is more or less exclusively caused by arterial narrowing. However, this idea has recently been challenged by the failure of the drug clazosentan to improve patient outcome, despite reversing vasoconstriction. In this article, we discuss the opinion that factors other than vasoconstriction are important in the pathophysiology and prognosis of cerebral vasospasm. Such factors include global ischemia, disruption of the blood–brain barrier, activation of apoptotic and inflammatory pathways, and cortical spreading depression.