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Cdc14 was defined by Hartwell in his famous screen for loci that control the cell cycle of Saccharomyces cerevisiae.〔Hartwell LH, Culotti J, Pringle JR, Reid BJ (1974) Genetic control of the cell division cycle in yeast. ''Science'' 183:46-51〕 Cdc14 was later shown to encode a protein phosphatase. Cdc14 is dual-specificity, which means it has serine/threonine and tyrosine-directed activity. A preference for serines next to proline is reported.〔Gray CH, Good VM, Tonks NK, Barford D (2003) The structure of the cell cycle protein Cdc14 reveals a proline-directed protein phosphatase. Embo J 22:3524-3535.〕 Many early studies, especially in the budding yeast Saccharomyces cerevisiae, demonstrated that the protein plays a key role in regulating late mitotic processes. However, more recent work in a range of systems suggests that its cellular function is more complex. == 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.〔McCollum D, Gould KL (2001) Timing is everything: Regulation of mitotic exit and cytokinesis by the MEN and SIN. Trends Cell Biol 11:89-95.〕 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.〔〔Higuchi T, Uhlmann F (2005) Stabilization of microtubule dynamics at anaphase onset promotes chromosome segregation. ''Nature'' 433:171-176.〕 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.〔Breitkreutz A, Choi H, Sharom JR, Boucher L, Neduva V, Larsen B, Lin ZY, Breitkreutz BJ, Stark C, Liu G, Ahn J, Dewar-Darch D, Reguly T, Tang X, Almeida R, Qin ZS, Pawson T, Gingras AC, Nesvizhskii AI, Tyers M (2010) A global protein kinase and phosphatase interaction network in yeast. ''Science'' 328:1043-1046.〕〔Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, Adams S-L, Millar A, Taylor P, Bennett K, Boutilier K, Yang L, Wolting C, Donaldson I, Schandorff S, Shewnarane J, Vo M, Taggart J, Goudreault M, Muskat B, Alfarano C, Dewar D, Lin Z, Michalickova K, Willems AR, Sassi H, Nielsen PA, Rasmussen KJ, Andersen JR, Johansen LE, Hansen LH, Jespersen H, Podtelejnikov A, Nielsen E, Crawford J, Poulsen V, Sorensen BD, Matthiesen J, Hendrickson RC, Gleeson F, Pawson T, Moran MF, Durocher D, Mann M, Hogue CWV, Figeys D, Tyers M (2002) Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature (London) 415:180-183.〕〔Visintin R, Hwang ES, Amon A (1999) Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus. ''Nature'' 398:818-823.〕 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.〔Cueille N, Salimova E, Esteban V, Blanco M, Moreno S, Bueno A, Simanis V (2001) Flp1, a fission yeast orthologue of the S. cerevisiae CDC14 gene, is not required for cyclin degradation or rum1p stabilisation at the end of mitosis. Journal of Cell Science 114:2649-2664.〕 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.〔Wolfe BA, Gould KL (2004) Fission yeast Clp1p phosphatase affects G2/M transition and mitotic exit through Cdc25p inactivation. Embo J 23:919-929.〕 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.〔Gruneberg U, Glotzer M, Gartner A, Nigg EA (2002) The CeCDC-14 phosphatase is required for cytokinesis in the Caenorhabditis elegans embryo. Journal of Cell Biology 158:901-914.〕〔Kaiser BK, Nachury MV, Gardner BE, Jackson PK (2004) Xenopus Cdc14 alpha/beta are localized to the nucleolus and centrosome and are required for embryonic cell division. BMC Cell Biol 5:27.〕 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.〔Kipreos ET (2004) Developmental quiescence: Cdc14 moonlighting in G1. Nat Cell Biol 6:693-695.〕〔Saito RM, Perreault A, Peach B, Satterlee JS, van den Heuvel S (2004) The CDC-14 phosphatase controls developmental cell-cycle arrest in C. elegans. Nat Cell Biol 6:777-783.〕 Contradictory data also exist with human Cdc14. Unlike CeCdc14, hCdc14A is not centrosomic in mitosis, but is cytoplasmic and centrosomic during interphase.〔Mocciaro A, Schiebel E (2010) Cdc14: a highly conserved family of phosphatases with non-conserved functions? J Cell Sci 123:2867-2876.〕 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 〔Mocciaro A, Berdougo E, Zeng K, Black E, Vagnarelli P, Earnshaw W, Gillespie D, Jallepalli P, Schiebel E (2010) Vertebrate cells genetically deficient for Cdc14A or Cdc14B retain DNA damage checkpoint proficiency but are impaired in DNA repair. J Cell Biol 189:631-639.〕〔Cho HP, Liu Y, Gomez M, Dunlap J, Tyers M, Wang Y (2005) The dual-specificity phosphatase CDC14B bundles and stabilizes microtubules. Mol Cell Biol 25:4541-4551.〕〔Wu J, Cho HP, Rhee DB, Johnson DK, Dunlap J, Liu Y, Wang Y (2008) Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication. J Cell Biol 181:475-483.〕 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.〔〔Berdougo, E. 2009. Human Cdc14 phosphatases are not essential for viability and do not regulate mitotic exit. Ph.D. thesis, Weill Medical College of Cornell University.〕 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.〔Bassermann F, Frescas D, Guardavaccaro D, Busino L, Peschiaroli A, Pagano M (2008) The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell 134:256-267.〕 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.〔Ah Fong A, Judelson HS (2003) Cell cycle regulator Cdc14 is expressed during sporulation but not hyphal growth in the fungus-like oomycete Phytophthora infestans. Molec Microbiol 50: 487-494.〕 PiCdc14 was found to accumulate near the basal bodies, at the base of the flagella.〔Ah-Fong AMV, Judelson HS, 2011 New Role for Cdc14 Phosphatase: Localization to Basal Bodies in the Oomycete Phytophthora and Its Evolutionary Coinheritance with Eukaryotic Flagella. PLoS ONE 6(2): e16725. .〕 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.〔Clement A, Solnica-Krezel L, Gould KL, 2012, Functional Redundancy Between Cdc14 Phosphatases in Zebrafish Ciliogenesis. Developmental Dynamics 241: 1911-1921.〕 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Cdc14」の詳細全文を読む スポンサード リンク
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