The Drosophila Ras1 gene is required for proper cell fate specification throughout development, and the loss-of-function phenotype of Ras1 suggests an additional role in cell proliferation or survival. A direct role for RAS1 in promoting cell proliferation, however, has not been established. We show that expression of an activated form of RAS1 (RAS1V12) during Drosophila imaginal disc development is sufficient to drive ectopic cell proliferation and hyperplastic tissue growth. In addition, expression of RAS1V12 induces widespread cell death in the imaginal discs, including cells not expressing the transgene, which results in ablation of adult structures. Loss-of-function mutations in the genes encoding RAF, MEK, MAPK and KSR dominantly suppress RAS1V12-induced cell proliferation. Furthermore, two RAS effector loop mutations (E37G and Y40C) that block the RAS-RAF interaction, also suppress RAS1V12-induced proliferation, consistent with a requirement for the MAPK cascade during the RAS1 mitogenic response. These two RAS effector loop mutants, however, retain some activity and can act synergistically with a MAPK gain-of-function mutation, suggesting that RAS1 may also act through signaling pathway(s) distinct from the MAPK cascade.

REFERENCES

Brand
A. H.
,
Perrimon
N.
(
1993
)
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.
Development
118
,
401
415
Brunner
D.
,
Oellers
N.
,
Szabad
J.
,
Biggs
W. H.
,
Zipursky
S. L.
,
Hafen
E.
(
1994
)
A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signalling pathways.
Cell
76
,
875
888
Bryant
P. J.
(
1996
)
Cell proliferation control in Drosophila: flies are not worms.
BioEssays
18
,
781
784
Bryant
P. J.
,
Watson
K. L.
,
Justice
R. W.
,
Woods
D. F.
(
1993
)
Tumor suppressor genes encoding proteins required for cell interactions and signal transduction.
Development
1993
,
239
249
Daum
G.
,
Eisenmann-Tappe
I.
,
Fries
H. W.
,
Troppmair
J.
,
Rapp
U. R.
(
1994
)
The ins and outs of Raf kinases.
Trends Biochem. Sci
19
,
474
480
de Nooij
J. C.
,
Hariharan
I. K.
(
1995
)
Uncoupling cell fate determination from patterned cell division in the Drosophila eye.
Science
270
,
983
985
Diaz-Benjumea
F. J.
,
Hafen
E.
(
1994
)
The sevenless signalling cassette mediates Drosophila EGF receptor function during epidermal development.
Development
120
,
569
578
Edgar
B. A.
,
Lehner
C. F.
(
1996
)
Developmental control of cell cycle regulators: A fly's perspective.
Science
274
,
1646
1652
El-Deiry
W. S.
,
Tokino
T.
,
Velculescu
V. E.
,
Levy
D.B.
,
Parsons
R.
,
Trent
J. M.
,
Lin
D.
,
Mercer
W. E.
,
Kinzler
K. W.
,
Vogelstein
B.
(
1993
)
WAF1, a potential mediator of p53 tumor suppression.
Cell
75
,
817
825
Fortini
M. E.
,
Simon
M. A.
,
Rubin
G. M.
(
1992
)
Signalling by the sevenless protein tyrosine kinase is mimicked by Ras1 activation.
Nature
355
,
559
561
Gateff
E.
(
1994
)
Tumor suppressor and overgrowth suppressor genes of Drosophila melanogaster: Developmental aspects.
Int. J. Dev. Biol
38
,
565
590
Harper
J. W.
,
Adami
G. R.
,
Wei
N.
,
Keyomarsi
K.
,
Elledge
S. J.
(
1993
)
The p21 Cdk-interaction protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
Cell
75
,
805
816
Hay
B. A.
,
Wolff
T.
,
Rubin
G. M.
(
1994
)
Expression of baculovirus p35 prevents cell death in Drosophila.
Development
120
,
2121
2129
Joneson
T.
,
White
M. A.
,
Wigler
M. H.
,
Bar-Sagi
D.
(
1996
)
Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of RAS.
Science
271
,
810
812
Karim
F. D.
,
Chang
H. C.
,
Therrien
M.
,
Wassarman
D. A.
,
Laverty
T.
,
Rubin
G. M.
(
1996
)
A Screen for genes that function downstream of Ras1 during Drosophila eye development.
Genetics
143
,
315
329
Kassis
J. A.
,
Noll
E.
,
VanSickle
E. P.
,
Odenwald
W. F.
,
Perrimon
N.
(
1992
)
Altering the insertional specificity of a Drosophila transposable element.
Proc. Natl. Acad. Sci. USA
89
,
1919
1923
Katz
M. E.
,
McCormick
F.
(
1997
)
Signal transduction from multiple Ras effectors.
Current Opinion in Genetics & Dev
7
,
75
79
Khosravai-Far
R.
