SUMMARY PARAGRAPH for PHO85
Pho85p is a cyclin-dependent kinase (CDK) with diverse roles in the regulation of cellular responses to nutrient levels and progression through the cell cycle, which are reflected by its interactions with ten different cyclins subunits (2). The cyclins that interact with Pho85p can be divided into two families based on sequence similarity (4). The Pho80p subfamily, comprised of Pho80p, Pcl6p, Pcl7p, Pcl8p, and Pcl10p, primarily regulate the response to nutrient levels and environmental conditions (4, 2). The Pcl1,2 subfamily, comprised of Pcl1p, Pcl2p, Pcl9p, Clg1p, and Pcl5p, is involved in regulating transcription during the cell cycle and progression through the cell cycle, with the exception of Pcl5p, which regulates the response to amino acid starvation (4, 5, 2).
Pho85p phosphorylates numerous proteins resulting in diverse regulatory consequences, including changes in the localization, stability, and/or enzymatic activity of its targets (6, 7). For example, under high phosphate conditions, phosphorylation of the transcription factor Pho4p by the Pho80p-Pho85p complex results in the nuclear export of Pho4p, thereby preventing the transcription of genes involved in the response to phosphate starvation (8). The phosphorylation of the cell cycle inhibitor Sic1p by Pcl1p-Pho85p contributes to its degradation, allowing exit from G1 (9, 10). Pcl10p-Pho85p phosphorylates the glycogen synthase Gsy2p to inhibit glycogen biosynthesis (11). In general, the substrate specificity of Pho85p can be determined by its cyclin partner; with Pcl10p and Pho80p, for example, targeting the phosphorylation of Gsy2p and Pho4p, respectively (12, 13).
Many substrates of Pho85p are also substrates of the CDK Cdc28p, which has more than 50% sequence identity with Pho85p (14, 15, 2, and references therein). Like CLN1 and CLN2, the cyclins associated with Cdc28p, the transcription of PCL1, PCL2, and PCL9 are cell cycle regulated with peak expression in the G1 phase (4). In addition, the synthetic lethality of a pcl1 pcl2 cln1 cln2 quadruple mutant suggests at least one overlapping essential function for these G1 cyclins, via their associated CDKs (16). The functional overlap between Pho85p and Cdc28p has led to the suggestions Pho85p may regulate the resumption of growth after cell cycle arrest (10, 2).
Pho85p is regulated under conditions of low phosphate where the small molecule inositol heptakisphosphate (IP7) and the CDK inhibitor Pho81p contribute to the inhibition of the Pho85p-Pho80p CDK-cyclin complex (17, 18). Pho85p is related to the mammalian cyclin-dependent kinase, CDK5, which is involved in development of the central nervous system and neurite outgrowth (19, 20). Overexpression of this mammalian CDK can complement yeast cells containing a pho85 null mutation (19, 20).
Last updated: 2008-02-29