We have identified six protein kinases that belong to the family of cdc2-related kinases in Caenorhabditis elegans. Results from RNA interference experiments indicate that at least one of these kinases is required for cell-cycle progression during meiosis and mitosis. This kinase, encoded by the ncc-1 gene, is closely related to human Cdk1/Cdc2, Cdk2 and Cdk3 and yeast CDC28/cdc2(+). We addressed whether ncc-1 acts to promote passage through a single transition or multiple transitions in the cell cycle, analogous to Cdks in vertebrates or yeasts, respectively. We isolated five recessive ncc-1 mutations in a genetic screen for mutants that resemble larval arrested ncc-1(RNAi) animals. Our results indicate that maternal ncc-1 product is sufficient for embryogenesis, and that zygotic expression is required for cell divisions during larval development. Cells that form the postembryonic lineages in wild-type animals do not enter mitosis in ncc-1 mutants, as indicated by lack of chromosome condensation and nuclear envelope breakdown. However, progression through G1 and S phase appears unaffected, as revealed by expression of ribonucleotide reductase, incorporation of BrdU and DNA quantitation. Our results indicate that C. elegans uses multiple Cdks to regulate cell-cycle transitions and that ncc-1 is the C. elegans ortholog of Cdk1/Cdc2 in other metazoans, required for M phase in meiotic as well as mitotic cell cycles.

Reference

Ahnn
J.
,
Fire
A.
(
1994
)
A screen for genetic loci required for body-wall muscle development during embryogenesis in Caenorhabditiselegans.
Genetics
137
,
483
498
Ajiro
K.
,
Yasuda
H.
,
Tsuji
H.
(
1996
)
Vanadate triggers the transition from chromosome condensation to decondensation in a mitotic mutant (tsTM13) inactivation of p34cdc2/H1 kinase and dephosphorylation of mitosis-specific histone H3.
Eur. J. Biochem
241
,
923
930
Austin
J.
,
Kimble
J.
(
1987
)
glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans.
Cell
51
,
589
599
Brenner
S.
(
1974
)
The genetics of Caenorhabditiselegans.
Genetics
77
,
71
94
Chae
T.
,
Kwon
Y. T.
,
Bronson
R.
,
Dikkes
P.
,
Li
E.
,
Tsai
L. H.
(
1997
)
Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality.
Neuron
18
,
29
42
De Bondt
H. L.
,
Rosenblatt
J.
,
Jancarik
J.
,
Jones
H. D.
,
Morgan
D. O.
,
Kim
S. H.
(
1993
)
Crystal structure of cyclin-dependent kinase 2.
Nature
363
,
595
602
Draetta
G.
,
Beach
D.
(
1988
)
Activation of cdc2 protein kinase during mitosis in human cells: cell cycle-dependent phosphorylation and subunit rearrangement.
Cell
54
,
17
26
Fang
F.
,
Newport
J. W.
(
1991
)
Evidence that the G1-S and G2-M transitions are controlled by different cdc2 proteins in higher eukaryotes.
Cell
66
,
731
742
Fernandez-Sarabia
M. J.
,
Fantes
P. A.
(
1990
)
Ribonucleotide reductase and its regulation during the cell cycle.
Trends Genet
6
,
275
276
Fire
A.
,
Xu
S.
,
Montgomery
M. K.
,
Kostas
S. A.
,
Driver
S. E.
,
Mello
C. C.
(
1998
)
Potent and specific genetic interference by double-stranded RNA in Caenorhabditiselegans.
Nature
391
,
806
811
Forsburg
S. L.
,
Nurse
P.
(
1991
)
Cell cycle regulation in the yeasts Saccharomycescerevisiae and Schizosaccharomycespombe.
Annu. Rev. Cell Biol
7
,
227
256
Francis
R.
,
Barton
M. K.
,
Kimble
J.
,
Schedl
T.
(
1995
)
gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans.
Genetics
139
,
579
606
Gilmore
E. C.
,
Ohshima
T.
,
Goffinet
A. M.
,
Kulkarni
A. B.
,
Herrup
K.
(
1998
)
Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex.
J. Neurosci
18
,
6370
6377
Girard
F.