,
White
M. A.
,
Westwick
J. K.
,
Solski
P. A.
,
Chrzanowska-Wodnicka
M.
,
Van Aelst
L.
,
Wigler
M. H.
,
Der
C. J.
(
1996
)
Oncogenic Ras activation of Raf/Mitogen-Activated Protein Kinase-idependent pathways is sufficient to cause tumorgenic transformation.
Mol. Cell Biol
16
,
3923
3933
Kimmel
B. E.
,
Heberlein
U.
,
Rubin
G. M.
(
1990
)
The homeo domain protein rough is expressed in a subset of cells in the developing Drosophila eye where it can specify photoreceptor cell subtype.
Genes Dev
4
,
712
727
Lowy
D. R.
,
Willumsen
B. M.
(
1993
)
Function and regulation of Ras.
Annu. Rev. Biochem
62
,
851
891
Lu
X.
,
Perkins
L. A.
,
Perrimon
N.
(
1993
)
The torso pathway in Drosophila: a model system to study receptor tyrosine kinase signal transduction.
Development
1993
,
47
56
Marshall
C. J.
(
1995
)
Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase Activation.
Cell
80
,
179
185
Milan
M.
,
Campuzano
S.
,
Garcia-Bellido
(
1996
)
Cell cycling and patterned cell proliferation in the wing primordium of Drosophila.
Proc. Natl. Acad. SciUSA
93
,
640
645
Milan
M.
,
Campuzano
S.
,
Garcia-Bellido
A.
(
1997
)
Developmental parameters of cell death in the wing disc of Drosophila.
Proc. Natl. Acad. Sci. USA
94
,
5691
5696
Moodie
S. A.
,
Wolfman
A.
(
1994
)
The 3Rs of life: Ras, Raf and Growth Regulation.
Trends Genet
10
,
44
48
Morata
G.
,
Ripoll
P.
(
1975
)
Minutes: Mutants of Drosophila autonomously affecting cell division rate.
Dev. Biol
427
,
211
–.
Morrison
D. K.
,
Cutler
R. E.
(
1997
)
The complexity of Raf-1 regulation.
Current Opinion in Cell Biol
9
,
174
179
Nishida
Y.
,
Hata
M.
,
Ayaki
T.
,
Ryo
H.
,
Yamagata
M.
,
Shimizu
K.
,
Nishizuka
Y.
(
1988
)
Proliferation of both somatic and germ cells is affected in the Drosophila mutants of raf proto-oncogene.
EMBO J
7
,
775
781
Schlessinger
J.
(
1993
)
How receptor tyrosine kinases activate Ras.
Trends Biochem. Sci
18
,
273
275
Schubiger
M.
,
Palka
J.
(
1987
)
Changing spatial patterns of DNA replication in the developing wing of Drosophila.
Dev. Biol
123
,
145
153
Serrano
M.
,
Lin
A. W.
,
McCurrach
M. E.
,
Beach
D.
,
Lowe
S. W.
(
1997
)
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.
Cell
88
,
593
602
Simon
M. A.
,
Bowtell
D. L.
,
Dodson
G. S.
,
Laverty
T. R.
,
Rubin
G. M.
(
1991
)
Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase.
Cell
67
,
701
716
Staehling-Hampton
K.
,
Jackson
P. D.
,
Clark
M. J.
,
Brand
A. H.
,
Hoffmann
F. M.
(
1994
)
Specificity of bone morphogenetic protein-related factors: cell fate and gene expression changes in Drosophila embryos induced by decapentaplegic but not 60A.
Cell Growth and Diff
5
,
585
593
Sundaram
M.
,
Han
M.
(
1996
)
Control and integration of cell signaling pathways during C. elegans vulval development.
BioEssays
18
,
473
480
Thummel
C. S.
,
Boulet
A. M.
,
Lipshitz
H. D.
(
1988
)
Vectors for Drosophila P-element-mediated transformation and tissue culture transfection.
Gene
7
,
445
456
Truman
J. W.
,
Bate
M.
(
1988
)
Spatial and temporal patterns of neurogenesis in the central nervous system of Drosophila melanogaster.
Dev. Biol
125
,
145
157
van der Geer
P.
,
Hunter
T.
,
Lindberg
R. A.
(
1994
)
Receptor protein-tyrosine kinases and their signal transduction pathways.
Annu. Rev. Cell Biol
10
,
251
337
White
M. A.
,
Nicolette
C.
,
Minden
A.
,
Polverino
A.
,
Van Aelst
L.
,
Karin
M.
,
Wigler
M. H.
(
1995
)
Multiple Ras functions can contribute to mammalian cell transformation.
Cell
80
,
533
541
Yochem
J.
,
Sundaram
M.
,
Han
M.
(
1997
)
Ras is Required for a Limited Number of Cell Fates and Not for General Proliferation in Caenorhabditis elegans.
Molec. Cell Biol
17
,
2716
2722
This content is only available via PDF.