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Conserved and novel regulators of the plant cell cycle John Doonan* and Pierre Fobertt Cell division is highly regulated, both spatially and temporally, during plant development. Recent evidence implicates cyclin-dependent kinases (cdks) and their associated proteins as the principal temporal regulators of cell division. It is now known that plants contain an extended family of cdks, some of which appear to be unique to this group. Positive rate-limiting regulators of cell proliferation and growth include mitotic or B-type cyclins whose transcription is restricted to the G 2 and M phases. Current research suggests that MYB-related transcription factors may be responsible for this restriction. Cdk-interacting proteins, such as cdk inhibitors and sucl homologues, have been isolated using yeast two-hybrid approaches. Addresses *John Innes Centre, Colney Lane, Norwich NR4 7UH, UK; e-mail: Doonan@bbsrc.ac.uk tNational Research Council Canada, Rant BiotechnologyInstitute, 110 Gymnasium Place, Saskatoon, Saskatchewan STN 0W9, Canada Current Opinion in Cell Biology 1997, 9:824-830
http:/Ibiomednet.com/elecref10955067400900824 Š Current Biology Ltd ISSN 0955-0674 Abbreviations cdk cyclin-dependentkinase pRb retinoblastomaprotein
Introduction T h e supposition that the basic molecular workings of the cell division cycle are similar in all eukaryotic cells has provided a convenient starting point for the study of cell division in different organisms, including higher plants. Compared with most animals, plants have a somewhat unusual lifestyle, to which many aspects of their morphogenesis and cell division are adapted. For instance, their body plan is an historical record, for the most part undisturbed by cell migration, of the cell divisions and cell enlargements that have occurred during its morphogenesis. Structurally, the plant cell cycle differs from that of animals, particularly in the early stages of mitosis: before spindle formation, a microtubule array called the preprophase band defines the future division plane of the cell. At the end of mitosis, another microtubule array, the phragmoplast, is involved in cytokinesis. Mutants with defects in cytokinesis or in the control of the plane of cell division display dramatic effects on plant development (recently reviewed in [1]), supporting the notion that the position and/or orientiation of cell division is crucial for plant development. In the mature plant, most cell proliferation is restricted to specialized regions called meristems. As they be-
come displaced from the meristem, cells differentiate and expand. Expansion is sometimes associated with endoreduplication, a process by which the DNA in re-replicated without intervening mitoses. There is much debate as to whether cell proliferation is a driving force in plant morphogenesis or is merely a response to expansion and subdivides the tissue into suitably sized compartments. While the jury is still out on this broader question, we will focus on the central cell cycle regulators, the cyclin-dependent kinases (cdks) and their associated proteins. Cdks play a central and well-characterized role in progression through the cell cycle in all eukaryotes, ensuring that cells progress through sequential stages of the division cycle in an orderly fashion. T h e activity and specificity of cdks are controlled at many levels, making them versatile regulators that are capable of integrating diverse cellular and extracellular signals. This makes cdks excellent candidates for mediating control of the cell cycle during the development of multicellular organisms and particularly so in plants where the balance between cell proliferation and differentiation is a key adaptive strategy for a sessile lifestyle. In this review, we will concentrate on the roles of cdks and their associated proteins in the plant cell cycle.
C o n s e r v e d a n d n o v e l c d k s in t h e p l a n t cell division cycle T h e essential core of the muhisubunit cdk is composed of a catalytic kinase subunit bound to a positive regulatory cyclin subunit. In many species, both the regulatory and the catalytic subunits are encoded by members of muhigene families, producing a diverse range of related enzymatic activities, often with distinct functions. Accessory regulatory proteins bind tO the core enzyme and further modulate activation of the cdk.
Plants contain an extended cdk gene family (Figure 1) that includes both cognate and variant cdc2-related proteins. T h e cognate homologues of cdc2 encode proteins that contain a perfectly conserved 16 amino acid domain, usually referred to as the ' P S T A I R E ' motif (the singleletter amino acid code is used here to describe the central region of the motif), in addition to the T loop and catalytic domain. T h e PSTAIRE motif has been shown to participate in cyclin binding, and may determine cyclin-cdk specificity (see [2] and references therein). Plants also express unusual cdc2-related genes which may be unique to these organisms. Structurally, these unusual cdks align with cdc2 (i.e. they belong to the cdkl group of cdks), but they also differ from the cdc2 kinases, most notably in that they contain variant PSTAIRE motifs. In this review, we will refer to these novel genes as cdc2 variants, and specific variants will be named after the
Conserved and novel regulators of the plant cell cycle Doonan and Fobert
amino acid sequence that corresponds to the PSTAIRE motif.
