|Yeast Physiological and Genetic Pathways|
Much of this model is well-established by experimental evidence from several labs, but some of it is speculative. Note that this is a highly personal view of this topic; it is not meant to be a comprehensive review of the field.
Red: the glucose repression mechanism
Mig1 is responsible for repression of many genes that are dispensable to yeast cells growing on high levels of glucose. (The related protein Mig2 also acts to repress some genes (Mol. Cell. Biol. 16: 4790-4797). Mig1 is Cys2-His2 zinc-finger-containing DNA-binding protein that represses transcription by recruiting the general repressors Ssn6 and Tup1. The nuclear localization of Mig1 is regulated by glucose: it moves into the nucleus upon glucose addition, and into the cytoplasm upon glucose removal (Mol. Biol. of the Cell. 8:1603-1618). The Snf1-Snf4 protein kinase phosphorylates Mig1 and causes it to move to the cytoplasm; the Reg1-Glc7 protein phosphatase may dephosphorylate Mig1, causing it to enter the nucleus. Snf1-Snf4 kinase activity is regulated by glucose availability, and the signal responsible for this is probably the AMP/ATP ratio (Curr Biol 6:1426-1434). It is not known whether Reg1-Glc7 acts directly upon Mig1, or on Snf1, or upstream of Snf1, nor is it known if Reg1-Glc7 activity is regulated by glucose. The low affinity, high capacity glucose transproter Hxt1 probably provides the cell with most of the glucose for metabolism.
Summary of glucose repression
In cells growing on high levels of glucose, high levels of ATP are generated by glycolysis, which prevents activation of the Snf1-Snf4 protein kinase, preventing Mig1 phosphorylation and causing it to enter the nucleus, where it binds to promoters of glucose-repressed genes and represses their expression. In cells growing without glucose or on low levels of glucose, AMP levels are high, causing the Snf1-Snf4 protein kinase to be active and phosphorylate Mig1, causing it to reside in the cytoplasm and thereby preventing it from repressing expression of glucose-repressed genes.
Green: the glucose-induction mechanism
Expression of several HXT genes, encoding glucose transporters, is induced by glucose. Different HXT genes are induced by different levels of glucose: the low affinity transproter HXT1 is induced only by high levels of glucose; the high affinity transporter HXT2 is induced only by low levels of glucose (Mol. Cell. Biol. 15:1564-1572). Expression of the HXT genes is repressed by Rgt1 (Mol. Cell. Biol. 1996; 16: 5536-5545), a Cys6 zinc-finger-containing DNA-binding protein (Mol. Cell. Biol. 16: 6419-6426). Repressor function of Rgt1 is inhibited by glucose, and this requires Grr1, which is part of a protein complex implicated in ubiquitination (EMBO J. 16:101-110). HXT2 is only induced by low levels of glucose because it is repressed by Mig1 at high levels of glucose. HXT1 is only induced by high levels of glucose because of a second regulatory mechanism (whose components are unidentified) that requires high glucose for maximum activity.
The glucose signal is generated by two glucose receptors: Snf3 is a high affinity receptor responsible for generating a signal in response to low levels of glucose; Rgt2 is a low affinity receptor that generates a signal in response to high levels of glucose (PNAS 93:12428-12432). These two glucose sensors are similar to glucose transporters, but they contain unusually long C-terminal tails (218 and 303 amino acids) that are predicted to be in the cytoplasm (all known glucose transporters have C-terminal cytoplasmic tails of only about 50 amino acids). The Snf3 and Rgt2 tails are only similar in a short stretch of amino acids (15 of 17 identical). Snf3 has 2 of these sequences, Rgt1 has only 1. Neither the nature of the glucose signal, nor how it is generated by the glucose receptors is known. The 17 amino acid region of the C-terminal tails of the receptors is necessary for signal generation.
Summary of glucose-induction
Low levels of glucose (0.2%)
are sensed by Snf3, which generates a signal that activates Grr1 to inhibit
Rgt1 function, thereby derepressing expression of HXT2 (and others),
which encodes a high affinity glucose transporter responsible for
transport of low levels of glucose. High levels of glucose (2%) are
sensed by Rgt2, which generates a signal that activates an undefined regulatory
mechanism that acts upon HXT1, and activates Grr1 to inhibit Rgt1
function. Thus, Hxt1, a low affinity glucose transporter, is maximally
expressed. The high levels of glucose activate Mig1 function, thereby
causing repression of HXT2 expression.