Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain1
Departamento de Microbiología y Genética, Instituto de Microbiología-Bioquímica, Edificio Departamental, Campus Miguel de Unamuno, Universidad de Salamanca/CSIC, 37007 Salamanca, Spain2
Department of Molecular and Cell Biology, Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720, USA3
Author for correspondence: César Nombela. Tel: +34 91 394 6393. Fax: +34 91 394 1745. e-mail: cnombela{at}rect.ucm.es
Keywords: Saccharomyces cerevisiae, Schizosaccharomyces pombe, morphogenesis, septins, checkpoint
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Overview |
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Co-regulation of the timing of nuclear division and budding in S. cerevisiae by the CDK Cdc28 |
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Nuclear dynamics are orchestrated by astral microtubules, which emanate from the SPB, a functional equivalent to the centrosome of higher eukaryotes (Shaw et al., 1997 ). Recent work has highlighted the role of interactions between cytoplasmic microtubules and the cortex via specific anchoring proteins to coordinate these dynamics (Heil-Chapdelaine et al., 1999
; Beach et al., 2000
; Korinek et al., 2000
; Lee et al., 2000
; Segal et al., 2000
). In G1, the SPB orientates towards the future bud site, driven by cytoplasmic astral microtubules. SPB duplication occurs early in the cell cycle and depends on G1 cyclins (see the pictures at the top in Fig. 3a to illustrate the topics presented). Next, in synchrony with S phase, SPB separation, which requires B cyclinCDK activity (Lim et al., 1996
), leads to the formation of a short premitotic spindle, which remains in the mother cell. One of the poles is oriented to the bud neck, probably by means of prevalent interactions of the astral microtubules with the neck and the bud cortex that depend on dynein and dynactin (Li et al., 1993
; Adames et al., 2001
). Thus oriented, the nucleus lies in wait for the onset of anaphase, which triggers spindle elongation through the bud neck towards the daughter cell. Finally, disassembly of the spindle at telophase relies on mitotic CDK inactivation by the APC and Sic1.
Cortical dynamics, based both on the highly dynamic actin cytoskeleton and on a septin-based ring that permanently marks the bud neck, are accurately synchronized with nuclear dynamics to achieve proper morphogenesis through budding (Lew & Reed, 1993 ; Cid et al., 2001a
; see Gladfelter et al., 2001
for a recent review on septins). Depending on G1 cyclinCDK activity, actin cortical patches support the emergence of a bud within a site marked by the appearance of a septin ring. As the bud emerges, the septins mark the bud neck, acting as a kind of submembrane barrier between the mother and the daughter (Barral et al., 2000
). Through the S phase and beyond, isotropic bud growth is monitored from this septin structure, since in its absence the bud will grow in length instead of adopting its typical ellipsoidal shape (Hartwell, 1971
; Cid et al., 1998
). The B cyclinCDK complex itself is responsible for the switch from polar to isotropic growth, since cdc28 point mutations cause the switch to fail (Ahn et al., 2001
). The bud keeps on growing, supported by scattered cortical patches, until actin is depolarized in late mitosis. Again, mitotic CDK inactivation by the APC is essential to relocate actin to the neck to form an actomyosin contractile ring in the middle section of the septin hourglass-like scaffold at the bud neck. Immediately, cytokinesis is committed by contraction of the ring, leaving a chitin-rich primary septum and dividing the septin structure into two parallel rings (Lippincott & Li, 1998
). Finally, repolarization of actin patches to the septation site reinforces the cell wall on both sides prior to cell separation by hydrolysis of chitin at the primary septum.
In sum, only one CDK orchestrates cytoskeletal rearrangements to coordinate the events that support cell division through budding both temporally and spatially. Many regulatory proteins are involved in the fine tuning of this CDK. In this review, we wish to refer to a recent body of evidence that suggests that the spatial distribution of CDK regulators to the SPB and the septins may play a capital role in this coordination.
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The morphogenesis checkpoint (MCP) operates from the bud neck |
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The spindle orientation checkpoint (SOC) operates from the SPB |
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Mitotic control exerted by the polo/Cdc5 protein kinase |
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Remarkably, several clues indicate that the S. cerevisiae polo kinase orthologue, Cdc5, may also participate in the MCP (Fig. 1). First, Cdc5 is able to interact with Swe1 in vivo (Bartholomew et al., 2001
); second, overproduction of Cdc5 leads to an ectopic localization of Swe1 to the SPB, instead of to the bud neck, regardless of its kinase activity (Bartholomew et al., 2001
); third, certain cdc5 alleles display an elongated bud phenotype that is alleviated by swe1
(Song & Lee, 2001
); and fourth, Cdc5 (but not Hsl1) is able to phosphorylate Swe1 in vitro (Cid et al., 2001b
; M. Shulewitz, K. S. Lee & J. Thorner, unpublished results).
