Abstract
Circadian rhythms form a self-sustaining, endogenous, time-keeping system that allows organisms to anticipate daily environmental changes. The core of the clock network consists of interlocking transcriptional-translational feedback loops that ensures that metabolic, behavioral, and physiological processes run on a 24 h timescale. The hierarchical nature of the clock manifests itself in multiple points of control on the daily cell division cycle, which relies on synthesis, degradation, and post-translational modification for progression. This relationship is particularly important for understanding the role of clock components in sensing stress conditions and triggering checkpoint signals that stop cell cycle progression. A case in point is the interplay among the circadian factor PERIOD2 (PER2), the tumor suppressor p53, and the oncogenic mouse double minute-2 homolog protein (MDM2), which is the p53’s negative regulator. Under unstressed conditions, PER2 and p53 form a stable complex in the cytosol and, along with MDM2, a trimeric complex in the nucleus. Association of PER2 to the C-terminus end of p53 prevents MDM2-mediated ubiquitylation and degradation of p53 as well as p53’s transcriptional activation. Remarkably, when not bound to p53, PER2 acts as substrate for the E3-ligase activity of MDM2; thus, PER2 is degraded in a phosphorylation-independent fashion. Unexpectedly, the phase relationship between PER2 and p53 are opposite; however, a systematic modeling approach, inferred from the oscillatory time course data of PER2 and p53, aided in identifying additional regulatory scenarios that explained, a priori, seemingly conflicting experimental data. Therefore, we advocate for a combined experimental/mathematical approach to elucidating multilevel regulatory cellular processes.
Highlights
Circadian oscillators provide living organisms an adaptive advantage by enabling them to anticipate the demands of an evolving environment
Overexpression of PER1downregulated the levels of Wee1, CcnB1, and Cdk1 mRNA and suppressed growth in cultured cancer cells (Gery et al, 2006). Another example is the product of human Timeless, a gene with a well-established function in the Drosophila clock system but with a debatable circadian role in mammalian cells (Mazzoccoli et al, 2016)
Following the analysis of the estimated parameters, we found that PER2:p53 binding should occur, regardless of p53’s ubiquitylation status, to properly simulate the antiphase relationship between PER2 and p53 that was reported to exist in total cell lysates (Prediction 3)
Summary
Circadian oscillators provide living organisms an adaptive advantage by enabling them to anticipate the demands of an evolving environment. Overexpression of PER1downregulated the levels of Wee, CcnB1 (encodes cyclin B1), and Cdk (encodes Cdc2) mRNA and suppressed growth in cultured cancer cells (Gery et al, 2006) Another example is the product of human Timeless (hTIM), a gene with a well-established function in the Drosophila clock system (dTim) but with a debatable circadian role in mammalian cells (Mazzoccoli et al, 2016). The rationale for an experimental design was conceptually simple: If PER2 were to favor p53 translocation, PER2 ectopic expression, or its downregulation, should impact the accumulation of p53 in either cellular compartment In accordance with this premise, PER-mediated nuclear shuttling of p53 was confirmed in cells overexpressing trace levels of PER2 and maintained in the presence of both proteasome and nuclear export inhibitors (Gotoh et al, 2016). The systematic mathematical approach helped to reconcile seemingly contradictory experimental data by generating theoretical predictions that were, experimentally confirmed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
