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The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung
Michele D Vos1, Alfredo Martinez, Chad A Ellis
1Department of Cell and Cancer Biology, National Cancer Institute, National Institutes of Health, 9610 Medical Center Drive, Rockville, MD 20850-3300, USA.
Abstract:
Ras oncoproteins mediate multiple biological effects by activating multiple effectors. Classically, Ras activation has been associated with enhanced cellular growth and transformation. However, activated forms of Ras may also inhibit growth by inducing senescence, apoptosis, and differentiation. Induction of apoptosis by Ras may be mediated by its effector RASSF1, which appears to function as a tumor suppressor. We now show that the Ras effector Nore1, which is structurally related to RASSF1, can also mediate a Ras-dependent apoptosis. Moreover, an analysis of Nore1 protein expression showed that it is frequently down-regulated in lung tumor cell lines and primary lung tumors. Like RASSF1, this correlates with methylation of the Nore1 promoter rather than gene deletion. Finally, re-introduction of Nore1, driven by its own promoter, impairs the growth in soft agar of a human lung tumor cell line. Consequently, we propose that the Ras effector Nore1 is a member of a family of Ras effector/tumor suppressors that includes RASSF1.
Insights
Ras oncoproteins can induce apoptosis via the Nore1 effector, similar to RASSF1. Nore1 is frequently down-regulated in lung tumors due to promoter methylation, suggesting its role as a tumor suppressor.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Ras oncoproteins regulate cellular processes, including growth and apoptosis.
- Ras effectors like RASSF1 can induce apoptosis and act as tumor suppressors.
Purpose of the Study:
- To investigate the role of the Ras effector Nore1 in Ras-dependent apoptosis.
- To determine Nore1 expression levels and potential mechanisms of regulation in lung tumors.
Main Methods:
- Assessing Nore1's ability to mediate Ras-dependent apoptosis.
- Analyzing Nore1 protein expression in lung tumor cell lines and primary tumors.
- Investigating promoter methylation as a mechanism for Nore1 down-regulation.
- Evaluating the effect of Nore1 re-introduction on tumor cell growth.
Main Results:
- Nore1 mediates Ras-dependent apoptosis.
- Nore1 is frequently down-regulated in lung tumor cell lines and primary tumors.
- Down-regulation of Nore1 correlates with promoter methylation, not gene deletion.
- Re-introduction of Nore1 inhibits anchorage-independent growth of lung tumor cells.
Conclusions:
- Nore1 functions as a Ras effector that can induce apoptosis.
- Nore1 acts as a tumor suppressor in lung cancer, with its expression regulated by promoter methylation.
- Nore1 is proposed to be part of a family of Ras effector/tumor suppressors, including RASSF1.