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K-Ras and H-Ras Activation Promote Distinct Consequences on Endometrial Cell Survival
- Source :
- Cancer Research. 64:2759-2765
- Publication Year :
- 2004
- Publisher :
- American Association for Cancer Research (AACR), 2004.
-
Abstract
- A considerable amount of evidence indicates that Ras signaling contributes to the development of endometrial cancer. We previously demonstrated that endometrial cancer cells carrying oncogenic [12Val]K-ras were susceptible to apoptosis. The present study examined the role of K-and H-Ras in the induction of apoptosis using rat endometrial cells (RENT4 cells). We found that constitutively activated K-Ras promoted apoptotic cell death, whereas the H-Ras mutant rescued rat endometrial cells from apoptosis. Expression of a constitutively active form of Raf-1 (Raf-CAAX) promoted apoptosis, whereas expression of a constitutively active catalytic subunit of phosphoinositide 3-kinase, p110K227E, allowed cells to escape from apoptosis. Moreover, inhibition of the MEK-MAPK pathway by the specific inhibitor, UO126, rescued the cells from apoptosis, whereas the inhibition of phosphoinositide 3-kinase by its specific inhibitor, LY294002, promoted apoptosis in RENT4 cells expressing activated K-Ras. However, both inhibitors promoted apoptosis in RENT4 cells expressing activated H-Ras. This difference in the regulation of apoptosis by the MEK inhibitor between K-Ras- and H-Ras-expressing cells depended on the interaction of effector proteins downstream of each Ras isoform. Finally, to elucidate the role of downstream K-Ras signal pathways, we generated K-Ras effector domain mutants (K12V35S, K12V40C). We examined the incidence of apoptotic cell death induced by the K-Ras effector domain mutants (K12V35S, K12V40C). The relative ratio of phospho-MAPK to phospho-Akt compared with that of mock cells was higher in K12V35S cells than in K12V40C cells. Ectopic expression of K12V35S protein increased the proportion of apoptotic cells, and in turn, the expression of K12V40C protein decreased compared with the expression of K12V protein without the effector domain mutant. These results demonstrate that K- and H-Ras-mediated signaling pathways exert distinct effects on apoptosis and that K-Ras downstream Raf/MEK/MAPK pathway is required for the induction of apoptosis in endometrial cells. Coordination of the two pathways contributes to endometrial cell survival.
- Subjects :
- MAPK/ERK pathway
Cancer Research
MAP Kinase Signaling System
Apoptosis
Protein Serine-Threonine Kinases
Biology
Transfection
Cell Line
Endometrium
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Proto-Oncogene Proteins
Animals
Protein Isoforms
LY294002
Inhibitor of apoptosis domain
Effector
Rats
Proto-Oncogene Proteins c-raf
Gene Expression Regulation
Oncology
chemistry
Cell culture
ras Proteins
Cancer research
Female
Mitogen-Activated Protein Kinases
Signal transduction
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 64
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....b84bcb1d82375f1d8cf631a1cf9e86e5
- Full Text :
- https://doi.org/10.1158/0008-5472.can-3487-2