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Inhibition of ras-mediated activator protein 1 activity and cell growth by merlin
Hongtae Kim1, Jung Yeon Lim, Young Hoon Kim
1Neuroscience Genome Research Center, The Catholic University of Korea, Seoul.
Abstract:
The neurofibromatosis type2 (NF2) gene encodes an intracellular-associated protein that is referred to as either merlin or schwannomin. Merlin/Schwannomin is a tumor suppressor protein that has been reported to block the Ras-mediated cell proliferation and -anchorage-independent cell growth. However, its inhibitory mechanism is uncertain. In this report, merlin was demonstrated to be effective in suppressing Ras-induced foci-formation and its associated AP-1 activity in NIH3T3cells. In addition, merlin blocked Ras-induced Rb phosphorylation, and inhibited the increase of cyclin D1 levels. It also blocked E2F-1-dependent transcription. These results suggest that merlin inhibits abnormal cell proliferation which is activated via Ras by repressing Rb phosphorylation, blocking the increase of the cyclin D1 protein level, and inhibiting the activation of AP-1- and E2F-1-dependent transcription in NIH3T3 cells.
Insights
The neurofibromatosis type 2 (NF2) gene
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The neurofibromatosis type 2 (NF2) gene encodes merlin/schwannomin, a tumor suppressor.
- Merlin/schwannomin is known to inhibit cell proliferation but its mechanism is unclear.
Purpose of the Study:
- To elucidate the inhibitory mechanism of merlin/schwannomin on Ras-mediated cell proliferation.
Main Methods:
- Utilized NIH3T3 cells.
- Investigated the effects of merlin on Ras-induced foci-formation, AP-1 activity, Rb phosphorylation, cyclin D1 levels, and E2F-1-dependent transcription.
Main Results:
- Merlin effectively suppressed Ras-induced foci-formation and AP-1 activity.
- Merlin inhibited Ras-induced Rb phosphorylation and the increase in cyclin D1 levels.
- Merlin blocked E2F-1-dependent transcription.
Conclusions:
- Merlin inhibits Ras-activated abnormal cell proliferation by repressing Rb phosphorylation, cyclin D1 upregulation, and AP-1/E2F-1 transcriptional activity.
- These findings clarify the molecular mechanisms by which merlin functions as a tumor suppressor.