Role of the map kinase pathways in maintenance of the transformed phenotype
Author: Ljungdahl, Sofia
Date: 1998-03-20
Location: Radiumhemmets föreläsningssal, Karolinska Sjukhuset
Time: 9.15
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
Abstract
In order to interfere pharmacologically with tumor growth and metastasis, it is of great importance to understand the status of the signal transduction systems in tumor cells. The effect of various oncogenes on cellular signal transduction events has largely been studied in short term experiments. Little is therefore known about activation of these systems in stably transformed cells. We have studied the relationship between activation of different mitogen-activated protein kinase (MAPK) pathways and expression o f transformation-related genes in ras-transformed fibroblasts. In these cells, a relatively small induction (2- to 3-fold) of extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activity was observed, where ERK, but not JNK, activity correlated with transformation-related gene expression. A similar increase in ERK activity was also observed in the metastatic breast cancer cell line MDA MB-231. In these cells, inhibition of MEK activity resulted in a decrease in the expression of the AP-I dependent tissue factor gene. Together our data suggest that either (i) small increases in ERK activity a r e sufficient to elicit a large response in gene expression in transformed cells, or (ii) that other, parallel pathways are involved in inducing the expression of these genes. In some of the ras-transformed cell lines, the c-jun gene was deleted. These cells are still transformed and tumorigenic. This is in obvious discrepancy with previous reports suggesting c-Jun as a key target for oncogenic Ras. We show that c-jun is co-deleted with the tumor suppressor gene CDKN2A. c-Jun is a member of the transcription factor family AP-I. No increase in binding activity of other AP- I components was observed in the c-jun(-/-) cells, suggesting that the existing AP-I complexes are sufficient to support cell growth and transformation. We observed that c-jun(-/-) cells expressed very low levels of collagenase (MMP-I), showing that at least some genes are specifically dependent on c-Jun. The discordant observations of transformation due to over expression of c-Jun and passive deletion of this gene in ras-transformed fibroblasts were considered in a separate study. We were able to s h o w that c-Jun-induced transformation of fibroblasts involves a MEK dependent autocrine loop affecting morphology, ERK activity an d tropomyosin expression. A similar mechanism is seen in ras- and raf transformed fibroblasts, including the c-jun deficient cells, indicating that induction of the loop is not necessarily c-Jun-dependent. In conclusion, these data suggest that transformation of rat fibroblasts by oncogenic ras is dependent on the MEK/ERK signaling pathway, whereas the SEK/JNK pathway is of minor importance.
Issue date: 1998-02-27
Publication year: 1998
ISBN: 91-628-2829-0
Statistics
Total Visits
Views | |
---|---|
Role ...(legacy) | 137 |
Role ... | 81 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Role ... | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
Top country views
Views | |
---|---|
Germany | 47 |
United States | 41 |
China | 30 |
Sweden | 24 |
Ireland | 8 |
South Korea | 7 |
Finland | 6 |
Russia | 4 |
Hong Kong | 3 |
Denmark | 2 |
Top cities views
Views | |
---|---|
Kiez | 17 |
Dublin | 8 |
Shenzhen | 7 |
Seoul | 6 |
Sunnyvale | 6 |
Tianjin | 4 |
Beijing | 3 |
Des Moines | 3 |
Easton | 3 |
Ashburn | 2 |