InteractiveFly: GeneBrief

greatwall: Biological Overview | References

Polo is a conserved kinase that coordinates many events of mitosis and meiosis, but how it is regulated remains unclear. Drosophila females having only one wild-type allele of the polo kinase gene and the dominant Scant mutation produce embryos in which one of the centrosomes detaches from the nuclear envelope in late prophase. Scant creates a hyperactive form of Greatwall (Gwl) with altered specificity in vitro. Greatwall is another protein kinase recently implicated in mitotic entry in Drosophila and Xenopus. Excess Gwl activity in embryos causes developmental failure that can be rescued by increasing maternal Polo dosage, indicating that coordination between the two mitotic kinases is crucial for mitotic progression. Revertant alleles of Scant that restore fertility to polo-Scant heterozygous females are recessive alleles or deficiencies of gwl; they show chromatin condensation defects and anaphase bridges in larval neuroblasts. One recessive mutant allele specifically disrupts a Gwl isoform strongly expressed during vitellogenesis. Females hemizygous for this allele are sterile, and their oocytes fail to arrest in metaphase I of meiosis; both homologues and sister chromatids separate on elongated meiotic spindles with little or no segregation. This allelic series of gwl mutants highlights the multiple roles of Gwl in both mitotic and meiotic progression. These results indicate that Gwl activity antagonizes Polo and thus identify an important regulatory interaction of the cell cycle (Archambault, 2007).

Studies of Greatwall in Xenopus reveal another side to Greatwall function that suggest that the picture in Drosophila is not the whole story. In Xenopus, Greatwall is required for the positive feedback loop that removes inhibitory tyrosine phosphate from the central mitotic regulatory kinase Cdc2. Immunodepletion of Greatwall kinase prevents Xenopus egg extracts from entering or maintaining M phase due to the accumulation of inhibitory phosphorylations on Thr14 and Tyr15 of Cdc2. M phase-promoting factor (MPF) in turn activates Greatwall, implying that Greatwall participates in an MPF autoregulatory loop. Activated Greatwall both accelerates the mitotic G2/M transition in cycling egg extracts and induces meiotic maturation in G2-arrested Xenopus oocytes in the absence of progesterone. Activated Greatwall can induce phosphorylations of Cdc25 in the absence of the activity of Cdc2, Plx1 (Xenopus Polo-like kinase) or mitogen-activated protein kinase, or in the presence of an activator of protein kinase A that normally blocks mitotic entry. The effects of active Greatwall mimic in many respects those associated with addition of the phosphatase inhibitor okadaic acid (OA); moreover, OA allows cycling extracts to enter M phase in the absence of Greatwall. Taken together, these findings support a model in which Greatwall negatively regulates a crucial phosphatase that inhibits Cdc25 activation and M phase induction (Zhao, 2008; full text of article).

Mutations in Drosophila Greatwall reveal its roles in mitosis and meiosis and interdependence with Polo kinase

Reversible protein phosphorylation and periodic protein destruction play major roles in regulating the eukaryotic cell division cycle. The major protein kinase that directs cell division is cyclin-dependent kinase 1 (Cdk1), the active component of Maturation Promoting Factor. The cyclical inactivation of Cdk1 prior to mitotic exit is brought about in part through destruction of its cyclin partner. Two other protein kinase families, the Polo and Aurora families, are known to have critical functions in progression into and through M phase (mitosis and cytokinesis) and functionally interact with each other and also with Cdk1 to mediate their functions (Archambault, 2007).

Polo, originally discovered in Drosophila, exemplifies an evolutionarily conserved mitotic protein kinase. Polo, as well as its close orthologs, has been shown to function in multiple events essential for cell division. Polo was initially found to be essential for centrosome maturation and separation. It promotes recruitment of the γ-tubulin ring complex and phosphorylates Asp to facilitate nucleation of an increased number of dynamic microtubules on mitotic entry. At the G2/M transition, Polo (Polo-like kinase 1 in vertebrates) phosphorylates and activates the Cdc25 phosphatase responsible for removing inhibitory phosphates on Cdk1; this promotes mitotic entry. It also functions at the kinetochore-microtubule interface to monitor tension; the 3F3/2 phospho-epitope seen on kinetochores in the absence of tension is a consequence of Plk1/Plx1 kinase activity in vertebrates. Removal of cohesins from chromosomal arms in mitosis and meiosis also requires phosphorylation of cohesin subunits by Polo kinases. In Drosophila meiosis II, Polo phosphorylates and inactivates the centromeric cohesion protector protein Mei-S332. In addition, Polo is required for cytokinesis. The growing list of Polo kinase substrates is evidence of its role in multiple mitotic events (Archambault, 2007).