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Expression of both cognate and variant cdc2 genes is associated with cell proliferation but there are significant differences in the timing of expression (Figure 2). For cognate cclc2 genes, levels of both transcript [3",4 °] and protein [4°] tend to be constant throughout the cell cycle although actively proliferating tissues tend to contain significantly higher levels than differentiated tissues. T h e variant cdc2 genes are expressed at specific phases of the cell cycle. The PPTALRE variants are expressed from S phase through to M phase whereas the P P T T L R E variants are expressed during a much narrower window of time, in G 2 phase and early M phase.
At least two classes of cdc2 variant are recognized: members of one class (Am-cdc2c, At-cdc2b, and Ms-cdc2d) contain a P P T A L R E motif and members of the other class (Am-cdc2d and Ms-cdc2f) contain a P P T T L R E motif [3°,4°,5]. This extended cdc2-1ike gene family may have arisen by gene duplication in plants soon after the animal and plant lineages diverged; although there are no reports of similar cdc2 variants from animals, the moss Physcomitrella patens (a primitive land plant) also expresses a related cdc2 variant, P A T T L R E (K Fujiwara, personal communication). T h e evolution of novel cyclin-interaction motifs in the variant cdc2s may reflect the divergent evolution of the plant cyclins [6°].
Available data suggest that these closely related cdc2 proteins are recruited into different kinase complexes which display distinct periods of activity. Activation
Figure 1
I
Ms-cdk2A Ms-cdk2B Am-cdk2a Am-cdk2b Zm-cdk2 Os-cdc2-1 Os-cdc2-2
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PSTAIRE proteins
At-cdc2a Hs-cdc2 Sp-cdc2 Hs-cdk2 Hs-cdk3
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i I - - I
Ms-cdc2c P~-P34KR Hs-PITAIRE Hs-CHED
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;o Current Opinionin Cell Biology
Phylogenetic tree of the cdc2 protein family. The tree was constructed with selected sequences from the EMBL/Genbank database using the CLUSTAL program. PSTAIRE proteins correspond to family members containing a perfectly conserved 16 amino acid cyclin-interaction motif. PSTAIRE-related proteins show variation in this motif. Sequences from plant sources are underlined and the plant-specific variant cdc2-related proteins are enclosed by a box. Ps-P34KR (Genbank accession number X56554) is an uncharacterized cdc2-related protein from pea; Os-R2 (Genbank accession number X58194) is a rice protein related to cdkT; CHED (Genbank accession number M80629) is required for haematopoiesis; and PITAIRE (Genbank accession number L25676) is a relatively uncharacterized protein that is capable of phosphorylating the retinoblastoma protein in vitro. Am, Antirrhinum majus; At, Arabidopsis thaliana; Hs, human; Mm, mouse; Ms, Medicago sativa (alfalfa), Ps, Pisum sativum; Os, Oryza safiva (rice); Sp, Schizosaccharomyces pombe; Zm, Zea mays. The scale beneath the tree measures the evolutionary distance between sequences; numbers (arbitrary units) represent the number of base substitution events.
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Cell multiplication
Figure 2
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I Current Opinion in Cell Biology
Summary of plant cdk and cyclin expression during phases of the cell cycle and some of the factors affecting their expression. Expression of cognate cdc2 genes (encoding proteins with perfectly conserved PSTAIRE [single-letter amino acid code] motifs) and variant cdc2 genes (encoding PITAIRE, R2, PPTALRE and PFrFI'LRE) is presented above the diagram of cell cycle phases. The expression of different classes of cyclins is indicated below the cell cycle phases. Open bars represent expression at the transcriptional level; black boxes represent protein production; and grey boxes represent kinase activity. Narrower bars represent lower levels of expression. In cases where data are not available, the phases of protein production or kinase activity are not indicated. The question mark near the 'PITAIRE' bar indicates that its expression in nondividing cells has not been assessed. Dotted lines or hatched boxes indicate periods during which gene expression has not been clearly demonstrated. Arrows next to sucrose, auxin and gibberellin (GA) indicate that these substances have been implicated in promoting the expression of the genes shown immediately above these substances upon entry into the cell division cycle (i.e. the Go--~Gl-phase transition). Gytokinin has been implicated in promoting either gene expression or kinase activity, as indicated by the single-line arrows.