Moreover, a participation of the polo kinase in the SOC/MEN networks has been detected as well. Cell-cycle-dependent phosphorylation of Bfa1 is at least partially dependent on Cdc5 (Fig. 2; Lee et al., 2001b
; Hu et al., 2001
). Since the Bfa1Bub2 complex seems to be bound to Tem1 permanently throughout budding (Pereira et al., 2000
; Lee et al., 2001b
), this phosphorylation event may be a major regulatory event for its GAP activity on Tem1 along mitosis. By these means, Cdc5 might negatively regulate Bfa1 GAP activity on Tem1 to promote mitotic exit (see below). Interestingly, activation of both the SAC and the SOC inhibits polo-dependent Bfa1 phosphorylation (Hu et al., 2001
). Concomitantly, the Tem1-GEF Lte1 is phosphorylated in mitosis as well in a Cdc5-dependent fashion (Fig. 2
; Lee et al., 2001b
).
In addition, Cdc5 is required for mitotic exit by modulation of MEN components (Lee et al., 2001a ; Hu et al., 2001
), namely by the controlled release of the Cdc14 protein phosphatase through anaphase (see below; Stegmeier et al., 2002
; Pereira et al., 2002
; Fig. 2
). Thus, being required for the eventual activation of the APC that leads to the degradation of B cyclins, Cdc5 is a target for the APC itself (Cheng et al., 1998
; Charles et al., 1998
; Shirayama et al., 1998
). The multifunctional role in mitotic control exerted by Cdc5 may be a key to our future understanding of how different cell-cycle-control mechanisms merge.
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Temporally ordered association of components of the MEN at the SPB |
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The localization of the components of the MEN (Fig. 3a) should shed light on how these events are coordinated. Like Cdc5 and Tem1, Cdc14, Cdc15 and the Dbf2Mob1 complex become attached to the SPB (Cenamor et al., 1999
; Xu et al., 2000
; Frenz et al., 2000
; Menssen et al., 2001
; Luca et al., 2001
; Visintin & Amon, 2001
; Pereira et al., 2002
). However, Tem1 stains the daughter cell SPB from the premitotic stage (Bardin et al., 2000
; Pereira et al., 2000
), whereas Cdc14, Cdc15 and the Mob1Dbf2 complex appear at the SPBs only in anaphase (Cenamor et al., 1999
; Xu et al., 2000
; Menssen et al., 2001
; Yoshida & Toh-e, 2001
; Pereira et al., 2002
). At least in the case of Mob1Dbf2, localization of these proteins to the SPB is a fine indicator of Tem1 activation by inhibition of the Bub2Bfa1 GAP (Pereira et al., 2002
). The early pool of Cdc14, released from the nucleolus by Cdc5 as cells commit anaphase, attaches to the SPB and binds Bfa1 and Tem1 (Pereira et al., 2002
). Such binding is important for MEN activation, but such function has not been related to Cdc14 phosphatase activity (Pereira et al., 2002
). However, in late anaphase, Cdc14 is involved in a dramatic dephosphorylation of Cdc15 (Xu et al., 2000
; Jaspersen & Morgan, 2000
) and Bfa1 (Pereira et al., 2002
), as well as in the dephosphorylation of Cdh1 and Sic1 that lead to cyclin B depletion and CDK inactivation (Visintin et al., 1998
). In summary (see Fig. 2
), as the daughter SPB passes through the bud neck, Tem1 becomes activated by inhibition of the Bfa1 GAP, a phenomenon in which Cdc5 and, somehow, Cdc14 (released by Cdc5 from the nucleolus) participate. GTP-bound Tem1 recruits the Cdc15 and Dbf2 kinases to the SPB, resulting in a signal that, by the end of anaphase, triggers the total release of Cdc14, which is necessary for the eventual inactivation of the mitotic CDK. Remarkably, the players involved in such regulation have their headquarters at the outer plaque of the anaphase SPB (see the dotted area in Fig. 2
).
Evidence is now gathering to suggest that some MEN components could play a direct role in cytokinesis. First, thermosensitive MEN mutants maintained at the restrictive temperature are able to eventually re-bud but are never able to perform septation (Jiménez et al., 1998 ); second, tem1 net1 mutants, which cannot efficiently sequester Cdc14 at the nucleolus, exit mitosis but fail to separate (Shou et al., 1999
); third, Tem1 is directly involved in triggering the dynamics of septin splitting and actomyosin contraction at cytokinesis, although it is not essential for actomyosin ring assembly (Lippincott et al., 2001
); and, finally, Cdc15, Dbf2 and Mob1 relocate from the SPB to the neck at the time of cytokinesis, such behaviour depending on Cdc14 activity (Frenz et al., 2000
; Xu et al., 2000
; Yoshida & Toh-e, 2001
). Also, the fact that a mutation that perturbs septin structure bypasses anaphase arrest in MEN mutants (Jiménez et al., 1998
) suggests that relocation of the MEN kinases to the neck at the time of cytokinesis may constitute a feedback mechanism to monitor mitotic CDK inactivation at this point. Such a mechanism might work in a similar fashion to that of the MCP (also dependent on neck-associated proteins) and might constitute a cytokinesis checkpoint.
