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Positive-feedback loops as a flexible biological module.

ABSTRACT: Bistability in genetic networks allows cells to remember past events and to make discrete decisions in response to graded signals. Bistable behavior can result from positive feedback, but feedback loops can have other roles in signal transduction as well.We introduced positive feedback into the budding-yeast pheromone response to convert it into a bistable system. In the presence of feedback, transient induction with high pheromone levels caused persistent pathway activation, whereas at lower levels a fraction of cells became persistently active but the rest inactivated completely. We also generated mutations that quantitatively tuned the basal and induced expression levels of the feedback promoter and showed that they qualitatively changed the behavior of the system. Finally, we developed a simple stochastic model of our positive-feedback system and showed the agreement between our simulations and experimental results.The positive-feedback loop can display several different behaviors, including bistability, and can switch between them as a result of simple mutations.

SUBMITTER: Ingolia NT

PROVIDER: S-EPMC1914375 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Positive-feedback loops as a flexible biological module.

Ingolia Nicholas T NT Murray Andrew W AW

Current biology : CB 20070329 8

<h4>Background</h4>Bistability in genetic networks allows cells to remember past events and to make discrete decisions in response to graded signals. Bistable behavior can result from positive feedback, but feedback loops can have other roles in signal transduction as well.<h4>Results</h4>We introduced positive feedback into the budding-yeast pheromone response to convert it into a bistable system. In the presence of feedback, transient induction with high pheromone levels caused persistent path ...[more]

PMID: 17398098

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Project description:Background and purposeThe aim of this study is to decipher the underlying mechanisms of CCAAT/enhancer-binding protein delta (CEBPD)-enhanced glycolysis as well as the biological significance of CEBPD and MYC coamplification in urothelial carcinoma (UC).MethodsIn vitro analyses were conducted to examine the effects of altered CEBPD or MYC expression on UC cells. The in vivo effects of CEBPD overexpression in a high-glucose environment on tumour growth were investigated in xenografted induced diabetic severe combined immunodeficiency/beige mice. Data mining was used to cross-validate the associations between CEBPD and MYC copy number and transcriptional expression, quantitative reverse transcription-polymerase chain reaction, immunohistochemistry, chromogenic in situ hybridization, and in situ hybridization targeting microRNA were performed on 635 UC patient samples and xenograft samples. UC patient survival in relation to diabetes was validated by using the National Health Insurance Research Database.ResultsCEBPD and MYC coamplification (29.6%) occurred at a high frequency, MYC expression promoted chromosomal instability, facilitating CEBPD copy number gain and expression. CEBPD promoted glucose uptake and lactate production by upregulating SLC2A1 and HK2, leading to mitochondrial fission, increased extracellular acidification rate and decreased oxygen consumption rate to fuel cell growth. CEBPD upregulated HK2 expression through multiple regulation pathways including MYC stabilization, suppression of FBXW7 transactivation and MYC-independent transcriptional suppression of hsa-miR-429. Clinical and xenografted experiments confirmed the growth advantage of CEBPD in relation to glucose metabolic dysregulation and the significant correlations between the expression of these genes.ConclusionsWe confirmed that CEBPD has an oncogenic role in UC by activating AKT signalling and initiating metabolic reprogramming from mitochondrial oxidative phosphorylation to glycolysis to satisfy glucose addiction. These novel CEBPD- and MYC-centric multilayered positive feedback loops enhance cancer growth that could complement theranostic approaches.

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Positive-feedback loops as a flexible biological module.

Publications

Positive-feedback loops as a flexible biological module.

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