of kinase complexes containing cognate cdc2 proteins is periodic, with peaks roughly corresponding to the Gl--OS-phase and G2-->M-phase transitions. In G2-phase alfalfa cells, the cognate cdc2 complexes are activated prior to P P T T L R E - c d c 2 complexes [4째]. Why should plants have an extra G2 phase activated cdc2 kinase? One attractive possibility is that the mid-G2-phase peak of kinase activity may reflect activation of a preprophase band (PPB)-associated cdc2 prior to mitosis and and that later mitotic events (as yet undefined) are controlled by the cdc2 variant kinases. T h e PPB is a transient microtubule structure that predicts the division plane, is formed in G z phase and disappears by metaphase. Kinases, probably cdc2-related, are implicated in PPB
assembly: both assembly and disassembly are sensitive to kinase inhibitors [7], and microinjection of active cdc2 kinase in the form of algal mitosis-promoting factor (MPF) [8,9] results in PPB disassembly. A cdc2-related kinase, one of the two cyclin B1 proteins and a cyclin A1 transiently associate with the PPB in maize [10]. T h e other cyclin B1 protein is present in the nucleus until the nuclear envelope disassembles at mitosis and remains associated with the spindle [10]. There is, therefore, a spread of circumstantial evidence to link the premitotic cdc2 activity with PPB formation. In mammalian cells, the interaction between the cdk complex and microtubules is mediated by microtubule-associated protein (MAP) 4 which binds cyclin B [11]. Phosphorylation of MAP4
Conserved and novel regulators of the plant cell cycle Doonan and Fobert
by the cdc2-cyclin B complex abolishes its ability to stabilize microtubules and may contribute to microtubule disassembly at the G2---~M-phase transition. Taken together, the above data suggest that the cognate and variant cdc2 proteins have distinct roles in the plant cell cycle. T h e plant cdc2 cognate genes appear to be functionally similar to cdc2 as they either complement or partly complement selected cdc2 mutants in fission yeast [3"] or cdc28 (a cdc2 homologue) mutants in budding yeast [12]. In plants, the expression of dominant-negative mutant forms of At-cdc2a (a cognate cdc2 protein) inhibit cell division [13]. In planta functions have yet to be attributed to the cdc2 variants but, when expressed in yeast, they fail to complement cdc2 mutations and can even interfere with cell division. This suggests that their ability to interact with the yeast cell cycle machinery is conserved but that their function has significantly diverged. Mutations in these genes would be extremely informative. A variety of other cdk-related kinases have been isolated but their role in cell cycle progression is unknown. The R2 gene from rice encodes a protein that is structurally similar to mammalian cdk7 and R2 transcripts accumulate to higher levels in G! phase than during the rest of the cycle [14]. The alfalfa Ms-cdc2C gene [4"] encodes a 57kDa protein that is similar to the human C H E D kinase (Genbank accession number M80629), which is required for haematopoiesis, and a human PITALRE kinase (Genbank accession number L25676), which can phosphorylate the retinoblastoma protein in vitro. A partial cDNA, Ms-cdc2E, encodes yet another distantly related kinase with no close homologs known in mammalian cells [4"].