It is clear that protein kinases such as Cdk1 and Polo are only part of a large network of protein kinases that regulate cell cycle progression, many of which are as yet poorly characterized. A genome-wide survey found that up to one-third of the protein kinome of Drosophila has some cell cycle role (Bettencourt-Dias, 2004). Depletion of the Gwl kinase from S2 cells by RNA interference (RNAi) led to a mitotic delay characterized by formation of long spindles and scattered chromosomes (Bettencourt-Dias, 2004). Yu (2004) also found a mitotic role for Gwl kinase by characterizing missense hypomorphic mutants. Reduced gwl function results in mitotic defects in larval neuroblasts and tissue culture cells, including delay between late G2 and anaphase onset and chromosome condensation defects. Gwl has close homologs across eukaryotes and more distant homologs in budding and fission yeasts. Indeed, Yu (2006) reported a function for Xenopus Gwl in mitotic entry, as part of the Cdc2/Cdk1 activation loop in oocyte extracts. In that system, Xenopus Gwl is directly activated by cyclin B-Cdc2 and is in turn needed to promote full activation of cyclin B-Cdc2, although the direct target(s) mediating this action is (are) still unknown and indeed no substrates of Gwl are yet known. The primary sequence of Gwl shows that the regions most homologous to other kinases are split by a long intervening sequence of unknown function (Yu, 2004). Despite this recent progress, nothing is known about how activity of this crucial kinase is coordinated with the multiple events of cell cycle progression. Moreover, it is not known how Gwl contributes to the different types of mitotic and meiotic cell cycles of a metazoan (Archambault, 2007).

Elucidation of protein function may be aided through the generation of multiple mutant alleles that can reveal separate functions of individual proteins in multiple cellular processes. Drosophila offers the possibility of such studies and, moreover, allows the study of protein function in different types of cell cycle during its development. This principle was applied to study the gene defined by Scant (Scott of the Antarctic), a gain-of-function, dominant enhancer of maternal-effect embryonic defects of polo mutants. Syncytial embryos derived from females heterozygous for both Scant and polo develop mitotic defects in which a centrosome disassociates from one pole (White-Cooper, 1996) that the Scant mutation is an allele of gwl that introduces a K97M amino-acid substitution into the Gwl protein; this results in a hyperactive kinase with altered specificity in vitro. Our results indicate an antagonistic relationship between Gwl and Polo and suggest that their activity has to be coordinated for proper embryonic mitotic function. An allelic series of new gwl mutations reveals multiple functions for the Gwl kinase in both mitosis and female meiosis. These display somatic developmental defects accompanied by chromosome condensation and segregation defects in larval neuroblasts. gwl⁺ encodes two isoforms, only one of which is expressed during vitellogenesis. An allele that specifically prevents the expression of this isoform reveals requirements for Gwl in meiosis and in the maternal contribution to the egg (Archambault, 2007).

The Gwl kinase seems to have multiple roles in progression through mitosis and meiosis. The phenotypes shown by gwl mutants differ at different stages of development reflecting both the nature of different alleles and the variety of ways in which the cell cycle is regulated in Drosophila. Indeed it is these different modes of cell cycle regulation as development proceeds that allow Gwl's multiple functions in cell division to be tackled (Archambault, 2007).

