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Homogeneous Time Constants Promote Oscillations in Negative Feedback Loops.

ABSTRACT: Biological oscillators are present in nearly all self-regulating systems, from individual cells to entire organisms. In any oscillator structure, a negative feedback loop is necessary, but not sufficient to guarantee the emergence of periodic behaviors. The likelihood of oscillations can be improved by careful tuning of the system time constants and by increasing the loop gain, yet it is unclear whether there is any general relationship between optimal time constants and loop gain. This issue is particularly relevant in genetic oscillators resulting from a chain of different subsequent biochemical events, each with distinct (and uncertain) kinetics. Using two families of genetic oscillators as model examples, we show that the loop gain required for oscillations is minimum when all elements in the loop have the same time constant. On the contrary, we show that homeostasis is ensured if a single element is considerably slower than the others.

SUBMITTER: Blanchini F

PROVIDER: S-EPMC6008730 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Homogeneous Time Constants Promote Oscillations in Negative Feedback Loops.

Blanchini Franco F Cuba Samaniego Christian C Franco Elisa E Giordano Giulia G

ACS synthetic biology 20180514 6

Biological oscillators are present in nearly all self-regulating systems, from individual cells to entire organisms. In any oscillator structure, a negative feedback loop is necessary, but not sufficient to guarantee the emergence of periodic behaviors. The likelihood of oscillations can be improved by careful tuning of the system time constants and by increasing the loop gain, yet it is unclear whether there is any general relationship between optimal time constants and loop gain. This issue is ...[more]

PMID: 29676894

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Project description:BACKGROUND: Feedback loops, both positive and negative are embedded in the Mitogen Activated Protein Kinase (MAPK) cascade. In the three layer MAPK cascade, both feedback loops originate from the terminal layer and their sites of action are either of the two upstream layers. Recent studies have shown that the cascade uses coupled positive and negative feedback loops in generating oscillations. Two plausible designs of coupled positive and negative feedback loops can be elucidated from the literature; in one design the positive feedback precedes the negative feedback in the direction of signal flow and vice-versa in another. But it remains unexplored how the two designs contribute towards triggering oscillations in MAPK cascade. Thus it is also not known how amplitude, frequency, robustness or nature (analogous/digital) of the oscillations would be shaped by these two designs. RESULTS: We built two models of MAPK cascade that exhibited oscillations as function of two underlying designs of coupled positive and negative feedback loops. Frequency, amplitude and nature (digital/analogous) of oscillations were found to be differentially determined by each design. It was observed that the positive feedback emerging from an oscillating MAPK cascade and functional in an external signal processing module can trigger oscillations in the target module, provided that the target module satisfy certain parametric requirements. The augmentation of the two models was done to incorporate the nuclear-cytoplasmic shuttling of cascade components followed by induction of a nuclear phosphatase. It revealed that the fate of oscillations in the MAPK cascade is governed by the feedback designs. Oscillations were unaffected due to nuclear compartmentalization owing to one design but were completely abolished in the other case. CONCLUSION: The MAPK cascade can utilize two distinct designs of coupled positive and negative feedback loops to trigger oscillations. The amplitude, frequency and robustness of the oscillations in presence or absence of nuclear compartmentalization were differentially determined by two designs of coupled positive and negative feedback loops. A positive feedback from an oscillating MAPK cascade was shown to induce oscillations in an external signal processing module, uncovering a novel regulatory aspect of MAPK signal processing.

Project description:Rationale: Colitis-associated colorectal cancer (CAC) usually exhibits an accelerated disease progression, an increased resistance to therapeutic drugs and a higher mortality rate than sporadic colorectal cancer (CRC). PIAS3 is a member of the protein inhibitor of activated STAT (PIAS) family; however, little is known about the expression and biological functions of PIAS3 in CAC. The aim of our study was to investigate the biological mechanisms of PIAS3 in CAC. Methods: PIAS3 expression was examined in colon tissues of CAC/CRC patients and azoxymethane-dextran sulfate sodium (AOM-DSS)-induced mice. The role of PIAS3 was studied using a series of in vitro, in vivo and clinical approaches. Results: Downregulated PIAS3 expression, upregulated miR-18a expression and highly activated NF-κB and STAT3 were observed in colon tissues of CAC/CRC patients and AOM-DSS-induced mice. In vitro experiments revealed that PIAS3 significantly inhibited the activation of NF-κB and STAT3 and demonstrated that activated NF-κB and STAT3 transcriptionally regulated miR-18a level, and up-regulation of miR-18a expression led to defective PIAS3 expression. Moreover, PIAS3-mediated autoregulatory feedback loops (PIAS3/NF-κB/miR-18a and PIAS3/STAT3/miR-18a) were verified in vitro and were found to regulate cell proliferation. Additionally, modulation of the feedback loops via overexpression of PIAS3 or knockdown of miR-18a significantly inhibited cell proliferation in a mouse CRC xenograft model. Furthermore, upregulation of PIAS3 by intracolonic administration of PIAS3 lentivirus or anti-miR-18a lentivirus in AOM-DSS-induced mice led to dramatically reduced tumor sizes/numbers, whereas knockdown of PIAS3 in CAC mice significantly promoted tumor growth. Conclusion: Our data clearly show that PIAS3-mediated feedback loops control cell proliferation and function as robust driving forces for CAC progression. Targeting these highly activated feedback loops might offer promising therapeutic strategies for CAC.

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Homogeneous Time Constants Promote Oscillations in Negative Feedback Loops.

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Homogeneous Time Constants Promote Oscillations in Negative Feedback Loops.

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