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Subcellular localization of mitotic regulators is similar in fission yeast |
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S. pombe homologues to Bfa1 and Bub2, respectively Byr4 and Cdc16, are negative regulators of cytokinesis, since their elimination leads to uncontrolled septation (Minet et al., 1979 ; Fankhauser et al., 1993
; Song et al., 1996
; Jwa & Song, 1998
) whereas their overproduction inhibits septation. However, the functional homologues of the small GTPase Tem1 and the protein kinase Cdc15 respectively Spg1 and Cdc7 exert the opposite effect, their inactivation leading to defects in the onset of septum formation and their overexpression to premature septation, indicating a positive role in the regulation of cytokinesis (Fankhauser & Simanis, 1994
; Schmidt et al., 1997
). Supporting the universality of the role of these pathways, the localization of Byr4, Cdc16, Spg1 and Cdc7 to the SPB is similar to that of their functional homologues in Saccharomyces, commented above (Fig. 3b
). However, the timing of these localizations is different. The Ras GTPase Spg1, for instance, is permanently located at the spindle poles, and the associated kinase Cdc7 joins it through mitosis (Sohrmann et al., 1998
). However, strikingly for a cell that divides symmetrically, as mitosis advances only one SPB is marked with Cdc7. Interestingly, Byr4 and Cdc16 also stain the SPB asymmetrically in mitotic cells, precisely bound to the Cdc7-free pole (Cerutti & Simanis, 1999
). Also, byr4 mutant cells show symmetric Cdc7 localization, supporting the notion that, as in the budding yeast, it is the active GTP-bound form of Spg1 that recruits Cdc7, whereas the GAP Byr4 favours a GDP-bound form that is unable to bind the kinase (Furge et al., 1999
; Li et al., 2000
). Other components of the SIN (for septation initiation network, which parallels the budding yeast MEN), such as Sid2 (the Dbf2 homologue) and Mob1, seem to play similar roles to those of their budding yeast homologues as well, localizing at the medial ring during cytokinesis and at the SPB along the cell cycle (Sparks et al., 1999
; Hou et al., 2000
). However, the association of the Sid2 complex with the SPB seems permanent rather than transient. Finally, recent characterization of the Cdc14 fission yeast homologue, Flp1/Clp1, has revealed a non-essential role in mitotic exit and cytokinesis (Cueille et al., 2001
; Trautmann et al., 2001
; reviewed by Oliferenko & Balasubramanian, 2001
). Dispensability of Cdc14 for mitosis marks the main difference between the fission and budding models of mitotic regulation. Flp1/Clp1 is released from the nucleolus specifically in mitosis, as in S. cerevisiae, but, peculiarly, it was found to localize to the cytokinetic ring in mitosis, a phenomenon that has not been reported for Cdc14 (Cueille et al., 2001
; Trautmann et al., 2001
; Fig. 3b
). The association of Flp1/Clp1 with the SPB, like that of Sid2, seems permanent through the cell cycle (Fig. 3b
), although its release from the nucleolus in mitosis results in an enhancement of the spindle polar mark and an association with the whole spindle structure (Cueille et al., 2001
; Trautmann et al., 2001
; reviewed by Oliferenko & Balasubramanian, 2001
).
The fission yeast polo kinase, namely Plo1, also seems to act at different levels of mitotic regulation. It is required for the assembly of the contractile actin ring at the cytokinetic plane, whereas its overexpression causes premature ring assembly and septation to occur (Ohkura et al., 1995 ). However, unlike the budding yeast Cdc5, Plo1 is essential for bipolar mitotic spindle assembly. Again, like Cdc5 in budding yeast, Plo1 temporarily decorates the SPB (Bahler et al., 1998
; Mulvihill et al., 1999
; Fig. 3
) and its function in the SIN precedes that of Spg1 (Tanaka et al., 2001
). Specifically, the polo kinase associates with the SPB as cells enter mitosis, such localization being dependent on activation of the mitotic CDK. Upon APC activation, in early anaphase B, Plo1 only weakly stains the spindle poles, partially decorating the spindle microtubules, like Clp1/Flp1 (a behaviour that has not been reported for either Cdc5 or Cdc14 in Saccharomyces), and eventually disappears from both structures at the time of cytokinesis. Plo1 is not associated with microtubular structures in interphase and forms a medial ring in metaphase (Bahler et al., 1998
). A striking difference between budding and fission yeasts as regards their polo kinases is that, in the latter, protein levels do not seem to vary along the cell cycle, although its removal from the SPB does depend on the APC function (Cheng et al., 1998
; Mulvihill et al., 1999
).
In a nutshell, the fission yeast SIN seems to work essentially like the homologue budding yeast MEN. Not only are the sequential activation and SPB localization conserved, but correlation of APC-dependent B cyclin removal and cytokinesis, already known to exist in budding yeast (Jaspersen et al., 1998 ), also might be true for fission yeast (Chang et al., 2001
). However, some aspects, related to the roles of their respective Cdc14 phosphatases and polo kinases, seem specific for each model. Their study will help to elucidate universal as well as particular rules for the regulation of mitosis.
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What sort of conversation arises between the bud neck and the SPB? |
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ACKNOWLEDGEMENTS |
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