,
Strausfeld
U.
,
Fernandez
A.
,
Lamb
N. J.
(
1991
)
Cyclin A is required for the onset of DNA replication in mammalian fibroblasts.
Cell
67
,
1169
1179
Graham
P. L.
,
Kimble
J.
(
1993
)
The mog-1 gene is required for the switch from spermatogenesis to oogenesis in Caenorhabditiselegans.
Genetics
133
,
919
931
Guo
S.
,
Kemphues
K. J.
(
1996
)
A non-muscle myosin required for embryonic polarity in Caenorhabditiselegans.
Nature
382
,
455
458
Hayashi
S.
(
1996
)
A Cdc2 dependent checkpoint maintains diploidy in Drosophila.
Development
122
,
1051
1058
Hedgecock
E. M.
,
White
J. G.
(
1985
)
Polyploid tissues in the nematode Caenorhabditiselegans.
Dev. Biol
107
,
128
133
Hendzel
M. J.
,
Wei
Y.
,
Mancini
M. A.
,
Van Hooser
A.
,
Ranalli
T.
,
Brinkley
B. R.
,
Bazett-Jones
D. P.
,
Allis
C. D.
(
1997
)
Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation.
Chromosoma
106
,
348
360
Hirose
T.
,
Tamaru
T.
,
Okumura
N.
,
Nagai
K.
,
Okada
M.
(
1997
)
PCTAIRE 2, a Cdc2-related serine/threonine kinase, is predominantly expressed in terminally differentiated neurons.
Eur. J. Biochem
249
,
481
488
Hocevar
B. A.
,
Burns
D. J.
,
Fields
A. P.
(
1993
)
Identification of protein kinase C (PKC) phosphorylation sites on human lamin B. Potential role of PKC in nuclear lamina structural dynamics.
J. Biol. Chem
268
,
7545
7552
Hong
Y.
,
Roy
R.
,
Ambros
V.
(
1998
)
Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditiselegans.
Development
125
,
3585
3597
Hunter
C. P.
,
Wood
W. B.
(
1990
)
The tra-1 gene determines sexual phenotype cell-autonomously in C. elegans.
Cell
63
,
1193
1204
Jeffrey
P. D.
,
Russo
A. A.
,
Polyak
K.
,
Gibbs
E.
,
Hurwitz
J.
,
Massague
J.
,
Pavletich
N. P.
(
1995
)
Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex.
Nature
376
,
313
320
Kadyk
L. C.
,
Kimble
J.
(
1998
)
Genetic regulation of entry into meiosis in Caenorhabditiselegans.
Development
125
,
1803
1813
Kimble
J.
,
Simpson
P.
(
1997
)
The LIN-12/Notch signaling pathway and its regulation.
Annu. Rev. Cell Dev. Biol
13
,
333
361
Kimble
J. E.
,
White
J. G.
(
1981
)
On the control of germ cell development in Caenorhabditiselegans.
Dev. Biol
81
,
208
219
Kirby
C.
,
Kusch
M.
,
Kemphues
K.
(
1990
)
Mutations in the par genes of Caenorhabditis elegans affect cytoplasmic reorganization during the first cell cycle.
Dev. Biol
142
,
203
215
Knighton
D. R.
,
Zheng
J. H.
,
Ten Eyck
L. F.
,
Ashford
V. A.
,
Xuong
N. H.
,
Taylor
S. S.
,
Sowadski
J. M.
(
1991
)
Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase.
Science
253
,
407
414
Le Bouffant
F.
,
Capdevielle
J.
,
Guillemot
J. C.
,
Sladeczek
F.
(
1998
)
Characterization of brain PCTAIRE-1 kinase immunoreactivity and its interactions with p11 and 14–3-3 proteins.
Eur. J. Biochem
257
,
112
120
Lehner
C. F.
,
O'Farrell
P. H.
(
1990
)
Drosophila cdc2 homologs: a functional homolog is coexpressed with a cognate variant.
EMBO J
9
,
3573
3581
Lieb
J. D.
,
Albrecht
M. R.
,
Chuang
P. T.
,
Meyer
B. J.
(
1998
)
MIX-1: an essential component of the C. elegans mitotic machinery executes X chromosome dosage compensation.
