| Autor: |
Lam, Vu H., Li, Ying H., Xianhui Liu, Murphy, Katherine A., Diehl, Jonathan S., Kwok, Rosanna S., Chiu, Joanna C. |
| Zdroj: |
Journal of Neuroscience; 12/12/2018, Vol. 38 Issue 50, p10631-10643, 13p |
| Abstrakt: |
The animal circadian timing system interprets environmental time cues and internal metabolic status to orchestrate circadian rhythms of physiology, allowing animals to perform necessary tasks in a time-of-day-dependent manner. Normal progression of circadian rhythms is dependent on the daily cycling of core transcriptional factors that make up cell-autonomous molecular oscillators. In Drosophila, PERIOD (PER), TIMELESS (TIM), CLOCK (CLK), and CYCLE (CYC) are core clock proteins that function in a transcriptionaltranslational feedback mechanism to regulate the circadian transcriptome. Posttranslational modifications of core clock proteins provide precise temporal control over when they are active as regulators of clock-controlled genes. In particular, phosphorylation is a key regulatory mechanism that dictates the subcellular localization, stability, and transcriptional activity of clock proteins. Previously, casein kinase la (CKlα) has been identified as a kinase that phosphorylates mammalian PERI and modulates its stability, but the mechanisms by which it modulates PER protein stability is still unclear. Using Drosophila as a model, we show that CKlα has an overall function of speeding up PER metabolism and is required to maintain the 24 h period of circadian rhythms. Our results indicate that CKlα collaborates with the key clock kinase DOUBLETIME (DBT) in both the cytoplasm and the nucleus to regulate the timing of PER-dependent repression of the circadian transcriptome. Specifically, we observe that CKlα promotes PER nuclear localization by antagonizing the activity of DBT to inhibit PER nuclear translocation. Furthermore, CKlα enhances DBT-dependent PER phosphorylation and degradation once PER moves into the nucleus. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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