We have identified recessive overproliferation mutations by screening and examining clones of mutant cells in genetic mosaics of the fruitfly Drosophila melanogaster. This type of screen provides a powerful approach for identifying and studying potential tumor suppressors. One of the identified genes, lats, has been cloned and encodes a putative protein kinase that shares high levels of sequence similarity with three proteins in budding yeast and Neurospora that are involved in regulation of the cell cycle and growth. Mutations in lats cause dramatic overproliferation phenotypes and various developmental defects in both mosaic animals and homozygous mutants.
Reference
Reference
Bier
E.
, Vaessin
H.
, Shepherd
S.
, Lee
K.
, McCall
K.
, Barbel
S.
, Ackerman
L.
, Carretto
R.
, Uemura
T.
, Grell
E. H.
, Jan
L. Y.
, Jan
Y. N.
(1989
) Searching for pattern and mutations in the Drosophila genome with a P- lacZ vector.
Genes Dev
3
, 1273
–1287
Bishop
J. M.
(1991
) Molecular themes in oncogenesis.
Cell
64
, 235
–248
Boedigheimer
M.
, Bryant
P.
, Laughon
A.
(1993
) Expanded, a negative regulator of cell proliferation in Drosophila, shows homology to the NF2 tumor suppressor.
Mechan. Dev
44
, 83
–84
Boedigheimer
M. J.
, Laughon
A. S.
(1993
) Expanded: a gene involved in the control of cell proliferation in imaginal discs.
Development
118
, 1291
–1301
Brook
J. D.
, McCurrach
M. E.
, Harley
H. G.
, Buckler
A. J.
, Church
D.
, Aburatani
H.
, Hunter
K.
, Stanton
V. P.
, Thirion
J. P.
, Hudson
T.
, Sohn
R.
, Zemelman
B.
, Snell
R. G.
, Rundle
S. A.
, Crow
S.
, Davies
J.
, Shelbourne
P.
, Buxton
J.
, Jones
C.
, Juvonen
V.
, Johnson
K.
, Harper
P. S.
, Shaw
D. J.
, Housman
D. E.
(1992
) Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3end of a transcript encoding a protein kinase family member.
Cell
68
, 799
–808
Featherstone
C.
, Russell
P.
(1991
) Fission yeast p107wee1mitotic inhibitor is a tyrosine/serine kinase.
Nature
349
, 808
–811
Fearon
E. R.
, Vogelstein
B.
(1990
) A genetic model for colorectal tumorigenesis.
Cell
61
, 759
–767
Fortini
M. E.
, Lai
Z.
, Rubin
G. M.
(1991
) The Drosophila zfh-1 and zfh-2 genes encode novel proteins containing both zinc-finger and homeodomain motifs.
Mechan. Dev
34
, 113
–122
Fu
Y. H.
, Friedman
D. L.
, Richards
S.
, Pearlman
M. B.
, Scarlato
G.
, Fenwick
R. G.
, Caskey
C. T.
(1993
) Decreased expression of mytonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy.
Science
260
, 235
–238
Gateff
E.
(1978
) Malignant neoplasms of genetic origin in Drosophila melanogaster.
Science
200
, 1448
–1459
Golic
K. G.
(1991
) Site-specific recombination between homologous chromosomes in Drosophila.
Science
252
, 958
–961
Golic
K. G.
, Lindquist
S.
(1989
) The FLP recombinase of yeast catalyzes site-specific recombination in the Drosophila genome.
Cell
59
, 499
–509
Hanks
S. K.
, Quinn
A. M.
, Hunter
T.
(1988
) The protein kinase family: conserved features and deduced phylogeny of the catalytic domains.
Science
241
, 42
–52
Hartl
D. L.
, Nurminsky
D. I.
, Jones
R. W.
, Lozovskaya
E. R.
(1994
) Genome structure and evolution in Drosophila: Applications of the framework P1 map.
Proc. Natl. Acad. Sci. USA
91
, 6824
–6829
Jacob
L.