Cyclins: targets for growth control in plants Plant cells contain positive regulatory molecules which can be titrated out by expression of a dominant-negative mutation of At-cdc2 (residues 147 and 223 were mutated to asparagine and alanine, respectively, and so the mutation is known as N147A223) [13]. T h e N147A223 mutation is predicted to produce an inactive kinase that retains the ability to interact with rate-limiting regulatory factors, probably cyclins, thereby reducing the amount of such factors available to activate the endogenous wild-type cdc2. Although the cell cycle was retarded in the N147A223 transgenics, there was not a specific arrest point. A given cdk catalytic subunit can associate sequentially with more than one type of cyclin subunit, so the mutant kinase could interfere with a number of distinct kinase complexes. Expression of the mutant cdc2 protein was lethal in Arabidopsis and strongly inhibited both cell proliferation and H1 kinase activity in tobacco [13]. Surprisingly, the tobacco plants grew fairly normally but most tissues contained bigger cells: cell expansion compensated for reduced proliferation. However, the effect was subtly different in flowers and seeds: these
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tissues also contained fewer cells but of normal size, implying that the nuclear division cycle and cell expansion are more tightly coupled here than in the stem and root. As a consequence, flowers and seeds were smaller. Plants tend to have rather large numbers of cyclins and their nomenclature has been somewhat chaotic. However, on the basis of detailed comparative analysis of large numbers of cyclins from different plant species, plant cyclins have been classified into three groups of A-type cyclins, two groups of B-type cyclins and at least three D-types (recently reviewed in [6째]). From an evolutionary point of view, it is arguable as to whether the major classes ofcyclins had evolved and developed specialized functions prior to plant/animal divergence. However, considerable radiation has occurred since then, giving plants their own distinctive cyclin subfamilies. T h e B1 cyclins, the best characterized group, are expressed at, and may be rate-limiting for, transition across the G2---~M-phase boundary. Cyclin B1 transcripts accumulate specifically in dividing cells in G 2 and M phases [15",16-18,19] and specific antibodies against cyclin B identify active cdk (the identity of the cdk is unknown) complexes during G 2 phase in synchronized alfalfa cells [4"]. Ectopic expression of the Arabidopsis BI cyclin gene, At-cycl, under the control of the At-cdc2a promoter accelerated root growth without inducing any developmental abnormality [15"']. The extra growth resulted from the formation of extra cells, suggesting that progression through the cell cycle had been significantly enhanced. Although the phase of the cycle affected was not determined experimentally, the cyclin B protein is probably only stable during G2 phase and so the simplest explanation is that the G 2 phase would be shortened in these plants. Given that at least some plant cells contain a cytokinin-dependent G2-phase checkpoint, this seems a reasonable expectation. Given that cyclin B promotes the Gz---)M-phase progression and that its availability limits growth, then the molecular basis of transcriptional controls acting on type B cyclins will be of great interest. Several groups have shown that 5' regions of the cyclin B gene can direct G 2 phase specific expression [17,20]. Four repeats of an nine base pair element, similar to MYB protein binding sites and termed MSA (M phase specific activator) elements, are both necessary and sufficient to direct expression of the reporter gene GUS during Gz and M phases (M Ito et al., personal communication). MSA elements were found in the 5" regions of other M phase specific genes, including B cyclins and kinesin-like genes, from other plant species (M Ito et al., personal communication). The At-cdc2a gene contains multiple binding sites for MYB proteins in a region of its promoter that enhances gene expression [21]. MYB proteins, implicated in regulating cell proliferation in animals, seem to have diversified to fulfil a large number of
828 Cellmultiplication
gene regulatory roles in plants, but at least one plant MYB gene is closely related to c-MYB, a factor which enhances Gl--->S-phase progression by activating transcription of the mammalian cdc2 kinase gene (reviewed in [22]). A MYB protein has been shown induce ectopic cell divisions in plants, albeit within a restricted developmental context: expression of a myb gene, MIXTA, from Antirrhinum in tobacco results in the formation of multicellular trichromes from epidermal cells which would otherwise have exited from the cell division cycle (see [22]). Taken together, these data strongly implicate MYB proteins as playing a role in regulating cell cycle progression in plants. A-type cyclins also display phase-specific gene expression but their period of expression is broader and not so dramatically defined as that of the B-type cyclins. Levels of cyclin A transcripts increase and may even peak in S phase but expression continues into G 2 and M phase [17,19,20,23]. An alfalfa cyclin A gene, Ms-cyc3, is transcribed very early after quiescent cells are induced to re-enter the cell division cycle by wounding, perhaps even before cells cross the G1/S-phase boundary [24].
