Circadian mRNA oscillations are the main feature of core clock genes. Among them, period 2 is a key component in negative-feedback regulation, showing robust diurnal oscillations. Moreover, period 2 has been found to have a physiological role in the cell cycle or the tumor suppression. The present study reports that 3′-untranslated region (UTR)-dependent mRNA decay is involved in the regulation of circadian oscillation of period 2 mRNA. Within the mper2 3′UTR, both the CU-rich region and polypyrimidine tract-binding protein (PTB) are more responsible for mRNA stability and degradation kinetics than are other factors. Depletion of PTB with RNAi results in mper2 mRNA stabilization. During the circadian oscillations of mper2, cytoplasmic PTB showed a reciprocal expression profile compared with mper2 mRNA and its peak amplitude was increased when PTB was depleted. This report on the regulation of mper2 proposes that post-transcriptional mRNA decay mediated by PTB is a fine-tuned regulatory mechanism that includes dampening-down effects during circadian mRNA oscillations.
The mouse PERIOD1 (mPER1) protein, along with other clock proteins, plays a crucial role in the maintenance of circadian rhythms. mPER1 also provides an important link between the circadian system and the cell cycle system. Here we show that the circadian expression of mPER1 is regulated by rhythmic translational control of mPer1 mRNA together with transcriptional modulation. This time-dependent translation was controlled by an internal ribosomal entry site (IRES) element in the 5= untranslated region (5=-UTR) of mPer1 mRNA along with the trans-acting factor mouse heterogeneous nuclear ribonucleoprotein Q (mhnRNP Q). Knockdown of mhnRNP Q caused a decrease in mPER1 levels and a slight delay in mPER1 expression without changing mRNA levels. The rate of IRES-mediated translation exhibits phase-dependent characteristics through rhythmic interactions between mPer1 mRNA and mhnRNP Q. Here, we demonstrate 5=-UTR-mediated rhythmic mPer1 translation and provide evidence for posttranscriptional regulation of the circadian rhythmicity of core clock genes.
Our findings indicate that yoga exercise improves adiponectin level, serum lipids, and metabolic syndrome risk factors in obese postmenopausal women. Consequently, yoga exercise will be effective in preventing cardiovascular disease caused by obesity in obese postmenopausal Korean women.
The mammalian circadian rhythm is observed not only at the suprachiasmatic nucleus, a master pacemaker, but also throughout the peripheral tissues. Its conserved molecular basis has been thought to consist of intracellular transcriptional feedback loops of key clock genes. However, little is known about posttranscriptional regulation of these genes. In the present study, we investigated the role of the 3-untranslated region (3UTR) of the mouse cryptochrome 1 (mcry1) gene at the posttranscriptional level. Mature mcry1 mRNA has a 610-nucleotide 3UTR and mediates its own degradation. The middle part of the 3UTR contains a destabilizing cis-acting element. The deletion of this element led to a dramatic increase in mRNA stability, and heterogeneous nuclear ribonucleoprotein D (hnRNP D) was identified as an RNA binding protein responsible for this effect. Cytoplasmic hnRNP D levels displayed a pattern that was reciprocal to the mcry1 oscillation. Knockdown of hnRNP D stabilized mcry1 mRNA and resulted in enhancement of the oscillation amplitude and a slight delay of the phase. Our results suggest that hnRNP D plays a role as a fine regulator contributing to the mcry1 mRNA turnover rate and the modulation of circadian rhythm.Circadian rhythms in living organisms are regulated by an endogenous clock. In mammals, it is well known that the circadian clock is located at the suprachiasmatic nucleus (SCN) in the brain. The SCN orchestrates circadian oscillations in various peripheral tissues (21,36,56). Because the circadian rhythm is conserved from the entire organism to the level of the single cell, many efforts have been made to understand the molecular basis of the regulation of circadian timing (15,20).Enormous progress has been made toward understanding the secrets of the rhythm generator, providing a view of the circadian clock mechanism. Each cell of the body contains a circadian core oscillator composed of essential components for normal circadian behavior. The RNA and protein levels of the components, called clock genes, are known to oscillate in a circadian rhythm, based on studies of the expression of genes, including Clock (49); Bmal1 (5); mPer1 and mPer2 (55); mCry1 and mCry12 (22); Rev-erb␣ (34); and Ror␣ (44). These key clock genes are involved in interacting positive and negative transcriptional feedback loops (9,34,37,44).In mammals, cryptochromes are expressed in every organ, and there are two homologues, mcry1 and mcry2. In general, mcry1 is expressed at a high level in the SCN, whereas mcry2 expression in this region is almost negligible (41). The oscillation of mcry1 transcripts persists when mice are kept in a "free-running" state, such as constant darkness (27), as has been observed for other clock genes and as would be expected of a true circadian regulator. mcry1 expression also shows circadian oscillation in other organs, most notably in the liver; however, the phase of its expression in internal organs is delayed or advanced compared to the phase of its expression in the SCN. Both mCRY1 and mCRY2 ...
The physiological and behavioral circadian rhythms of most creatures are controlled by a harmony of functional relationships between clock genes. In mammals, several core clock genes show rhythmic profiles of their mRNA and protein expression. Among them, Rev-erb α functions as a transcriptional repressor, affecting expression patterns of other clock genes. For the continuous and robust oscillation of the molecular clock system, the levels of Rev-erb α protein are expected to be tightly regulated with the correct timing. Here, we demonstrate that Rev-erb α has an internal ribosomal entry site (IRES) in its 5′ untranslated region. Furthermore, we demonstrate that heterogeneous nuclear ribonucleoprotein Q and polypyrimidine tract-binding protein (PTB) modulate the IRES-mediated translation of Rev-erb α. We suggest that the rhythmic binding affinity of hnRNP Q to the Rev-erb α IRES and the change in PTB cytosolic levels lead to maintenance of the oscillation profile of the Rev-erb α protein.
Our findings indicate that aerobic exercise improves body composition, SHBG, insulin levels, and metabolic syndrome factors. These findings suggest that in obesepostmenopausal Korean women, 16 weeks of aerobic exercise is effective for preventing the metabolic syndrome caused by obesity.
Metabolic activity indicative of cellular demand is emerging as a key player in cell fate decision. Numerous studies have demonstrated that diverse metabolic pathways have a critical role in the control of the proliferation, differentiation and quiescence of stem cells. The identification of neural stem/progenitor cells (NSPCs) and the characterization of their development and fate decision process have provided insight into the regenerative potential of the adult brain. As a result, the potential of NSPCs in cell replacement therapies for neurological diseases is rapidly growing. The aim of this review is to discuss the recent findings on the crosstalk among key regulators of NSPC development and the metabolic regulation crucial for the function and cell fate decisions of NSPCs. Fundamental understanding of the metabolic circuits in NSPCs may help to provide novel approaches for reactivating neurogenesis to treat degenerative brain conditions and cognitive decline.
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