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J. Biol. Chem., Vol. 275, Issue 30, 22916-22924, July 28, 2000
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From the Departments of The cellular responses to activated Ras vary
depending on cell type. Normal cells are often induced into pathways
that lead to cell growth arrest, senescence, and/or apoptosis in
response to activated Ras expression. These are important protective
anti-tumorigenic responses that restrict the propagation of cells
bearing activated oncogenes. Here we show that induction of
Ha-RasVal-12 in Rat-1 fibroblasts resulted in
G1 growth arrest and apoptosis with loss of viable cells
that is accompanied by a marked decrease in cyclin D1 levels via
increased ubiquitin-proteasome-dependent cyclin D1
turnover. This is in contrast with a rat intestinal epithelial cell
line in which induction of Ha-RasVal-12 results in
transformation associated with sustained proliferation and increased
levels of cyclin D1, that is not accompanied by anoikis or apoptosis.
Expression of the cyclin D1 mutant (T286A) that contains an alanine for
threonine 286 substitution and is resistant to ubiquitin-proteasome
degradation in the Ha-RasVal-12 expressing Rat-1 cells
resulted in a sustained transformed phenotype with no accumulation of
cells in G1. Inhibition of mitogen-activated protein kinase
(MEK1/2) pathway partially reversed the Ras-mediated decrease in cyclin
D1. Induction of Ha-RasVal-12 resulted in activation of Akt
kinase and inactivation of glycogen-synthase-3
Oncogenic Ras-mediated Cell Growth Arrest and Apoptosis are
Associated with Increased Ubiquitin-dependent Cyclin D1
Degradation*
,,§, and
Medicine, ¶ Surgery and
§ Cell Biology, The Vanderbilt-Ingram Cancer Center,
Vanderbilt University Medical Center, Nashville, Tennessee 37232
kinase that are
associated with reduction of cyclin D1 protein. These results suggest
that Ras-mediated cyclin D1 degradation in Rat-1 cells appears to be
partially dependent on activation of mitogen-activated protein kinase
pathway and independent of glycogen-synthase-3 kinase pathway.
*
This work was supported by the National Institutes of Health
Grants DK-52334, CA-69457 (to R. D. B.), DK-47297 (to R. N. D.), and CA 68485 (to the Vanderbilt Cancer Center).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Surgery,
Vanderbilt University Medical Center, 21st Ave. South, MCN D-5230, Nashville, TN 37232. E-mail:
daniel.beauchamp@mcmail.vanderbilt.edu.
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