Substrate Competition as a Source of Ultrasensitivity in the Inactivation of Wee1

SummaryThe mitotic regulators Wee1 and Cdk1 can inactivate each other through inhibitory phosphorylations. This double-negative feedback loop is part of a bistable trigger that makes the transition into mitosis abrupt and decisive. To generate a bistable response, some component of a double-negative feedback loop must exhibit an ultrasensitive response to its upstream regulator. Here, we experimentally demonstrate that Wee1 exhibits a highly ultrasensitive response to Cdk1. Several mechanisms can, in principle, give rise to ultrasensitivity, including zero-order effects, multisite phosphorylation, and competition mechanisms. We found that the ultrasensitivity in the inactivation of Wee1 arises mainly through two competition mechanisms: competition between two sets of phosphorylation sites in Wee1 and between Wee1 and other high-affinity Cdk1 targets. Based on these findings, we were able to reconstitute a highly ultrasensitive Wee1 response with purified components. Competition provides a simple way of generating the equivalent of a highly cooperative allosteric response

Thinning Black Hills Pine

Guide to thinning Black Hills pine trees to eliminate the least productive, low quality trees giving room to remaining trees and increased rate of growth. Discusses are reason not to clear-cut, types of thinning, spacing guides, slash disposal, equipment needed, and government cost-share programs

Cutting Posts and Poles for Profit

Guide to cutting posts and poles for profit discusses thinning a timber stand and how to cut an acceptable product

Cutting Posts and Poles for Profit

This publication provides guidance on harvesting timber for posts and poles. It includes suggestions to check with the farm forester for technical assistance, secure a market for the product before cutting, cut the post to the proper length with square-cut ends, and limb smoothly

Pruning Black Hills Pine

Guide to pruning Black Hills pine addresses selecting crop trees, equipment needed for pruning, safety, and government cost-share

Modeling the Cell Cycle: Why Do Certain Circuits Oscillate?

Computational modeling and the theory of nonlinear dynamical systems allow one to not simply describe the events of the cell cycle, but also to understand why these events occur, just as the theory of gravitation allows one to understand why cannonballs fly in parabolic arcs. The simplest examples of the eukaryotic cell cycle operate like autonomous oscillators. Here, we present the basic theory of oscillatory biochemical circuits in the context of the Xenopus embryonic cell cycle. We examine Boolean models, delay differential equation models, and especially ordinary differential equation (ODE) models. For ODE models, we explore what it takes to get oscillations out of two simple types of circuits (negative feedback loops and coupled positive and negative feedback loops). Finally, we review the procedures of linear stability analysis, which allow one to determine whether a given ODE model and a particular set of kinetic parameters will produce oscillations

Bistability in cell signaling: How to make continuous processes discontinuous, and reversible processes irreversible

Xenopus oocyte maturation is an example of an all-or-none, irreversible cell fate induction process. In response to a submaximal concentration of the steroid hormone progesterone, a given oocyte may either mature or not mature, but it can exist in intermediate states only transiently. Moreover, once an oocyte has matured, it will remain arrested in the mature state even after the progesterone is removed. It has been hypothesized that the all-or-none character of oocyte maturation, and some aspects of the irreversibility of maturation, arise out of the bistability of the signal transduction system that triggers maturation. The bistability, in turn, is hypothesized to arise from the way the signal transducers are organized into a signaling circuit that includes positive feedback ͑which makes it so that the system cannot rest in intermediate states͒ and ultrasensitivity ͑which filters small stimuli out of the feedback loop, allowing the system to have a stable off-state͒. Here we review two simple graphical methods that are commonly used to analyze bistable systems, discuss the experimental evidence for bistability in oocyte maturation, and suggest that bistability may be a common means of producing all-or-none responses and a type of biochemical memory. © 2001 American Institute of Physics. ͓DOI: 10.1063/1.1349894͔ One of the key questions of the postgenomic era is how the biological behavior of cells emerges out of the organization of regulatory proteins into cascades and networks. Here we examine one type of signaling circuit that can be used by cells to convert continuous stimuli into discrete responses, and can be used to ''remember'' a stimulus long after the stimulus has been withdrawn; in other words, the circuit exhibits bistability and hysteresis. We have hypothesized that a bistable circuit consisting of the Mos, MEK-1, and p42 MAP kinase proteins is responsible for the all-or-none character of Xenopus oocyte maturation, an interesting example of a cell fate induction process that is amenable to a variety of powerful experimental approaches. Here we review what is required to produce a satisfactory bistable signaling circuit, using two simple graphical methods, and review the experimental evidence for bistability in oocyte maturation and other important examples of switch-like biological processes. Our hope is to introduce biologists to the conceptual basis of bistability, and to introduce nonlinear scientists to a biological process where bistability appears to be of critical importance