Cell
92
,
265
277
Massague
J.
(
1998
)
TGF-beta signal transduction.
Annu. Rev. Biochem
67
,
753
791
Masui
Y.
,
Markert
C. L.
(
1971
)
Cytoplasmic control of nuclearbehavior during meiotic maturation of frog oocytes.
J. Exp. Zool
177
,
129
145
Matsushime
H.
,
Quelle
D. E.
,
Shurtleff
S. A.
,
Shibuya
M.
,
Sherr
C. J.
,
Kato
J. Y.
(
1994
)
D-type cyclin-dependent kinase activity in mammalian cells.
Mol. Cell. Biol
14
,
2066
2076
Matsushime
H.
,
Roussel
M. F.
,
Ashmun
R. A.
,
Sherr
C. J.
(
1991
)
Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle.
Cell
65
,
701
713
McCarter
J.
,
Bartlett
B.
,
Dang
T.
,
Schedl
T.
(
1999
)
On the control of oocyte meiotic maturation and ovulation in Caenorhabditis elegans.
Dev. Biol
205
,
111
128
Meyerson
M.
,
Enders
G. H.
,
Wu
C. L.
,
Su
L. K.
,
Gorka
C.
,
Nelson
C.
,
Harlow
E.
,
Tsai
L. H.
(
1992
)
A family of human cdc2-related protein kinases.
EMBO J
11
,
2909
2917
Mori
H.
,
Palmer
R. E.
,
Sternberg
P. W.
(
1994
)
The identification of a Caenorhabditiselegans homolog of p34cdc2 kinase.
Mol. Gen. Genet
245
,
781
786
Nigg
E. A.
(
1995
)
Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle.
BioEssays
17
,
471
480
Nikolic
M.
,
Dudek
H.
,
Kwon
Y. T.
,
Ramos
Y. F.
,
Tsai
L. H.
(
1996
)
The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation.
Genes Dev
10
,
816
825
Nonet
M. L.
,
Staunton
J. E.
,
Kilgard
M. P.
,
Fergestad
T.
,
Hartwieg
E.
,
Horvitz
H. R.
,
Jorgensen
E. M.
,
Meyer
B. J.
(
1997
)
Caenorhabditis elegansrab-3 mutant synapses exhibit impaired function and are partially depleted of vesicles.
J. Neurosci
17
,
8061
8073
Norbury
C.
,
Nurse
P.
(
1992
)
Animal cell cycles and their control.
Annu. Rev. Biochem
61
,
441
470
Ohtsubo
M.
,
Roberts
J. M.
(
1993
)
Cyclin-dependent regulation of G1 in mammalian fibroblasts.
Science
259
,
1908
1912
Pagano
M.
,
Pepperkok
R.
,
Lukas
J.
,
Baldin
V.
,
Ansorge
W.
,
Bartek
J.
,
Draetta
G.
(
1993
)
Regulation of the cell cycle by the cdk2 protein kinase in cultured human fibroblasts.
J. Cell Biol
121
,
101
111
Peter
M.
,
Nakagawa
J.
,
Doree
M.
,
Labbe
J. C.
,
Nigg
E. A.
(
1990
)
In vitro disassembly of the nuclear lamina and M phase-specific phosphorylation of lamins by cdc2 kinase.
Cell
61
,
591
602
Quelle
D. E.
,
Ashmun
R. A.
,
Shurtleff
S. A.
,
Kato
J. Y.
,
Bar-Sagi
D.
,
Roussel
M. F.
,
Sherr
C. J.
(
1993
)
Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts.
Genes Dev
7
,
1559
1571
Riabowol
K.
,
Draetta
G.
,
Brizuela
L.
,
Vandre
D.
,
Beach
D.
(
1989
)
The cdc2 kinase is a nuclear protein that is essential for mitosis in mammalian cells.
Cell
57
,
393
401
Rose
K. L.
,
Winfrey
V. P.
,
Hoffman
L. H.
,
Hall
D. H.
,
Furuta
T.
,
Greenstein
D.