The retinoblastoma protein/cyclin D pathway: a conserved pathway for regulating G1/S phase specific gene expression? T h e G1/S-phase expression of Gl-phase cyclins and S phase specific genes is very well understood in mammalian cells where extracellular growth factors induce the expression of D cyclins, by way of a mitogenactivated protein kinase signal transduction pathway [25]. A CDK4-cyclin D kinase phosphorylates the retinoblastoma protein (pRb)-E2F complex, an inhibitor of S-phase gene expression. E2F is then released from the complex to promote S-phase gene transcription. An analogous pathway has been proposed in plants, whereby plant growth substances affect cell proliferation by controlling the production of Gl-phase cyclins [25]. Three different D-type cyclins were isolated by complementation of yeast G1 phase deficient mutants with a plant cDNA library [26,27]. At-cyclin D3 gene expression in quiescent cells is strongly stimulated by the plant growth factor cytokinin [19], while Ms-cyc4 gene expression is induced prior to S phase by wounding. The expression of other D-type cyclins responds to other types of extracellular factors is important for plant growth; for instance, At-cyclin D2 expression requires a carbon source but not cytokinin [27]. Plant D cyclins contain a pRb-binding motif, LxCxE (single-letter code for amino acids, where x represents any amino acid), in their amino terminus that enhances their binding to both plant and animal pRb (R Huntley et al., personal communication), pRb-related proteins are also developmentally regulated during leaf growth, being expressed more highly in nondividing regions. Maize pRb undergoes changes in level and phosphorylation state concomitant with endoreduplication, and it is phosphorylated in vitro by an S-phase kinase from endoreduplicating
endosperm cells [28]. T h e maize pRb has the capacity to prevent DNA replication as judged by its effect on virus replication [29], and, when expressed in mammalian cells, can prevent E2F-mediated gene transcription (R Huntley et al., personal communication). Together, these results suggest that the maize pRb is a representative of the pocket protein family in plants and may play a role in cell cycle progression.
Novel cdk-interacting proteins Another important facet of cdk regulation is mediated by their interaction with specific interacting proteins other than cyclins. Interaction screens, such as the yeast two-hybrid system, are being exploited to isolate genes encoding proteins that interact with plant cdks. In one of the first studies of this type, Wang et al. [30"] isolated a novel cdk inhibitor by its ability to bind to At-cdc2a. At nanomolar concentrations, the purified protein (ICK1) significantly inhibited (by up to 80%) the pl3sucl-associated histone H1 kinase activity of Arabidopsis extracts. Structurally, ICK1 shares limited sequence similarity with the mammalian p27Kip 1 cdk inhibitor. The region of similarity (77%) is restricted to a 31 amino acid stretch, corresponding to the carboxy-terminal portion of the p27Kipl cdk-inhibitory domain (see Polyak et al. [31] for a definition of this domain). Otherwise, ICK1 is structurally distinct from p27Kip 1. T h e region of similarity is located in the carboxyl terminus of ICK1, in contrast to in the amino terminus of p27Kipl, and ICK1 contains a strong coiled-coil domain that is absent in the mammalian protein. Outside the 31 amino acid conserved region, the remainder of ICK1 shows no homology to p27Kip I or to any other known proteins. This structural divergence appears to be reflected at the functional level, as ICK1 was found to have no inhibitory effects against a mammalian cdc2-cyclin B complex. Independently, Graft and Larkins [32] demonstrated that endoredupticating maize endosperm extracts contain an inhibitor(s) of an M phase specific H1 kinase. T h e molecular nature of the maize inhibitor is unknown, as is the cell cycle specificity of ICK1. Mammalian cdk inhibitors have been implicated in terminal differentiation and tumorigenesis [33], two processes that differ considerably between plants and animals, so it will be interesting to determine whether ICK1 plays as important a role in plant development as do cdk inhibitors during mammalian development. An Arabidopsis homologue of p!13sucl, a putative cdk-docking protein, has been isolated on ~he basis of its interaction with both At-cdc2a and At-cdc2b in a two-hybrid screen ([34]; H Wang et al., unpublished data). Unlike the cdk inhibitors, amino acid identity (45-'65%) is conserved throughout an extensive region in the central part of sucl proteins from plant, yeast and animal sources. The plant g e n e can also rescue a yeast sue1 + mutant, suggesting that sucl function has been well-conserved between these classes of organisms. Interestingly, the plant sucl gene is preferentially expressed outside dividing regions. Cells
Conserved and novel regulators of the plant cell cycle Doonan and Fobert
found just beyond meristems accumulate high levels of sue1 transcripts, suggesting that elevated levels of gene expression may be correlated with the cessation or reduction of cell division activity. Alternatively, upregulation of sue1 expression may be associated with cell elongation, a characteristic of cells just outside the meristem. Although cell division in other systems has been shown to be sensitive to elevated levels of sucl, these data are the first to indicate developmental regulation of sucl levels within muhicellular organisms, and could represent an important clue in understanding the function of this mysterious cell cycle gene.