, Opper
M.
, Metzroth
B.
, Phannavong
B.
, Mechler
B. M.
(1987
) Structure of the I(2)gl gene of Drosophila and delimitation of its tumor suppressor domain.
Cell
50
, 215
–225
Johnston
L. H.
, Eberly
S. L.
, Chapman
J. W.
, Araki
H.
, Sugino
A.
(1990
) The product of the Saccharomyces cerevisiae cell cycle gene DBF2 has homology with protein kinases and is periodically expressed in the cell cycle.
Mol. Cell. Biol
10
, 1358
–1366
Johnston
L. H.
, Thomas
A. P.
(1982
) The isolation of new DNA synthesis mutants in the yeast Saccharomyces cerevisiae.
Mol. Gen. Genet
186
, 439
–444
Karpen
G. H.
, Spradling
A. C.
(1992
) Analysis of subtelomeric heterochromatin in the Drosophila minichromosome Dp1187 by single P element insertional mutagenesis.
Genetics
132
, 737
–53
Knudson
A. G.
Jr (1971
) Mutation and cancer: statistical study of retinoblastoma.
Proc. Natl. Acad. Sci. USA
68
, 820
–823
Lai
Z.-C.
, Rushton
E.
, Bate
M.
, Rubin
G. M.
(1993
) Loss of function of the Drosophila zfh-1 gene results in abnormal development of mesodermally derived tissues.
Proc. Natl. Acad. Sci. USA
90
, 4122
–4126
Lutzelschwab
R.
, Klämbt
C.
, Rossa
R.
, Schmidt
O.
(1987
) A protein product of the Drosophila recessive tumor gene, l (2) giant gl, potentially has cell adhesion properties.
EMBO J
6
, 1791
–1797
Mahadevan
M. S.
, Amemiya
C.
, Jansen
G.
, Sabourin
L.
, Baird
S.
, Neville
C. E.
, Wormskamp
N.
, Segers
B.
, Batzer
M.
, Lamerdin
J.
, de Jong
P.
, Wieringa
B.
, Korneluk
R. G.
(1993
) Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene.
Hum. Mol. Genet
2
, 299
–304
Mahoney
P. A.
, Weber
U.
, Onofrechuk
P.
, Biessmann
H.
, Bryant
P. J.
, Goodman
C. S.
(1991
) The fat tumor suppressor gene in Drosophila encodes a novel member of the Cadherin gene superfamily.
Cell
67
, 853
–868
Mansfield
E.
, Hersperger
E.
, Biggs
J.
, Shearn
A.
(1994
) Genetic and molecular analysis of hyperplastic discs, a gene whose product is required for regulation of cell proliferation in Drosophila melanogaster imaginal discs and germ cells.
Dev. Biol
165
, 507
–526
Mitchell
M. B.
, Mitchell
H. K.
(1954
) A partial map of linkage group D in Neurospora crassa.
Proc. Natl. Acad. Sci. USA
40
, 436
–440
Ponder
B. A. J.
(1990
) Inherited predisposition to cancer.
Trends Genet
6
, 213
–218
Ren
R.
, Mayer
B. J.
, Cicchetti
P.
, Baltimore
D.
(1993
) Identification of a ten-amino acid Proline-rich SH3 binding site.
Science
259
, 1157
–1161
Robertson
H. M.
, Preston
C. R.
, Phillis
R. W.
, Johnson-Schlitz
D. M.
, Denz
W. K.
, Engels
W. R.
(1988
) A stable genomic source of P element transposase in Drosophila melanogaster.
Genetics
118
, 461
–470
Russell
P.
, Nurse
P.
(1987
) Negative regulation of mitosis by wee1+, a gene encoding a protein kinase homolog.
Cell
49
, 559
–567
Sanger
F.
, Nicklen
S.
, Coulson
A.
(1977
) DNA sequencing with chain terminating inhibitors.
