SUMMARY PARAGRAPH for FKH2
FKH2 is a member of the winged-helix/forkhead (FOX) transcription factor gene family that regulates the expression of the CLB2 cluster of genes during the G2/M phase of the mitotic cell cycle (reviewed in 11 and 12). The CLB2 cluster includes mitotic regulators such as CLB1, CLB2, CDC5 and CDC20, as well as SWI5 and ACE2, transcription factors required for the subsequent temporal wave of cell cycle regulated gene expression in the M/G1 phase interval (13). Promoter sequences responsible for restricting transcription of genes in this cluster to the late S, G2 and M phases were first identified upstream of SWI5 and CLB2 (14, 15). These cell cycle regulated upstream activating sequences (UAS) contain binding sites for the MADS-box protein Mcm1p and for SWI five factor (SFF), an activity known to be involved in the formation of ternary complexes at these promoters in the presence of Mcm1p (14, 15). Fkh2p was subsequently identified as a component of SFF (16, 3). Inclusion of Fkh2p in the complex is facilitated by DNA bending induced by Mcm1p (16, 3, 17). The rate-limiting transcriptional coactivator Ndd1p is subsequently recruited to the chromatin of G2/M regulated promoters through interactions with Fkh2p in a manner that is dependent on both the phosphorylation of Ndd1p by the Cdc28p-Clb2p kinase complex and the phosphorylation of Fkh2p by one or more complexes containing Cdc28p with a B-type cyclin (Clb2p or Clb5p) (see below) (18, 19, 20, 7). Fkh2p is also required for the recruitment of the Cdc5p polo-like kinase, nucleating the formation of a Fkh2p-Ndd1p-Cdc5p complex on CLB2 cluster promoters and leading to the phosphorylation of Ndd1p by Cdc5p, an event required for the proper temporal activation of CLB2 cluster genes during G2/M (21). In contrast, Fkh2p can also cooperate with Isw2p, a chromatin-remodeling ATPase, to remodel chromatin which may be important for repression of CLB2 transcription during the G1 phase (22).
FHK1 and FKH2 appear to have partially redundant roles in the activation and periodic regulation of genes in the CLB2 cluster based on phenotypes associated with the double deletion strain (2, 16, 3, 1). Strains deleted for both genes also display morphological alterations including defects in cell separation, budding, and the induction of a nutrient-independent pseudohyphal-like growth phenotype that can be suppressed by multicopy CLB2 (2, 16, 3, 1). However, Fkh1p and Fkh2p have distinct functions in the control of G2/M phase transcription and regulation of the cell cycle (2, 16, 3, 1). First, as discussed above, Fkh2p (but not Fkh1p) is a component of SFF, an activity that forms ternary complexes at relevant promoters in the presence of Mcm1p (16, 3). Second, strains deleted for FKH2 display reduced CLB2 transcription and a reduced rate of progression through the cell cycle while strains deleted for FKH1 display enhanced transcription of CLB2 and a slightly elevated rate of progression through the S and G2/M phases of the cell cycle (1). Third, Fkh1p and Fkh2p display differential promoter occupancy in vivo, and in many cases compete for target promoter occupancy; purified Fkh2p, but not Fkh1p, binds to promoters in a cooperative manner with Mcm1p in vitro (4). Fourth, Fkh2p cooperates with Isw2p to remodel chromatin and repress transcription of CLB2 during G1 phase, while Fkh1p cooperates with Isw1p to remodel chromatin and repress CLB2 transcription during G2/M phase (22). Finally, Fkh1p and Fkh2p associate with the coding regions of active genes where they regulate transcriptional elongation and termination in opposing ways by affecting the phosphorylation status of the C-terminal repeat domain (CTD) of RNA Polymerase II (5).
FKH2 is subject to both transcriptional and post-translational regulation. FKH2 is periodically expressed in late S-phase through the actions of another forkhead family transcription factor, Hcm1p (23). Post-translationally Fkh2p is subject to cell cycle-dependent C-terminal phosphorylation by Cdc28p-Clb5p complexes, although Cdc28p-Clb2p complexes are also capable of phosphorylating the same residues (7). Phosphorylation of the C-terminal region of Fkh2p facilitates the recruitment of the rate-limiting transcriptional coactivator Ndd1p to CLB2 cluster promoters (7).
FKH2 is a member of a conserved forkhead (FOX) family of transcription factors that includes at least 43 members identified in humans, some of which have been implicated in cell cycle regulation (24, 25). Several parallels exist between one of these forkhead factors, FOXM1 (OMIM), and both FKH1 and FKH2. Similar to FKH1 and FKH2, the expression of FOXM1 is induced during the G1/S phase transition (23 and reviewed in 25). FOXM1 regulates the expression of a similar cluster of genes during G2 and M phases and is required for the proper execution of mitosis, cytokinesis, as well as chromosome stability and the spindle checkpoint (reviewed in 26). The expression of FOXM1 is tightly correlated with cellular proliferative rate, is often elevated in human carcinomas, and is actively involved in tumor development (reviewed in 26, 25).
Last updated: 2010-01-28