Post-translational mechanisms for regulating mitotic progression in plant cells Much attention has focused on the abundance of plant cdks and their associated proteins because this may provide clues to those factors that are limiting for cell cycle progression. However, overexpression of wild-type cdc2 produced no recognizable mutant phenotype [13] implying that, at least for cognate cdc2 genes, the plants were not sensitive to the absolute amount of cdc2 protein. In many organisms, the final activation of the cdc2 kinase complex is post-translational, involving the dephosphorylation of a phosphotyrosine residue, Y15, on cdc2. Although the possible involvement of a tyrosine phosphatase in activating plant cdks has been proposed, no such enzyme has yet been isolated. Mutation of the tyrosine residue to phenylalanine produces a kinase that is no longer subject to inhibition by phosphorylation on Y15 and, if cyclin partners are not limiting, this kinase should be constitutively active. A cdc2 gene containing this mutation failed to produce a mutant phenotype, either morphologically or biochemically, suggesting that tyrosine phosphorylation is not an important regulatory mechanism under normal growth conditions [13]. However, Zhang et al. [35] have shown that cytokinindeprived Nicotiana plumbaginifolia cell cultures (which absolutely require cytokinin in late G 2 phase) arrest in G 2 phase with an inactive tyrosine-phosphorylated p34cdc2-1ike H1 histone kinase. Bacterially expressed yeast cdc25 phosphatase, which is specific for removal of phosphate from the regulatory Y15 residue in p34cdce, could activate the histone H1 kinase. T h e differentiated, highly vacuolate pith cells in the central region of the stem are in G O phase but can be induced to re-enter the cell cycle by culturing in the presence of cytokinin. If cultured in the absence of cytokinin the cells produce high levels of inactive tyrosine-phosphorylated cdc2 protein, whereas in the presence of cytokinin the cdc2 is dephosphorylated and active. These data suggest that the effects of cytokinin are mediated by stimulation of a tyrosine phosphatase which activates the cdc2 complex. T h e apparent contradiction between the transgenic experiments and the tissue culture experiments may simply reflect a redundancy in the mechanisms that are available for preventing premature entry into M phase:
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certainly in other eukaryotes, Y15 dephosphorylation varies markedly in both importance and function between species (reviewed in [36]) and maybe, as the above observations suggest, even between different cell types within the same species.
Prospects T h e linking of cell cycle controls to plant growth has opened an fascinating window onto plant development. For the first time, we have a glimpse of how the rate of growth of a plant might be modulated by the availability of rate-limiting activators of cell cycle progression, such as cyclins. In turn, the molecular mechanisms that regulate the production of cyclins and other proteins that are required for cell cycle progression are beginning to be elucidated. Localized variations in cell division rates are characteristic of many developmental processes in plants, and developmental genes could have a role as local regulators of cell division [37,38]. Whether this regulation is direct or indirect is still open to debate, and the challenge now is to determine how these genes act mechanistically on the central cell cycle machine. Given the additional complexity of the plant cdc2 gene family, the diversity of controls that can act on cdk activity and the fact that the relative importance of those controls may change during the developmental history of an organism, the next few years should reveal just how plants do regulate cell division during growth and development.
Acknowledgements We thank M Ito, K Fujiwara and P John for communicating unpublished data and C Lloyd for comments on this manuscript. We acknowledge financial support for this work from the Biotechnology and Biological Sciences Research Council and the National Research Gouncil Canada.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • of special interest ee of outstanding interest 1.
Jurgens G: Cell division and morphogenesis in angiosperm embryogenesis. Semin Cell Dev B/o/1997, 7:867-879.
2.
Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz G, Massagu6 J, Pavletich NP: Mechanism of CDK activation revealed by the structure of a cyclin A-CDK2 complex. Nature 1995, 376:313320.
3. •
Fobert PR, Gaudin V, Lunness P, Coen ES, Doonan JH: Distinct classes of cdc2-related genes are differentially expressed during the cell division cycle in plants. Plant Cell 1996, 8:14651476. This paper describes a plant-specific class of cdc2 genes, which are expressed during specific phases of the cell cycle. 4. •
Magyar Z, Meszaros T, Miskolczi P, Deak M, Feher A, Brown S, Kondorosi E, Athanasiadis A, Pongor S, Bilgin M e t al.: Cell cycle phase specificity of putative cyclin-dependent kinase variants in synchronized alfalfa cells. Plant Cell 1997, 9:923-235. Confirms the widespread presence of divergent cdc2-1ike genes in plants, and indicates that the activation of different cdc2 kinase complexes occurs at different times during the cell cycle. 5.