The starting point of this study was the strong genetic interaction between the Scant mutation and polo mutations; heterozygous females lay embryos that die, presumably as a consequence of mitotic failure whose first observed defect is that a single centrosome moves away from the nucleus before nuclear envelope breakdown in all cases examined. This centrosome misbehavior is probably the primary defect; developmental failure probably results from secondary defects of abnormal spindles. It will be interesting to reexamine the phenotype of other maternal-effect mutants showing free centrosomes to see if they disassociate from the nuclear envelope in the same manner. It will also be interesting to find out whether the detaching centrosome always contains either the older or the younger centriole, since they may harbor different amounts of biochemical factors in their pericentriolar material. If so, the history of the centrosome determines its vulnerability to detachment when the Gwl/Polo balance is compromised. The Scant-polo genetic interaction is moderately specific since a screen for mutants reverting the maternal-effect embryonic lethality generated only one third-site interactor among two independent polo⁺ duplication events plus two revertants of the Scant allele itself. Scant encodes a Gwl kinase with a K97M substitution that results in hyperactivity in vitro (albeit with altered specificity on the artificial substrates tested); a wild-type transgene with just this amino acid mutated interacts dominantly with polo mutants, so this amino acid substitution is Scant. Moreover, mothers overexpressing wild-type Gwl kinase in the presence of reduced Polo kinase function produce embryos with the same kinds of defects as Scant. Therefore, the increased activity of Gwl-K97M and not its altered substrate specificity is responsible for the functional interaction between Scant and polo. It follows that a balance between Gwl and Polo activities in embryos is crucial, but because there does not seem to be any such interaction in cell cycles at later stages (in proliferating larval, pupal, or adult tissues), since polo¹¹ +/+ Scant itself has normal viability, the balance appears particularly important for these early embryonic cell cycles. The syncytial nuclear division cycles are unusual in that they comprise rapidly alternating cycles of S phase and M phase without intervening gap (either G1 or G2) phases. A G2 phase is only introduced following cellularization when String (the Cdc25 dual-specificity phosphatase that activates Cdk1) is degraded; its expression then comes under transcriptional regulation in a spatio-temporally defined pattern. The critical balance of Polo and Gwl kinase activities in the syncytium may reflect the absence of a G2 state; mitotic proteins are held on continual standby, awaiting their use in the next cycle, rather than being degraded and resynthesized each cell cycle as is the case for cycles with a G2. Alternatively, centrosome detachment may be frequent in other tissues of polo-Scant flies where it may be better tolerated. However, this is unlikely because only normal centrosome positioning is observed in polo-Scant testes (Archambault, 2007).

This antagonism between Polo and Gwl was not predicted from studies of these enzymes in Xenopus cell-free systems, which have been used to model the entry into mitosis from G2 through the activation of the Cdc25 phosphatase. There the evidence indicates that both Gwl and Plk1 kinases participate in the autoregulatory loop that activates the Cdk1/cyclin B MPF kinase complex (Yu, 2004). This apparent cooperation of the two kinases in this process suggests that the Xenopus cell-free system may be assessing a different aspect of cell cycle progression than in vivo studies on the syncytial cycles of Drosophila embryos. The apparent differences in results may also reflect the different aspects of mitosis under study; activation of Cdk1 in one system and the integrity of the mitotic apparatus in the other. There are few clues about the directionality of the antagonism observed for Polo and Gwl function in fly embryos or whether it involves direct interactions between the two protein kinases. Yu (2006) observed that xPlk1 is capable of phosphorylating xGwl, but that study did not observe changes in xGwl activity or a synergistic effect in combination with cyclin B-Cdc2-mediated phosphorylation. However, any inhibitory effect of Polo kinase on Gwl need not be mediated through regulation of kinase activity but could also occur by regulating Gwl's localization or stability. In this case, reduced dosage of Polo in the fly embryo might provide only a subthreshold activity, insufficient for the efficient downregulation of the hyperactive Gwl kinase encoded by gwl^Scant. That Gwl needs to be downregulated is suggested by its subcellular localization in mitosis. Gwl is enriched in the nucleus in interphase, but it is excluded from the nucleus during prophase, before nuclear envelope breakdown. This could occur through active nuclear export or through degradation. In favor of the latter, it was observed that Gwl is ubiquitinated (Archambault, 2007).

Gwl could also inhibit the function of Polo. In vitro experiments suggest that Gwl does not readily phosphorylate Polo, but it is also possible that phosphorylation of an intermediate substrate by Gwl mediates the hypothetical inhibitory effect. Since Scant causes a decrease in female fertility that is stronger in stronger polo mutant alleles, and the meiotic divisions occur in the embryonic cytoplasm, it is possible that Scant lowers Polo's activity during meiosis. Xiang (2007) has recently observed a functional interaction between polo and matrimony (mtrm); heterozygous mtrm/+ females have an elevated frequency of chromosome nondisjunction in meiosis, and this is suppressed by lowering the polo dosage. Therefore, if Scant acts to lower Polo's activity in female meiosis, then Scant might suppress the increased level of nondisjunction in mtrm heterozygotes. Indeed it does, though Scant needs to be homozygous for the suppression to be detectable, so the possibility that this suppression reflects homozygosity of some closely linked third player rather than Scant itself cannot be eliminated. Furthermore, even in Scant/Scant, the suppression of mtrm/+ is much weaker than halving the dosage of polo⁺ directly. This is consistent with the effects of Scant on fertility; homozygous Scant in a homozygous polo⁺ background is much more fertile than polo¹¹ Scant/+ +, so regardless of how Scant acts to reduce the functional level of polo⁺, one copy of Scant does not reduce the activity of one copy of polo⁺ completely. Nevertheless, the Scant-mtrm interaction result strongly suggests that the polo-Scant (and probably polo-gwl) interaction occurs during female meiosis as well as embryonic mitosis, and the unexpected Scant-mtrm interaction lowering female fertility implies a role for mtrm in embryogenesis (Archambault, 2007).