Proc. Natl. Acad. Sci. USA
74
, 5463
–5467
Shortridge
R. D.
, Yoon
J.
, Lending
C. R.
, Bloomquist
B. T.
, Perdew
M. H.
, Pak
W. L.
(1991
) A Drosophila phospholipase C gene that is expressed in the central nervous system.
J. Biol Chem
266
, 12474
–12480
Stewart
M. J.
, Denell
R.
(1993
) Mutations in the Drosophila gene encoding ribosomal protein S6 cause tissue overgrowth.
Mol. Cell. Biol
13
, 2524
–2535
Thummel
C. S.
, Pirrotta
V.
(1992
) New pCaSpeR P element Vectors.
Drosophila Inform. Service
71
, 150
–.Tomlinson
A.
, Ready
D. F.
(1987
) Cell fate in Drosophila ommatidium.
Dev. Biol
123
, 264
–275
Török
T.
, Tick
G.
, Alvarado
M.
, Kiss
I.
(1993
) P-lacW insertional mutagenesis on the second chromosome of Drosophila melanogaster: Isolation of lethals with different overgrowth phenotypes.
Genetics
135
, 71
–80
Toyn
J. H.
, Araki
H.
, Sugino
A.
, Johnston
L. H.
(1991
) The cell-cycle-regulated budding yeast gene DBF2, encoding a putative protein kinase, has a homologue that is not under cell-cycle control.
Gene
104
, 63
–70
Toyn
J. H.
, Johnston
L. H.
(1994
) The Dbf2 and Dbf20 protein kinasesof budding yeast are activated after the metaphase to anaphase cell cycle transition.
EMBO J
13
, 1103
–1113
Vogelstein
B.
, Kinzler
K. W.
(1993
) The multistep nature of cancer.
Trends Genet
9
, 138
–141
Watson
K. L.
, Konrad
K. D.
, Woods
D. F.
, Bryant
P. J.
(1992
) Drosophila homolog of the human S6 ribosomal protein is required for tumor suppression in the hematopoietic system.
Proc. Natl. Acad. Sci. USA
89
, 11302
–11306
Weinberg
R. A.
(1991
) Tumor suppressor genes.
Science
254
, 1138
–1146
Wharton
K. A.
, Yedvobnick
B.
, Finnerty
V. G.
, Artavanis-Tsakonas
S.
(1985
) Opa: a novel family of transcribed repeats shared by the Notch locus and other developmentally regulated loci in Drosophila melanogaster.
Cell
40
, 55
–62
Woods
D. F.
, Bryant
P. J.
(1989
) Molecular cloning of the lethal(1)Discs large-1 oncogene of Drosophila.
Dev. Biol
134
, 222
–235
Woods
D. F.
, Bryant
P. J.
(1991
) The discs-large tumor suppressor gene of Drosophila encodes a guanylate kinase homolog localized at septate junctions.
Cell
66
, 451
–464
Woods
D. F.
, Bryant
P. J.
(1993
) ZO-1, DlgA and PSD-95/SAP90: homologous proteins in tight, septate and synaptic cell juctions.
Mechan. Dev
44
, 85
–89
Xu
T.
, Artavanis-Tsakonis
S.
(1990
) deltex, a locus interacting with the neurogenic genes, notch, delta and mastermind in Drosophila melanogaster.
Genetics
126
, 665
–677
Xu
T.
, Harrison
S.
(1994
) Mosaic analysis using FLP recombinase.
Methods in Cell Biology
44
, 655
–682
Xu
T.
, Rubin
G. M.
(1993
) Analysis of genetic mosaics in developing and adult Drosophila tissues.
Development
117
, 1223
–1237
Yarden
O.
, Plamann
M.
, Ebbole
D. J.
, Yanofsky
C.
(1992
) cot-1, a gene required for hyphal elongation in Neurosporacrassa, encodes a protein kinase.
EMBO J
11
, 2159
–2166
This content is only available via PDF.
© 1995 by Company of Biologists
1995
