RESUMEN
Homeostatic and adaptive control mechanisms are essential for keeping organisms structurally and functionally stable. Integral feedback is a control theoretic concept which has long been known to keep a controlled variable A robustly (i.e. perturbation-independent) at a given set-point A(set) by feeding the integrated error back into the process that generates A. The classical concept of homeostasis as robust regulation within narrow limits is often considered as unsatisfactory and even incompatible with many biological systems which show sustained oscillations, such as circadian rhythms and oscillatory calcium signaling. Nevertheless, there are many similarities between the biological processes which participate in oscillatory mechanisms and classical homeostatic (non-oscillatory) mechanisms. We have investigated whether biological oscillators can show robust homeostatic and adaptive behaviors, and this paper is an attempt to extend the homeostatic concept to include oscillatory conditions. Based on our previously published kinetic conditions on how to generate biochemical models with robust homeostasis we found two properties, which appear to be of general interest concerning oscillatory and homeostatic controlled biological systems. The first one is the ability of these oscillators ("oscillatory homeostats") to keep the average level of a controlled variable at a defined set-point by involving compensatory changes in frequency and/or amplitude. The second property is the ability to keep the period/frequency of the oscillator tuned within a certain well-defined range. In this paper we highlight mechanisms that lead to these two properties. The biological applications of these findings are discussed using three examples, the homeostatic aspects during oscillatory calcium and p53 signaling, and the involvement of circadian rhythms in homeostatic regulation.
Asunto(s)
Adaptación Fisiológica , Relojes Biológicos/fisiología , Homeostasis , Modelos Biológicos , Señalización del Calcio , Ritmo Circadiano , Retroalimentación Fisiológica , Cinética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/fisiologíaRESUMEN
Colorectal cancer (CRC) is, for sporadic forms, most strongly related to lifestyle factors. The epidemic of obesity and physical inactivity has great impact on disease patterns. Likewise, an altered metabolism has consequences at the cellular and molecular level with implications for cancer initiation and growth. Understanding the genetic hallmarks of cancers has improved over the years and now also includes cancer metabolic reprogramming. The initiation of cancer through genetic instability, including chromosomal instability, microsatellite instability and epigenetic silencing through the CpG island methylator phenotype follows pathways with distinct clinical, pathological, and genetic characteristics. These can potentially be used for molecular classification and comprehensive tumor profiling for improved diagnostics, prognosis and treatment in CRC. For one, epidermal growth factor receptor-directed treatment now considerably prolongs survival in metastatic disease, but defining the true responders from non-responders has emerged as complex. Further, the use of both non-steroidal anti-inflammatory drugs including cyclooxygenase-2 inhibitors is associated with a decreased incidence of adenoma and reduced mortality rate of CRC. This review gives a brief yet updated overview of the current understanding of CRC as a genetic and molecular disease with potential for clinical pathways of prevention, improved prediction and better prognosis in the future.
Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Adenoma/genética , Adenoma/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinogénesis/genética , Carcinogénesis/metabolismo , Inestabilidad Cromosómica/genética , Islas de CpG/genética , Metilación de ADN , Epigenómica , Genotipo , Humanos , Mutación , Fenotipo , PronósticoRESUMEN
The biological clock, present in nearly all eukaryotes, has evolved such that organisms can adapt to our planet's rotation in order to anticipate the coming day or night as well as unfavorable seasons. As all modern high-precision chronometers, the biological clock uses oscillation as a timekeeping element. In this review, we describe briefly the discovery, historical development, and general properties of circadian oscillators. The issue of temperature compensation (TC) is discussed, and our present understanding of the underlying genetic and biochemical mechanisms in circadian oscillators are described with special emphasis on Neurospora crassa, mammals, and plants.
