Breast cancer is the third most common type of cancer diagnosed. Cell cycle is a complex but highly organized and controlled process, in which normal cells sense mitogenic growth signals that instruct them to enter and progress through their cell cycle. This process culminates in cell division generating two daughter cells with identical amounts of genetic material. Uncontrolled proliferation is one of the hallmarks of cancer. In this study, we analyzed the expression of the cell cycle-related genes receptor for hyaluronan (HA)mediated motility (RHAMM), AURKA, TPX2, PLK1, and PLK4 and correlated them with the prognosis in a collective of 3952 breast cancer patients. A high messenger RNA expression of all studied genes correlated with a poor prognosis. Stratifying the patients according to the expression of hormonal receptors, we found that in patients with estrogen and progesterone receptorpositive and human epithelial growth factor receptor 2-negative tumors, and Luminal A and Luminal B tumors, the expression of the five analyzed genes correlates with worse survival. qPCR analysis of a panel of breast cancer cell lines representative of major molecular subtypes indicated a predominant expression in the luminal subtype. In vitro experiments showed that radiation influences the expression of the five analyzed genes both in luminal and triplenegative model cell lines. Functional analysis of MDA-MB-231 cells showed that small interfering RNA knockdown of PLK4 and TPX2 and pharmacological inhibition of PLK1 had an impact on the cell cycle and colony formation.Looking for a potential upstream regulation by microRNAs, we observed a differential expression of RHAMM, AURKA, TPX2, PLK1, and PLK4 after transfecting the MDA-MB-231 cells with three different microRNAs. Survival
Proper timing of rhythmic locomotor behavior is the consequence of integrating environmental conditions and internal time dictated by the circadian clock. Rhythmic environmental input like daily light and temperature changes (called Zeitgeber) reset the molecular clock and entrain it to the environmental time zone the organism lives in. Furthermore, depending on the absolute temperature or light intensity, flies exhibit their main locomotor activity at different times of day, i.e., environmental input not only entrains the circadian clock but also determines the phase of a certain behavior. To understand how the brain clock can distinguish between (or integrate) an entraining Zeitgeber and environmental effects on activity phase, we attempted to entrain the clock with a Zeitgeber different from the environmental input used for phasing the behavior. 150 clock neurons in the Drosophila melanogaster brain control different aspects of the daily activity rhythms and are organized in various clusters, During regular 12 hr light: 12 hr dark cycles at constant mild temperature (LD 25°C, LD being the Zeitgeber), so called morning oscillator (MO) neurons control the increase of locomotor activity just before lights-on, while evening oscillator (EO) neurons regulate the activity increase at the end of the day, a few hours before lights-off. Here, using 12 h: 12 h 25°C:16°C temperature cycles as Zeitgeber, we attempted to look at the impact of light on phasing locomotor behavior. While in constant light and 25°C:16°C temperature cycles (LLTC), flies show an unimodal locomotor activity peak in the evening, during the same temperature cycle, but in the absence of light (DDTC), the phase of the activity peak is shifted to the morning. Here, we show that the EO is necessary for synchronized behavior in LLTC but not for entraining the molecular clock of the other clock neuronal groups, while the MO controls synchronized morning activity in DDTC. Interestingly, our data suggest that the influence of the EO on the synchronization increases depending on the length of the photoperiod (constant light vs 12h of light). Hence, our results show that effects of different environmental cues on clock entrainment and activity phase can be separated, allowing to decipher their integration by the circadian clock.
words)Proper timing of rhythmic locomotor behavior is the consequence of integrating environmental conditions and internal time within the circadian clock. The 150 clock neurons in the Drosophila melanogaster brain are organized in various clusters, controlling different aspects of the daily activity rhythms. For example, during regular 12 hr light : 12 hr dark cycles at constant temperature (LD), so called Morning (M) neurons control the activity peak in the morning, whileEvening (E-) neurons regulate the activity increase at the end of the day. During the remaining times of day and night, flies are inactive, giving rise to the crepuscular behavior observed in LD. Here, we investigate if the same neuronal groups also control behavioral activity under very different environmental conditions of constant light and temperature cycles (LLTC). While the morning activity is completely absent in LLTC, a single pronounced activity peak occurs at the end of the thermophase. We show that the same E-neurons operating in LD, also regulate the evening peak in LLTC. Interestingly, neuronal activity of E-neurons is inversely correlated with behavioral activity, suggesting an inhibitory action on locomotion. Surprisingly, the E-cells responsible for synchronization to temperature cycles belong to the clock neurons containing the circadian photoreceptor Cryptochrome, previously suggested to be more important for synchronization to LD. Our results therefore support a more deterministic function of the different clock neuronal subgroups, independent of specific environmental conditions. Significance statement (119 words)Master circadian clocks in the brains of mammals and fruit fly are composed of neurons expressing varying types of neuropeptides and transmitters. This diversity along with anatomical differences indicate diverse functions of different clock neurons. In Drosophila, socalled Morning (M) and Evening (E) neurons control locomotor activity at the respective time of day during normal day/night (LD) cycles. Recent reports point to a certain degree of plasticity with regard to circadian clock neuron function, depending on specific environmental
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