That Gwl downregulates Polo's function in the embryo is also suggested by the cellular phenotype, which is in line with the known functions of Polo at the centrosome. Moreover, the Scant phenotype is increased by the severity of the polo mutant. Occasional displacement of centrosomes early in mitosis is seen in syncytial embryos derived from heterozygous polo mutant females themselves, and Polo promotes centrosome separation, maturation, and integrity. In Drosophila, Polo phosphorylates Asp and together they promote the recruitment of γ-tubulin to the centrosome. In mammalian cells, Plk1 phosphorylates Nlp, triggering its dissociation from the centrosome and recruitment of several factors. Plk1 also phosphorylates Kizuna, which is required to preserve centrosome cohesion. The detached centrosomes observed in the polo-Scant-derived embryos do not show a reduction in γ-tubulin staining, and astral microtubules nucleate normally. Similar centrosome detachment was observed in Scant/+ and Scant/Scant-derived embryos, albeit with much lower frequencies. Therefore, it seems likely that the partial loss of Polo activity and the gain of Gwl activity both weaken centrosome function in a similar fashion; this is consistent with the mutually antagonistic interaction between polo and Scant mutations. Furthermore, it is noted that centrosome detachment occurs before nuclear envelope breakdown, a time when both Polo and Gwl are enriched around the nuclear envelope in syncytial embryos. This suggests that coordination between the centrosome, microtubules, and the nuclear envelope before nuclear envelope breakdown is sensitive to the balance between Polo and Gwl. Gwl (or cyclin B-Cdk1, which it activates in frog extracts) may share substrates with Polo and regulate them antagonistically in early mitosis (Archambault, 2007).

Centrosome loss can also occur in response to DNA damage, allowing damaged nuclei to fall into the interior of the syncytial embryo and be discarded from the developing fly. This response depends on Mnk/Chk2. The centrosome detachment observed in polo-Scant-derived embryos does not depend on Chk2 and thus seems to arise from a more direct effect on the centrosome-nuclear envelope association (Archambault, 2007).

Hypomorphic gwl mutants do not appear to impact directly upon centrosome behavior in the more conventional cell cycles of the larval central nervous system. Previously, Yu (2004) reported a long delay in late G2 to anaphase in gwl mutant neuroblasts in addition to chromatin condensation defects and has suggested that these defects, particularly undercondensation of chromatin, could all be attributed to the function of Gwl in activating cyclin B-Cdk1, although no direct substrate of Gwl is known. However, the prevalence of condensation defects and anaphase bridges that was observed in gwl mutant neuroblasts, together with the nuclear localization of Gwl in interphase, suggests that Gwl may act directly at the chromosome level. The anaphase bridges observed could be a consequence of tangled chromatids or dicentric chromosomes resulting from telomere fusion or other aberrant DNA damage repair events. When Gwl is depleted from cultured cells, they delay at the spindle assembly checkpoint with high levels of cyclin B and checkpoint proteins at kinetochores. The chromosomes of these cells are scattered upon an elongated spindle as though they have defects in kinetochore function. Since metaphase cells with highly condensed chromosomes accumulate in the larval CNS of gwl mutants, prolonged checkpoint arrest probably also occurs here. However, the polyploid cells seen in the null mutant indicate that cells can slip past the checkpoint without segregating their chromosomes; since this also happens in wild-type neuroblasts in the presence of colchicine, polyploidy is probably not a direct consequence of Gwl failure (Archambault, 2007).

A major role for Gwl kinase in regulating aspects of chromosome behavior is also suggested by the meiotic phenotype seen in gwl^Sr18/Df females. gwl^Sr18 disrupts the only form of Gwl expressed during vitellogenesis without disrupting the second mitotic isoform of Gwl. Therefore gwl^Sr18 provides a unique opportunity to study how loss of Gwl kinase affects vitellogenesis and meiosis. Although gwl^Sr18/Df ovaries develop normally, yolk distribution is abnormal in stages 13-14, females are sterile, and the severe meiotic defects include scattered chromosomes with separated chromatids and elongated spindles (Archambault, 2007).