Segers G, Gadisseur I, Bergounioux C, de Almeida Engler J, Jacqmard A, Van Montagu M, Inze D: The Arebidopsis cyclindependent kinase gene cdc2bAt is preferentially expressed during S and G 2 phases of the cell cycle. PlantJ 1996, 10:601o 619.
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6. •
Renaudin JP, Doonan JH, Freeman D, Hashimoto J, Hirt H, Inze D, Jacobs T, Kouchi H, Rouze P, Sauter M e t a/.: Plant cyclins: a unified nomenclature for plant A-, B- and D-type cyclins based on sequence organization. P/ant Mo/Biol 1996, 32:1003-1018. This paper organizes the naming system for plant cyclin genes. 7.
Katsuka J, Shibaota H: Inhibition by kinase inhibitors of the development and the disappearance of the preprophese band of microtubules in tobacco BY-2 cells. J Cell Sci 1995, 103:397-405.
8.
Hush J, Wu L, John PC, Hepler LH, Hepler PK: Plant mitosis promoting factor disassembles the microtubule preprophase band and accelerates prophase progression in TradescanUa. Cell Biol Int 1996, 20:275-287.
9.
Wu L, Hepler PK, John PCL: The met1 mutation in Chlamydomonas reinhardtii causes arrest at mitotic metaphase with persisting p34cdc2-1ike H1 h/stone kinase activity that can promote mitosis when injected into higher plant cells. Protoplasma 1997, 199:in press.
10.
Mews M, Sek FJ, Moore R, Volkmann D, Gunning BES, John PCL: Mitotic cyclin distribution during maize cell division: implications for the sequence diversity and function of cyclins in plants. Protoplasma 1997, 200:in press.
11.
Oakato K, Hisanaga S, Bulinski JC, Murofushi H, Aizawa H, Itoh TJ, Hotani H, Okumura E, Tachibana K, Kishimoto T: Cyclin B interaction with microtubule-associated protein 4 (MAP4) targets p34cdc2 kinase to microtubules and is a potential regulator of M-phase microtubule dynamics. J Cell Biol 1995, 128:849-862.
12.
Hirt H, Pay A, Bogre L, Meskiene I, Heberte-Bors E: cdc2MsB, a cognate cdc2 gene from alfalfa, complements the G1/S but not the G=/M transition of budding yeast cdc28 mutants. Plant J 1993, 4:61-69.
13.
Hemerly A, Engler J de A, Bergounioux C, Van Montagu M, Engler G, Inze D, Ferreira P: Dominant negative mutants of the Cdc2 kinase uncouple cell division from iterative plant development. EMBO J 1995, 14:3925-3936.
14.
Sauter M: Differential expression of a CAK (cdc2-activating kinase)-Iike protein kinase, cyclins and cdc2 genes from rice during the cell cycle and in response to gibberellin. Plant J 1997, 11:181-190.
transcriptional oscillation in synchronized tobacco BY-2 cells. Proc Nat/Acad Sci USA 1996, 93:4868-4872. 21.
Chung SK, Parish RW: Studies on the promoter of the Arabidopsis thaliana cdc2a gene. FEBS Lett 1995, 362:215-
22.
Martin C, Paz-Ares J: MYB transcription factors in plants. Trends Genet 1997, 13:67-73.
23.
Reichheld JP, Chaubet N, Shen WH, Renaudin JP, Gigot C: Multiple A-type cyclins express sequentially during the cell cycle in Nicotiana tabacum BY2 cells. Proc Nat/Acad Sci USA 1996, 93:13819-13824.
24.
Meskiene I, Bogre L, Dahl M, Pirck M, Ha DT, Swoboda I, Heberle Bors E, Ammeter G, Hirt H: cycMs3, a novel B-type alfalfa cyclin gene, is induced in the G0-to-G 1 transition of the cell cycle. Plant Cell 1995, 7:759-771.
25.
MurrayJAH: The retinoblastoma protein is in plantsl Trends Plant Sci 1997, 2:82-84.
26.