Asunto(s)
Relojes Circadianos/genética , Relojes Circadianos/fisiología , Eucariontes/genética , Eucariontes/fisiología , Animales , Drosophila melanogaster/genética , Drosophila melanogaster/fisiología , Retroalimentación Fisiológica , Humanos , Mamíferos/genética , Mamíferos/fisiología , Modelos Biológicos , Neurospora crassa/genética , Neurospora crassa/fisiología , Fenómenos Fisiológicos de las Plantas , Plantas/genética , Biología de Sistemas , TemperaturaRESUMEN
Homeostatic mechanisms are essential for the protection and adaptation of organisms in a changing and challenging environment. Previously, we have described molecular mechanisms that lead to robust homeostasis/adaptation under inflow or outflow perturbations. Here we report that harmonic oscillations occur in models of such homeostatic controllers and that a close relationship exists between the control of the p53/Mdm2 system and that of a homeostatic inflow controller. This homeostatic control model of the p53 system provides an explanation why large fluctuations in the amplitude of p53/Mdm2 oscillations may arise as part of the homeostatic regulation of p53 by Mdm2 under DNA-damaging conditions. In the presence of DNA damage p53 is upregulated, but is subject to a tight control by Mdm2 and other factors to avoid a premature apoptotic response of the cell at low DNA damage levels. One of the regulatory steps is the Mdm2-mediated degradation of p53 by the proteasome. Oscillations in the p53/Mdm2 system are considered to be part of a mechanism by which a cell decides between cell cycle arrest/DNA repair and apoptosis. In the homeostatic inflow control model, harmonic oscillations in p53/Mdm2 levels arise when the binding strength of p53 to degradation complexes increases. Due to the harmonic character of the oscillations rapid fluctuating noise can lead, as experimentally observed, to large variations in the amplitude of the oscillation but not in their period, a behavior which has been difficult to simulate by deterministic limit-cycle models. In conclusion, the oscillatory response of homeostatic controllers may provide new insights into the origin and role of oscillations observed in homeostatically controlled molecular networks.
Asunto(s)
Homeostasis , Modelos Biológicos , Proteína p53 Supresora de Tumor/metabolismo , Animales , Humanos , Cinética , Proteínas Proto-Oncogénicas c-mdm2RESUMEN
Circadian rhythms are considered to play an essential part in the adaptation of organisms to their environments. The occurrence of circadian oscillations appears to be based on the presence of transcriptional-translational negative feedback loops. In Neurospora crassa, the protein FREQUENCY (FRQ) is part of such a negative feedback loop apparently by a direct interaction with its transcription factor WHITE COLLAR-1 (WC-1). Based on the observation that nuclear FRQ levels are significantly lower than nuclear WC-1 levels, it was suggested that FRQ would act more like a catalyst in inhibiting WC-1 rather than binding to WC-1 and making an inactive FRQ:WC-1 complex. Intrigued by this hypothesis, we constructed a model for the Neurospora circadian clock, which includes expression of the frq and the wc-1 genes and their possible interactions. The model suggests that even small amounts of nuclear FRQ-protein are capable of inhibiting frq transcription in a rhythmic manner by binding to WC-1 and promoting its degradation. Our model predicts the importance of a FRQ dependent degradation of WC-1 in closing the negative feedback loop. The model shows good agreement with experimental levels in nuclear and cytosolic FRQ and WC-1, their phase relationships, and several clock mutant phenotypes.
Asunto(s)
Relojes Biológicos/fisiología , Ritmo Circadiano/fisiología , Proteínas de Unión al ADN/metabolismo , Oscuridad , Proteínas Fúngicas/metabolismo , Modelos Biológicos , Neurospora crassa/fisiología , Factores de Transcripción/metabolismo , Simulación por Computador , Retroalimentación/fisiología , Regulación Fúngica de la Expresión Génica/fisiología , Transducción de Señal/fisiologíaRESUMEN
In many organisms, the presence of lithium leads to an increase of the circadian period length. In Neurospora crassa, it was earlier found that lithium results in a decrease of overall growth and increased circadian periods. In this article, the authors show that lithium leads to a reduction of FRQ degradation with elevated FRQ levels and to a partial loss of temperature compensation. At a concentration of 13 mM lithium, FRQ degradation is reduced by about 60% while, surprisingly, the activity of the 20S proteasome remains unaffected. Experiments and model calculations have shown that the stability of FRQ is dependent on its phosphorylation state and that increased FRQ protein stabilities lead to increased circadian periods, consistent with the observed increase of the period when lithium is present. Because in Neurospora the proteasome activity is unaffected by lithium concentrations that lead to significant FRQ stabilization, it appears that lithium acts as an inhibitor of kinases that affect phosphorylation of FRQ and other proteins. A competition between Li(+) and Mg(2+) ions for Mg(2+)-binding sites may be a mechanism to how certain kinases are inhibited by Li(+). A possible kinase in this respect is GSK-3, which in other organisms is known to be inhibited by lithium. The partial loss of temperature compensation in the presence of lithium can be understood as an increase in the overall activation energy of FRQ degradation. This increase in activation energy may be related to a reduction in FRQ phosphorylation so that more kinase activity, that is, higher temperature and longer times, is required to achieve the necessary amount of FRQ phosphorylation leading to turnover. Using a modified Goodwin oscillator as a semiquantitative model for the Neurospora clock, the effects of lithium can be described by adding lithium inhibitory terms of FRQ degradation to the model.