Scattered chromosomes could result from a number of problems. One possibility is that Gwl is required for proper meiotic recombination; if so, the multiple DNA masses observed could correspond to chromosome fragments resulting from failure to complete chromatid exchange and to repair double-strand breaks. This would also lead to failure to arrest at metaphase I because bivalents would not be held together by chiasmata. This is unlikely for several reasons: (1) if the masses were fragmented chromosomes, they should vary widely in size; they do not; (2) Gwl accumulates in the oocyte nucleus and the nuclei of the nurse cells directly connected to the oocyte at (but not before) stage 8, which is much later than the time of meiotic recombination. However, it is noted that if Gwl is involved in meiotic recombination, the tiny amounts of it present in pachytene (germarial) nuclei could be below the detection limit of the antibody. (3) Two of the five nuclei that accumulate Gwl never entered pachytene; (4) FISH data prove that chromatid cohesion fails in gwl^Sr18 oocytes, and this is sufficient to account for the scattering of DNA masses observed. The number of DNA masses was often higher than six, the maximum expected number for disassociated bivalent chromosomes, disregarding the tiny fourth chromosomes. Therefore, Gwl is required for sister chromatid cohesion in meiosis I. In the absence of Gwl-long, the premature loss of (or failure to establish) arm cohesion would lead to the release of chiasmata if indeed any are formed (Archambault, 2007).

However, neither of these defects alone is expected to lead to complete female sterility. For example, mutants in c(3)G prevent all meiotic recombination but are still partially fertile (Hall, 1972). Mutants in ord do not keep sister chromatid cohesion yet show only a partial loss of female fertility. While the dissolution of sister chromatid cohesion in ord leads to progression through metaphase I into meiosis II, no normal meiosis II figures were seen in gwl^Sr18 oocytes, though it is possible that the elongated bipolar spindles represent attempts to do meiosis II after a failed anaphase I. Thus, the absence of Gwl-long in meiosis does not lead to a simple lack of meiotic recombination nor does it lead only to a premature dissolution of cohesion. The lack of Gwl could lead to a combination of both defects or to yet some other kind of defect that leads to full female sterility. Even if the occasional meiosis succeeds, it is very likely that these embryos would fail to develop because maternal Gwl-long is expected to be required for early embryonic mitoses; indeed, these embryos fail to reach cellular blastoderm (Archambault, 2007).

Most female meioses in gwl^Sr18 have scattered chromosomes on a single elongated spindle; it is thought that the minority (8%) that have multiple bundles of spindle are just the extreme of this scattering, since microtubules are nucleated by the chromatin in the acentriolar oocyte. Failure of karyosome formation might cause this scattering; however, oocytes of earlier stages do at least often form a single karyosome. Mutants that affect the spindle directly such as those affecting the microtubule-associated protein Msps show more spindle defects than chromosome scattering. A mutant disrupting the female germline-specific Cdk1-adaptor Cks30A disrupts the integrity of meiotic spindles in addition to showing chromosome alignment defects, but in this case the chromosome scattering observed is much more modest than that in the gwl^Sr18 mutant (Archambault, 2007).

How does Gwl regulate sister chromatid cohesion? The results suggest that Gwl antagonizes Polo, which is known to negatively regulate sister chromatid cohesion. It is therefore possible that the absence of Gwl during meiosis results in excessive and/or premature Polo activity, leading to premature loss of sister chromatid cohesion. In budding yeast, Polo (Cdc5) promotes the cleavage of the cohesin Scc1 by direct phosphorylation. In meiosis, sister chromatid cohesion is protected at centromeres until anaphase II by Mei-S332 in Drosophila (Shugoshin). Indeed, mei-S332 mutants show premature sister separation in meiosis I. In budding yeast, Shugoshin prevents cleavage of the cohesin Rec8, which replaces Scc1 in meiosis, and Cdc5 is required in meiosis for cleavage of Rec8. In Drosophila, Polo also negatively regulates Mei-S332 activity and localization. Thus, the lack of Gwl in meiosis could lead to premature activity of Polo, which could negatively regulate Mei-S332 and lead to precocious sister separation in meiosis I. This study examined Mei-S332′s localization in gwl^Sr18 hemizygous oocytes and found that Mei-S332 was largely properly localized to centromeres. However, Mei-S332 can be inactivated even when it remains localized at centromeres. Therefore, the possiblity cannot ruled out the possibility that Mei-S332 is being negatively regulated in the absence of Gwl. Alternatively, Gwl could promote sister chromatid cohesion by directly phosphorylating effectors of cohesion. Gwl-long is better than Gwl-short at performing a maternal function and we suspect that Gwl-long will be a better kinase for a yet unknown maternal substrate (Archambault, 2007).