Dahl M, Meskiene I, Bogre L, Ha DT, Swoboda I, Hubmann R, Hirt H, Heberle-Bors E: The D-type alfalfa cyclin gene cycMs4 complements G1 cyclin-deficient yeast and is induced in the G 1 phase of the cell cycle. Plant Cell 1995, 7:1847-1857.
27.
Soni R, Carmichael JP, Shah ZH, Murray JA: A family of cyclin D homologs from plants differentially controlled by growth regulators and containing the conserved retinoblastoma protein interaction motif. Plant Cell 1995, 7:85-103.
28.
Graft G, Burnett RJ, Helentjaris T, Larkins BA, DeCaprio JA, Sellers WR, Kaelin WG Jr: A maize cDNA encoding a member of the retinoblastoma protein family: involvement in endoreduplication. Proc Nat/Acad Sci USA 1996, 93:89628967.
29.
Xie Q, Sanz-Burgos AP, Hannon GJ, Gutierrez C: Plant cells contain a novel member of the retinoblastoma family of growth regulatory proteins. EMBO J 1996, 15:4900-4908.
219.
30.
Wang H, Fowke LC, Crosby WL: A plant cyclin-dependent kinase inhibitor gene. Nature 1997, 386:451-452. his is the first report of a plant cyclin dependent kinase inhibitor.
31.
Polyak K, Lee M-H, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massagu~ J: Cloning of P27 Ktpl " , a cycrin -d ependent kinase inhibitor and a potential mediator of extracallular antimitogenic signals. Cell 1994, 78:59-66.
Doerner P, Jorgensen JE, You R, Steppuhn J, Lamb C: Control of root growth and development by cyclin expression. Nature 1996, 380:520-523. Provides an important demonstration that cyclin B can enhance growth rate in transgenic plants. This is strongly suggestive that cyclin B is ratelimiting for growth under these conditions. Moreover, morphogenesis is normal, showing that the plant can incorporate the extra cells that are produced as a result of high cyclin expression into its developmental programme.
32.
Graft G, Larkins BA: Endoreduplication in maize endosperm: involvement of M-phase promoting factor inhibition and induction of S phase-related kinases. Science 1995, 269:12621264.
33.
Elledge SJ, Winston J, Harper JW: A question of balance: the role of cyclin-kinase inhibitors in development and tumorigenesis. Trends Ceil Biol 1996, 6:388-392.
16.
Fobert P, Coen E, Murphy G, Doonan JH: Patterns of cell division revealed by transcriptional regulation of genes during the cell cycle in plants. EMBO J 1994, 13:616-624.
34.
De Veyler L, Segers G, Glab N, Casteels P, Montagu MV, Inze D: The Arabidopsis Cksl At protein binds the cyclin-dependent kinases Cdc2aAt and Cdc2bAL FEBS Lett 1997, 412:446-452.
17.
Ito M, Marie-Claire C, Sakabe M, Ohno T, Hata S, Kouchi H, Hashimoto J, Fukuda H, Komamine A, Watanabe A: Cell-cycleregulated transcription of A- and B-type plant cyclin genes in synchronous cultures. Plant J 1997, 11:983-992.
35.
Zhang K, Letham DS, John PC: Cytokinin controls the cell cycle at mitosis by stimulating the tyrosine dephosphorylation and activation of p34cdc2-1ike H1 h/stone kinase. Planta 1996, 200:2-12.
18.
Kouchi H, Sekine M, Hata S: Distinct classes of mitotic cyclins are differently expressed in the soybean shoot apex during the cell cycle. P/ant Cell 1995, 7:1143-1155.
36.
Osmani SA, Ye XS: Targets of checkpoints controlling mitosis: lessons from lower eukaryotes. Trends Cell Bio11997, 7:283288.
19.
FuerstRA, Son/R, Murray JA, Lindsey K: Modulation of cyclin transcript levels in cultured calls of Arabidopsis thaliana. Plant Physio/1996, 112:1023-1033.
37.
Meyerowitz EM: Genetic control of cell division patterns in developing plants. Cell 1997, 88:299-308.
38.
TraasJ, Laufs P: Cell cycle mutants in higher plants: a phenotypical overview. In Plant Cell Division. Edited by Francis D, Dudits D, Inze D. London: Portland Press; 1997:319336.
15. •.
20.
Shaul O, Mironov V, Burssens S, Van Montagu M, Inze D: Two Arabidopsis cyclin promoters mediate distinctive