CDC14 - Cellular Function

Cellular Function

In Saccharomyces cerevisiae, the species in which Cdc14 activity is best understood and most-studied, the activity of Cdc14 (ScCdc14) leads to mitotic exit by dephosphorylating targets of Cdk1, a well-studied cyclin-dependent protein kinase. Cdc14 antagonizes Cdk1 by stimulating proteolysis of its cyclin partner (cyclin B), through the dephosphorylation of Cdh1, a regulator of the anaphase-promoting complex. Cdc14 also dephosphorylates Swi5 to enhance transcription of Sic1, an inhibitor of Cdk1.

This "simple" mitotic exit model became complicated as additional roles in mitosis were attributed to ScCdc14. These included stabilizing the spindle and regulating cytokinesis and rDNA/ telomere segregation. Consistent with such multiple roles, ScCdc14 has been found to bind several proteins that regulate the cell cycle and DNA replication, or that associate with the spindle or kinetochore.

Work in other yeasts further complicated the understanding of the role of Cdc14. Mutants in the ortholog of the fission Schizosaccharomyces pombe exit mitosis normally (unlike S. cerevisiae) but are altered in septation and cytokinesis. Also, while the protein regulates the Cdk1 ortholog of S. pombe, this occurs through a process unlike that of S. cerevisiae; it does not dephosphorylate the Sic1 or Cdh1 orthologs, but promotes the inactivation of Cdc2 by down-regulating Cdc25 phosphatase. Cdc14 of Candida albicans is also involved in septation and cytokinesis, but not mitotic exit.

Studies of Cdc14 in animal systems has further muddled the Cdc14 story. Animals have up to three diverged Cdc14 genes, with multiple splice variants, that appear to diverge in function and location. Also, several crucial studies have yielded contradictory results. The nematode Caenorhabditis elegans makes one Cdc14 (CdCdc14), which localizes to the spindle and centrosomes in mitosis, and to the cytoplasm at interphase. One RNAi study with CeCdc14 caused cytokinesis defects, which was consistent with similar work in Xenopus laevis. However, a second RNAi study showed no defects, and it was suggested that the first experiment used too many oligonucleotides which caused off-target effects. Contradictory data also exist with human Cdc14. Unlike CeCdc14, hCdc14A is not centrosomic in mitosis, but is cytoplasmic and centrosomic during interphase. HCdc14B was shown in one study to be primarily nucleolar like ScCdc14 (but unlike CeCdc14), but others detected hCdc14B on nuclear filaments and the spindle

While RNAi depletion of hCdc14A and hCdc14B led to defects in centriole duplication, cell cycle progression, and mitotic exit, cells deleted for the genes showed no defects in growth or mitosis, and a similar failure of a cell cycle defect was also shown in cultured human cells using conditional hCdc14A and hCdc14B knockouts. Finally, in chicken, knockout lines totally lacked defects in cell-cycle progression, mitotic entry or exit, cytokinesis, or centrosome behavior. There is evidence that Cdc14 may participate in a DNA damage checkpoint.

A novel role for Cdc14 in eukaryotes was suggested by studies of Phytophthora infestans, a eukaryotic microbe known best as the cause of the Irish Potato Famine. Notably, while the species mentioned above are all relatively close taxonomic relatives (in the Fungi/Metazoa group), P. infestans has a distinct evolutionary history; it is classified as an oomycete, and is a member of the Kingdom Stramenopila (the Heterokonts in some schemes) along with diatoms and brown algae. The single Cdc14 gene of P. infestans (PiCdc14) is expressed distinctly from those of fungi and metazoans; instead of being transcribed throughout the cell cycle and regulated post-translationally, PiCdc14 is under strong transcriptional control and is not expressed in hyphae, where most mitosis takes place. Instead, PiCdc14 is made during the formation of asexual spores, including its biflagellated zoospores. PiCdc14 was found to accumulate near the basal bodies, at the base of the flagella. In light of the varying roles of Cdc14 in fungi and animals, it was suggested that the P. infestans data implied that an ancestral role of Cdc14 involved the flagella stage of eukaryotes. Additional data in support of this theory was later obtained from studies in zebrafish, where its Cdc14 proteins were also found to localize to the basal body and play roles in the formation of cilia, which are short forms of flagella.