Regulation of the yeast PHO5 and PHO8 genes: A network of regulatory proteins, transcription factors and chromatin

The yeast Saccharomyces cerevisiae contains several phosphatases and permea ses involved in phosphate uptake and metabolism, the synthesis of which is regulated in response to the phosphate concentration in the growth medium. In phosphate containing media, transcription of these genes is repressed, w hile phosphate starvation results in strong induction. The most strongly re gulated gene of this PHO system is PHO5 which encodes a secreted non-specif ic acid phosphatase. Repression of PHO5 transcription is achieved through n egative regulation of the specific activator, Pho4. Under repressing condit ions Pho4 is phosphorylated by the Pho80-Pho85 cyclin-cdk complex, and tran scription prevented by its subsequent export out of the nucleus by interact ion with the Msn5 receptor. Under phosphate limitation, the Pho80-Pho85 com plex is inhibited through the action of the cyclin inhibitor Pho81, which r esults in the accumulation of non-phosphorylated Pho4 in the nucleus. Howev er in addition to the regulation of the Pho4 subcellular localization, ther e is another as yet unclarified mechanism which regulates PHO5 transcriptio n. Activation of PHO5 transcription requires the cooperative interaction of Pho4 with the pleiotropic homeodomain protein Pho2. Pho2 plays a role in i ncreasing both the DNA binding affinity and transactivation potential of Ph o4. The PHO5 promoter is also regulated through a repressive chromatin stru cture. Upon induction, massive, Pho4-dependent remodeling of chromatin occu rs, which is a prerequisite for promoter activation. The PHO8 gene, encodin g a non-specific alkaline phosphatase, is coordinately regulated with PHO5 through the same set of regulatory proteins and also through chromatin repr ession. However, in comparison to PHO5, the PHO8 promoter is transcriptiona lly rather weak. This low level of PHO8 induction can be explained by the i nability of Pho4 to accomplish full chromatin remodeling at this promoter. Complexes which influence the ability to remodel chromatin are discussed. T hese results highlight the importance of chromatin structure in the regulat ion of promoter activity.