In conclusion, it appears that Gwl, in common with the other major mitotic protein kinases, has multiple roles in mitotic and meiotic progression. These have been revealed through a series of gwl alleles that exhibit different characteristics and reveal aspects of Gwl kinase function in the different types of cell cycle during Drosophila development. A gain-of-function allele of gwl reveals a requirement for coordinate activity of the Gwl and Polo kinases in the rapidly oscillating M and S phase cycles of early embryos. Partial and total loss of Gwl function leads to frequent chromosome condensation defects and anaphase bridge formation in the conventional division cycles of cells in the larval CNS. Finally, loss of Gwl function in the female germline leads to severe meiotic abnormalities including loss of sister chromatid cohesion. It will be of interest to identify potential binding partners of the Gwl protein kinase both in interphase, when it is present predominantly in the nucleus, and in mitosis, when it moves out to the cytoplasm. This may in turn facilitate the identification of its substrates; this is crucial for understanding exactly how it regulates these various aspects of cell division (Archambault, 2007).

Greatwall kinase: a nuclear protein required for proper chromosome condensation and mitotic progression in Drosophila

Mutations in the Drosophila gene greatwall cause improper chromosome condensation and delay cell cycle progression in larval neuroblasts. Chromosomes are highly undercondensed, particularly in the euchromatin, but nevertheless contain phosphorylated histone H3, condensin, and topoisomerase II. Cells take much longer to transit the period of chromosome condensation from late G2 through nuclear envelope breakdown. Mutant cells are also subsequently delayed at metaphase, due to spindle checkpoint activity. These mutant phenotypes are not caused by spindle aberrations, by global defects in chromosome replication, or by activation of a caffeine-sensitive checkpoint. The Greatwall proteins in insects and vertebrates are located in the nucleus and belong to the AGC family of serine/threonine protein kinases; the kinase domain of Greatwall is interrupted by a long stretch of unrelated amino acids (Yu, 2004; full text of article).

Search PubMed for articles about Drosophila Greatwall

Archambault, V., Zhao, X., White-Cooper, H., Carpenter, A. T. and Glover, D. M. (2007). Mutations in Drosophila Greatwall/Scant reveal its roles in mitosis and meiosis and interdependence with Polo kinase. PLoS Genet. 3(11): e200. PubMed citation: 17997611

Bettencourt-Dias, M., et al. (2004). Genome-wide survey of protein kinases required for cell cycle progression. Nature 432: 980-987. PubMed citation: 15616552

Hall, J. C. (1972). Chromosome segregation influenced by two alleles of the meiotic mutant c(3)G in Drosophila melanogaster. Genetics 71: 367-400. PubMed citation: 4624918

Oshimori, N., Ohsugi, M. and Yamamoto, T. (2006). The Plk1 target Kizuna stabilizes mitotic centrosomes to ensure spindle bipolarity. Nat. Cell Biol. 8: 1095-1101. PubMed citation: 16980960

White-Cooper, H., Carmena, M., Gonzalez, C. and Glover, D. M. (1996). Mutations in new cell cycle genes that fail to complement a multiply mutant third chromosome of Drosophila. Genetics 144: 1097-1111. PubMed citation: 8913753

Xiang, Y, et al. (2007) The inhibition of polo kinase by matrimony facilitates G2 arrest in the meiotic cell cycle. PLoS Biol. (12): e323. PubMed citation: 18052611

Yu, J., et al. (2004). Greatwall kinase: a nuclear protein required for proper chromosome condensation and mitotic progression in Drosophila. J. Cell Biol. 164(4): 487-92. PubMed citation: 14970188

Yu, J., Zhao, Y., Li, Z., Galas, S. and Goldberg. M. L. (2006). Greatwall kinase participates in the Cdc2 autoregulatory loop in Xenopus egg extracts. Mol. Cell 22(1): 83-91. PubMed citation: 16600872

Zhao, Y., Haccard, O., Wang, R., Yu, J., Kuang, J., Jessus, C. and Goldberg, M. L. (2008). Roles of greatwall kinase in the regulation of cdc25 phosphatase. Mol. Biol. Cell 19(4): 1317-27. PubMed citation: 18199678

date revised: 10 June 2008

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