Livas et al. BMC Genomics 2011, 12:405 http://www.biomedcentral.com/1471-2164/12/405 lived and, in fact, induction of PDC1 is maintained or even increased during exponential growth (Table 1). For ALD5, TMT1, YMC2 and ATR1 two signalling pathways appear to be operative, one of them inde- pendent of PKA and acting both shortly after glucose addition and during growth, the other one depending on PKA and with transient effects. The behaviour of PDC5 could be explained by the operation of a PKA- independent system whose effects are transient. We have also observed that for some genes, that show no response to the sugar in the absence of PKA, repres- sion by glucose in the wild-type strain is transient (Table 2). Our observations on the involvement of PKA in induction and repression by glucose, together with the results of Wang et al [5], allow the classification of genes responding to glucose in four categories (Table 4). Genes in class 1 are controlled exclusively by signalling pathway(s) independent of PKA These genes can be induced (or repressed) in the absence of PKA and are not induced (or repressed) upon activation of PKA in the absence of glucose. In this category, induced genes are mostly related with glu- cose metabolism, while repressed genes are involved in utilization of alternative carbon sources. Genes in class 2 are controlled only by signalling pathway (s) dependent on PKA These genes can be induced/repressed by activation of PKA and do not respond to glucose in the absence of PKA. Many of the induced genes in this category encode proteins involved in amino acid biosynthesis, while the repressed genes form a heterogeneous group. Genes in class 3 are controlled by redundant PKA- dependent and PKA-independent signalling pathways These genes can be fully induced/repressed by activation of PKA, but also by glucose in the absence of PKA. Among the induced genes in this category, those Page 8 of 12 encoding glucose transporters and ribosomal proteins are prevalent, while many of the repressed genes are involved in the utilization of non-fermentable carbon sources. Genes in class 4 are controlled by cooperative signalling pathways, of which at least one is PKA-dependent These genes encode proteins of different types. Some of them do not respond to the activation of PKA nor to the addition of glucose in the absence of PKA. For others, a partial induction/repression may be observed in one of these conditions or in both. What could be the advantages to the cell of employing these different modes of regulation? While control through a single signal may be adequate in many cases, regulation of genes by redundant signalling pathways could confer a greater robustness to their response to glucose. On the other hand, regulation by several coop- erative pathways that, individually, cannot give a full transcriptional response, could provide a greater flexibil- ity, as discussed by Chen and Thorner [29] for the case of yeast responses to nutrient limitation. The next important goal will be to establish the PKA- dependent and PKA-independent pathways operating in each case, since information on this topic is still very incomplete. A notable exception is the PKA-indepen- dent pathway controlling the glucose-induced HXT genes that encode glucose transporters. The plasma membrane proteins Snf3/Rgt2 act as sensors for external glucose and, when bound to the sugar, initiate a chain of reactions that results in the dissociation of the repres- sor Rgt1 from the promoters of the corresponding HXT genes [30,31]. For other types of genes induced by glu- cose the situation is less clear. The protein kinase Snf1 may play a role in the case of genes encoding enzymes involved in amino acid biosynthesis, since Snf1 represses the translation of the transcriptional activator Gcn4 [32]. As glucose inactivates Snf1 [33], this would result in the induction of the genes activated by Gcn4. Table 4 Involvement of PKA in the transcriptional regulation of different classes of genes controlled by glucose Class 1 2 3 4 Transcriptional effect Induction Repression Induction Repression Induction Repression Induction Repression Glucose added to strain PKA+ + + + + + + + + PKA- + + - - + + - - No glucose added PKA activated - - + + + + - - Representative genes PFK1, ENO2 CRC1, PCK1, MLS1 ARG3, THR4 GRX2, PEP4 HXT3, RPL7A, HOR2 ACS1, ADY2, CIT3 SDT1, STR3 HXT6, MDH1 The presence or absence of transcriptional response after addition of glucose to yeast strains with or without PKA activity is indicated by + or -. The column labelled “No glucose added” shows the transcriptional response when PKA is activated through an increase in cAMP that does not involve the presence of glucose [5].