(
1997
)
The POU gene ceh-18 promotes gonadal sheath celldifferentiation and function required for meiotic maturation and ovulation in Caenorhabditis elegans.
Dev. Biol
192
,
59
77
Sauer
K.
,
Weigmann
K.
,
Sigrist
S.
,
Lehner
C. F.
(
1996
)
Novel members of the cdc2-related kinase family in Drosophila: cdk4/6, cdk5, PFTAIRE, and PITSLRE kinase.
Mol. Biol. Cell
7
,
1759
1769
Sherr
C. J.
(
1994
)
G1 phase progression: cycling on cue.
Cell
79
,
551
555
Sherr
C. J.
(
1996
)
Cancer cell cycles.
Science
274
,
1672
1677
Sherr
C. J.
,
Roberts
J. M.
(
1995
)
Inhibitors of mammalian G1 cyclin-dependent kinases.
Genes Dev
9
,
1149
1163
Sigrist
S.
,
Ried
G.
,
Lehner
C. F.
(
1995
)
Dmcdc2 kinase is required for both meiotic divisions during Drosophila spermatogenesis and is activated by the Twine/cdc25 phosphatase.
Mech. Dev
53
,
247
260
Slack
F.
,
Ruvkun
G.
(
1997
)
Temporal pattern formation by heterochronic genes.
Annu. Rev. Genet
31
,
611
634
Stern
B.
,
Ried
G.
,
Clegg
N. J.
,
Grigliatti
T. A.
,
Lehner
C. F.
(
1993
)
Genetic analysis of the Drosophila cdc2 homolog.
Development
117
,
219
232
Storfer-Glazer
F. A.
,
Wood
W. B.
(
1994
)
Effects of chromosomal deficiencies on early cleavage patterning and terminal phenotype in Caenorhabditiselegans embryos.
Genetics
137
,
499
508
Sulston
J. E.
,
Horvitz
H. R.
(
1977
)
Post-embryonic cell lineages of the nematode, Caenorhabditiselegans.
Dev. Biol
56
,
110
156
Sulston
J. E.
,
Horvitz
H. R.
(
1981
)
Abnormal cell lineages in mutants of the nematode Caenorhabditiselegans.
Dev. Biol
82
,
41
55
Sulston
J. E.
,
Schierenberg
E.
,
White
J. G.
,
Thomson
J. N.
(
1983
)
The embryonic cell lineage of the nematode Caenorhabditiselegans.
Dev. Biol
100
,
64
119
Tabara
H.
,
Grishok
A.
,
Mello
C. C.
(
1998
)
RNAi in C. elegans: soaking in the genome sequence.
Science
282
,
430
431
TheSequencing Consortium
(
1998
)
Genome sequence of the nematode C. elegans: a platform for investigating biology.
Science
282
,
2012
2018
Th'ng
J. P.
,
Wright
P. S.
,
Hamaguchi
J.
,
Lee
M. G.
,
Norbury
C. J.
,
Nurse
P.
,
Bradbury
E. M.
(
1990
)
The FT210 cell line is a mouse G2 phase mutant with a temperature-sensitive CDC2 gene product.
Cell
63
,
313
324
Tsai
L. H.
,
Lees
E.
,
Faha
B.
,
Harlow
E.
,
Riabowol
K.
(
1993
)
The cdk2 kinase is required for the G1-to-S transition in mammalian cells.
Oncogene
8
,
1593
1602
Tsai
L. H.
,
Takahashi
T.
,
Caviness
V. S.
Jr.
,
Harlow
E.
(
1993
)
Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system.
Development
119
,
1029
1040
van den Heuvel
S.
,
Harlow
E.
(
1993
)
Distinct roles for cyclin-dependent kinases in cell cycle control.
Science
262
,
2050
2054
Ward
G. E.
,
Kirschner
M. W.
(
1990
)
Identification of cell cycle-regulated phosphorylation sites on nuclear lamin C.
Cell
61
,
561
577
Williams
B. D.
,
Schrank
B.
,
Huynh
C.
,
Shownkeen
R.
,
Waterston
R. H.
(
1992
)
A genetic mapping system in Caenorhabditiselegans based on polymorphic sequence-tagged sites.
Genetics
131
,
609
624
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