Chemotherapy and radiation therapy for cancer often have severe side effects that limit their efficacy. Because these effects are in part determined by p53-mediated apoptosis, temporary suppression of p53 has been suggested as a therapeutic strategy to prevent damage of normal tissues during treatment of p53-deficient tumors. To test this possibility, a small molecule was isolated for its ability to reversibly block p53-dependent transcriptional activation and apoptosis. This compound, pifithrin-alpha, protected mice from the lethal genotoxic stress associated with anticancer treatment without promoting the formation of tumors. Thus, inhibitors of p53 may be useful drugs for reducing the side effects of cancer therapy and other types of stress associated with p53 induction.
Mice deficient in the circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Here we report that Bmal1 −/− mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early aging phenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1 −/− animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses, may provide a mechanistic explanation for the early onset of age-related pathologies in the absence of BMAL1.Supplemental material is available at http://www.genesdev.org.Received March 22, 2006; revised version accepted May 9, 2006. BMAL1 (brain and muscle ARNT-like protein, also known as MOP3 or ARNT3) belongs to the family of the basic helix-loop-helix (bHLH)-PAS domain-containing transcription factors. In a complex with another member of this family, CLOCK, BMAL1 regulates expression of genes through E-box elements in their promoters. BMAL1, CLOCK, and some of their transcriptional targets (PERIODs and CRYPTOCHROMEs) are the key components of the molecular oscillator that generates circadian rhythms. These 24-h oscillations in behavior, physiology, and metabolism are thought to ensure adaptation of organisms to the 24-h periodicity of the Earth's rotation (Panda et al. 2002b;Lowrey and Takahashi 2004). Although the master circadian clock is located within the hypothalamic suprachiasmatic nucleus (SCN), the key circadian proteins are expressed in many peripheral tissues, determining circadian periodicity in gene expression and physiology for many organs (Reppert and Weaver 2002). Indeed, microarray data show that up to 10% of genes in different tissues are directly or indirectly regulated by the circadian clock system (Panda et al. 2002a;Storch et al. 2002). At the same time, only a few oscillating genes (most of them encoding components of the molecular clock itself) are common to all organs tested. Since different tissues have characteristic sets of genes with clock-regulated timing and amplitude of expression (Panda et al. 2002a;Storch et al. 2002), it is likely that the circadian clock is involved in control of homeostasis in different organs.Mice with mutations or targeted disruptions of core circadian genes that have been generated during the last decade all show impaired circadian behavior and deregulation of circadian patterns in gene expression (Lowrey and Takahashi 2004). In addition to this universal phenotype, other pathological defects are specific for particular circadian mutants. Thus, Clock mutation results in reduced fertility and complications of pregnancy (Miller et al. 2004), obesity and metabolic syndrome (Turek et al. 2005), and sensitization to cocaine (McClung et al. 2005). Period2 deficiency leads to the enhanced voluntary alcohol consumption and alterations in the glutamatergic syste...
Ageing leads to functional deterioration of many brain systems, including the circadian clock - an internal time-keeping system that generates 24 hr rhythms in physiology and behaviour. Numerous clinical studies have established a direct correlation between the severity of neurodegenerative disorders, sleep disturbances and weakening of circadian clock functions. The latest data from model organisms, gene expression studies and clinical trials imply that the dysfunction of the circadian clock may contribute to the progression of ageing and age-associated pathologies, suggesting a functional link between the circadian clock, and age-associated decline of brain functions. Potential molecular mechanisms underlying this link include the circadian control of brain metabolism, reactive oxygen species homeostasis, hormone secretion, autophagy and stem cell proliferation.
Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease 1, 2, but the molecular basis is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (e.g. short or long QT syndromes, heart failure) 3-5 or pattern (e.g. Brugada syndrome) 6 of myocardial repolarization. Here we provide the first molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion channel expression and QT interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a novel clock-dependent oscillator, Krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of KChIP2, a critical subunit required for generating the transient outward potassium current (Ito). 7 Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. In sum, these findings identify circadian transcription of ion channels as a novel mechanism for cardiac arrhythmogenesis.
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