Tunable Signal Processing Through Modular Control of Transcription Factor Translocation

Hao, Nan; Budnik, Bogdan; Gunawardena, Jeremy; O’Shea, Erin K.

doi:10.1126/science.1227299

Cited by 141 publications

(167 citation statements)

References 33 publications

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“…Recently, new biological sensors have been developed that translocate between the nucleus and the cytoplasm in response to a stimulus. These molecules typically maintain high signal-to-noise ratios, provide robust readouts in response to changes in signaling activity and are generally easier to use than FRET reporters (Hao et al, 2013;Regot et al, 2014;Spencer et al, 2013). Here, we have developed and characterized a translocation reporter for Akt kinase activity based on the transcription factor FoxO1.…”

Section: Development Of a Translocation Reporter For Akt Activitymentioning

confidence: 99%

Akt signaling dynamics in individual cells

Gross

Rotwein

2015

Journal of Cell Science

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The protein kinase Akt (for which there are three isoforms) is a key intracellular mediator of many biological processes, yet knowledge of Akt signaling dynamics is limited. Here, we have constructed a fluorescent reporter molecule in a lentiviral delivery system to assess Akt kinase activity at the single cell level. The reporter, a fusion between a modified FoxO1 transcription factor and clover, a green fluorescent protein, rapidly translocates from the nucleus to the cytoplasm in response to Akt stimulation. Because of its long half-life and the intensity of clover fluorescence, the sensor provides a robust readout that can be tracked for days under a range of biological conditions. Using this reporter, we find that stimulation of Akt activity by IGF-I is encoded into stable and reproducible analog responses at the population level, but that single cell signaling outcomes are variable. This reporter, which provides a simple and dynamic measure of Akt activity, should be compatible with many cell types and experimental platforms, and thus opens the door to new insights into how Akt regulates its biological responses.

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Section: Development Of a Translocation Reporter For Akt Activitymentioning

confidence: 99%

Akt signaling dynamics in individual cells

Gross

Rotwein

2015

Journal of Cell Science

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“…Changes in the subcellular localization of signaling proteins as a consequence of signal progression offer the opportunity to observe signaling as it occurs. In the yeast Saccharomyces cerevisiae, signaling has been monitored employing cytoplasmic-nuclear shuttling of protein kinases and transcription factors for the osmo-sensing High Osmolarity Glycerol (HOG) pathway (the Hog1 MAP kinase) (1)(2)(3)(4)(5), the calcineurin pathway (the Crz1 transcriptional activator) (6), the protein kinase A pathway (the Msn2 transcriptional activator) (7)(8)(9), and oxidative stress signaling through Yap1 (10). Several interesting system properties have been observed, including perfect adaptation of the Hog1 signaling system (1), slowdown of protein movements as a consequence of molecular crowding in compressed cells following osmostress (3,5), the potential benefits of nuclear accumulation bursts to coordinate multigene responses to external signals or for the survival of cell populations (8,9), and how coupling of dynamic phenomena may establish a rate of change sensor (7).…”

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confidence: 99%

Yeast AMP-activated Protein Kinase Monitors Glucose Concentration Changes and Absolute Glucose Levels

Bendrioua

Smedh

Almquist

et al. 2014

Journal of Biological Chemistry

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Background:Little is known about the signaling dynamics of AMP-activated protein kinase. Results: We define the dynamics of yeast AMPK signaling under different glucose concentrations. Conclusion: The Snf1-Mig1 signaling system monitors glucose concentration changes and absolute glucose levels to adjust the metabolism to a wide range of conditions. Significance: This description of AMPK signaling dynamics will stimulate studies defining the integration of signaling and metabolism.

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“…This has been very recently described for yeast Msn2, a transcription factor responding to general stress and capable of filtering different stress inputs to generate graded gene expression outputs (13). Furthermore, among the often numerous genes activated in response to a given stress, the cell has to impose different sensitivities to guarantee an equilibrated adaptive response.…”

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confidence: 99%

Different Mechanisms Confer Gradual Control and Memory at Nutrient- and Stress-Regulated Genes in Yeast

Rienzo

Poveda-Huertes

Aydin

et al. 2015

Molecular and Cellular Biology

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c Cells respond to environmental stimuli by fine-tuned regulation of gene expression. Here we investigated the dose-dependent modulation of gene expression at high temporal resolution in response to nutrient and stress signals in yeast. The GAL1 activity in cell populations is modulated in a well-defined range of galactose concentrations, correlating with a dynamic change of histone remodeling and RNA polymerase II (RNAPII) association. This behavior is the result of a heterogeneous induction delay caused by decreasing inducer concentrations across the population. Chromatin remodeling appears to be the basis for the dynamic GAL1 expression, because mutants with impaired histone dynamics show severely truncated dose-response profiles. In contrast, the GRE2 promoter operates like a rapid off/on switch in response to increasing osmotic stress, with almost constant expression rates and exclusively temporal regulation of histone remodeling and RNAPII occupancy. The Gal3 inducer and the Hog1 mitogen-activated protein (MAP) kinase seem to determine the different dose-response strategies at the two promoters. Accordingly, GAL1 becomes highly sensitive and dose independent if previously stimulated because of residual Gal3 levels, whereas GRE2 expression diminishes upon repeated stimulation due to acquired stress resistance. Our analysis reveals important differences in the way dynamic signals create dose-sensitive gene expression outputs.C ells continuously adapt their protein composition to changing environmental conditions. The regulation of gene expression is one of the fundamental mechanisms to adjust the global protein repertoire of the cell in order to maintain cell function and integrity in response to environmental challenges. Budding yeast is a powerful model to unravel the modes of transcriptional adaptation at the levels both of specific genes and of the whole organism (1, 2). Additionally, the basic structure of the signaling cascades responding to environmental perturbations is conserved from yeast to humans. It implies the alteration of core kinase activities, which modulate the expression of defense genes through a range of specific transcription factors. Extensive knowledge which precisely describes the molecular machinery and its global impact on gene expression in response to many types of stress has accumulated (3-7). However, the vast majority of these studies are performed with harsh environmental insults and therefore saturating stimulation. As a consequence, only very limited information or approaches are available to understand how cells adapt their gene expression programs to small or gradual changes in their environment.It is assumed that cells have acquired mechanisms that ensure a transcriptional response which is finely adjusted according to the strength of the stress or stimulation. However, the nature of the signaling molecules which confer gradual transcription outputs remains to be determined in most cases. Fine-tuning of gene expression responses can occur with different purposes, and th...

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Tunable Signal Processing Through Modular Control of Transcription Factor Translocation

Cited by 141 publications

References 33 publications

Akt signaling dynamics in individual cells

Akt signaling dynamics in individual cells

Yeast AMP-activated Protein Kinase Monitors Glucose Concentration Changes and Absolute Glucose Levels

Different Mechanisms Confer Gradual Control and Memory at Nutrient- and Stress-Regulated Genes in Yeast

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