Biomedical subjects

Attila Becskei

Publications and source records attributed to Attila Becskei.

7 recordsLinked to original sources

PubMed2005

Contributions of low molecule number and chromosomal positioning to stochastic gene expression.

The presence of low-copy-number regulators and switch-like signal propagation in regulatory networks are expected to increase noise in cellular processes. We developed a noise amplifier that detects fluctuations in the level of low-abundance mRNAs in yeast. The observed fluctuations are not due to the low number of molecules expressed from a gene per se but originate in the random, rare events of gene activation. The frequency of these events and the correlation between stochastic expressions of genes in a single cell depend on the positioning of the genes along the chromosomes. Transcriptional regulators produced by such random expression propagate noise to their target genes.

Chromosomes, Fungal↗

PubMed2005

Enhancement of cellular memory by reducing stochastic transitions.

On induction of cell differentiation, distinct cell phenotypes are encoded by complex genetic networks. These networks can prevent the reversion of established phenotypes even in the presence of significant fluctuations. Here we explore the key parameters that determine the stability of cellular memory by using the yeast galactose-signalling network as a model system. This network contains multiple nested feedback loops. Of the two positive feedback loops, only the loop mediated by the cytoplasmic signal transducer Gal3p is able to generate two stable expression states with a persistent memory of previous galactose consumption states. The parallel loop mediated by the galactose transporter Gal2p only increases the expression difference between the two states. A negative feedback through the inhibitor Gal80p reduces the strength of the core positive feedback. Despite this, a constitutive increase in the Gal80p concentration tunes the system from having destabilized memory to having persistent memory. A model reveals that fluctuations are trapped more efficiently at higher Gal80p concentrations. Indeed, the rate at which single cells randomly switch back and forth between expression states was reduced. These observations provide a quantitative understanding of the stability and reversibility of cellular differentiation states.

Cell Differentiation↗

PubMed2005

Quantitative models of nuclear transport.

Nuclear pore complexes mediate the rapid trafficking of target macromolecules between the nucleus and the cytoplasm but exclude non-targets. Mathematical modeling helps to define the physical properties of a transport medium that can selectively enhance the permeation of some molecules but block others. Recent pioneering work has established a basis for quantitative modeling of nuclear translocation, and we expect this field to expand rapidly. A second area where modeling of nucleocytoplasmic transport has been prominently employed is in efforts to understand the regulatory networks by which signals pass between the nuclear and cytoplasmic compartments. Recent evidence suggests that the distinctive kinetics and spatial organization of nuclear transport processes can be used to efficiently propagate signals by new and unexpected pathways.

Active Transport, Cell Nucleus↗

PubMed2005

A system of counteracting feedback loops regulates Cdc42p activity during spontaneous cell polarization.

Cellular polarization is often a response to distinct extracellular or intracellular cues, such as nutrient gradients or cortical landmarks. However, in the absence of such cues, some cells can still select a polarization axis at random. Positive feedback loops promoting localized activation of the GTPase Cdc42p are central to this process in budding yeast. Here, we explore spontaneous polarization during bud site selection in mutant yeast cells that lack functional landmarks. We find that these cells do not select a single random polarization axis, but continuously change this axis during the G1 phase of the cell cycle. This is reflected in traveling waves of activated Cdc42p which randomly explore the cell periphery. Our integrated computational and in vivo analyses of these waves reveal a negative feedback loop that competes with the aforementioned positive feedback loops to regulate Cdc42p activity and confer dynamic responsiveness on the robust initiation of cell polarization.

Cell Polarity↗

PubMed2004

Amplitude control of cell-cycle waves by nuclear import.

Propagation of waves of biochemical activities through consecutive stages of the cell cycle is essential to execute the steps of cell division in a strict temporal order. Mechanisms that ensure the proper amplitude and timing of these waves are poorly understood. Using a synthetic gene circuit, we show that a transcriptional activator driven by yeast cell-cycle promoters propagates transcriptional oscillations with substantial damping. Although regulated nuclear translocation has been implicated in the timing of oscillatory events, mathematical analysis shows that increasing the rate of nuclear transport is an example of a general regulatory principle, which enhances the fidelity of wave propagation. Indeed, increasing the constitutive import rate of the activator counteracts the damping of waves and concurrently preserves the intensity of the signal. In contrast to the regulatory range of nuclear transport, the range of mRNA turnover considerably limits transcriptional wave propagation. This classification of cellular processes outlines potential regulatory mechanisms that can contribute to faithful transmission of oscillations at different stages of the cell cycle.

Active Transport, Cell Nucleus↗

PubMed2003

The strategy for coupling the RanGTP gradient to nuclear protein export.

The Ran GTPase plays critical roles in both providing energy for and determining the directionality of nucleocytoplasmic transport. The mechanism that couples the RanGTP gradient to nuclear protein export will determine the rate of and limits to accumulation of export cargoes in the cytoplasm, but is presently unknown. We reasoned that plausible coupling mechanisms could be distinguished by comparing the rates of reverse motion of export cargoes through the nuclear pore complex (NPC) with the predictions of a mathematical model. Measurement of reverse export rates in Xenopus oocytes revealed that nuclear export signals can facilitate RanGTP-dependent cargo movement into the nucleus against the RanGTP gradient at rates comparable to export rates. Although export cargoes with high affinity for their receptor are exported faster than those with low affinity, their reverse transport is also greater. The ratio of the rates of reverse and forward export of a cargo is proportional to its rate of diffusion through the NPC, i.e., to the ability of the cargo to penetrate the NPC permeability barrier. The data substantiate a diffusional mechanism of coupling and suggest the existence of a high concentration of RanGTP-receptor complexes within the NPC that decreases sharply at the cytoplasmic boundary of the NPC permeability barrier.

Models, Biological↗

PubMed2002

Binary and graded responses in gene networks.

Although gene expression can be regulated in a graded or a binary fashion, the majority of eukaryotic genes are either fully activated or not expressed at all in individual cells. This binary response might be an inherent property of many eukaryotic promoters. Analysis of transcription under the control of yeast GAL1 promoter suggests, however, that graded and binary modes of transcription are not mutually exclusive, but that both can occur at the same promoter when the activity of different signaling pathways is varied. In view of that, it can be expected that forthcoming experimental studies on the combinatorial effects of signaling and transcriptional mechanisms will reveal new strategies for generating graded or binary responses.

Animals↗