One clear finding from previous studies is that a two-component genetic switch is the key to both the EMT and MET. The switch contains two specialized pairs of proteins. One pair is SNAIL and microRNA34 (SNAIL/miR34), and the other is ZEB and microRNA200 (ZEB/miR200).
Each pair is "mutually inhibitory," meaning that the presence of one of the partners inhibits the production of the other.
In the mesenchymal cell state -- the state that corresponds to cancer metastasis -- both SNAIL and ZEB must be present in high levels. In the epithelial state, the microRNA partners dominate, and neither ZEB nor SNAIL is available in high levels.
"Usually, if you have two genes that are mutually limiting, you have only two possibilities," Ben-Jacob said. "In the first case, gene A is highly expressed and inhibits gene B. In the other, gene B is highly expressed and it inhibits A. This is true in the case of ZEB and miR200. One of these is 'on' and the other is 'off,' so it's clear that this is the decision element in the switch."
SNAIL and miR34 interact more weakly. As a result, both can be present at the same time, with the amount of each varying based upon inputs from a number of other proteins, including several other cancer genes.
"One of the most important things the model showed us was how SNAIL and miR34 act as an integrator," Ben-Jacob said. "This part of the circuit is acted on by multiple cues, and it integrates those signals and feeds information into the decision element. It does this based upon the level of SNAIL, which activates ZEB and inhibits miR200."
In modeling the ZEB/miR200 decision circuit, the team found that it operates as a "ternary" or three-way, switch. The rea
|Contact: David Ruth|