Mini-reviewThe role of the NORE1A tumor suppressor in Oncogene-Induced Senescence

- Oncogene-Induced Senescence is a protective mechanism against transformation.
- Ras can paradoxically inhibit growth by promoting Oncogene-Induced Senescence.
- NORE1A is a tumor suppressor that is silenced in a variety of human cancers.
- NORE1A links Ras to p53 and Rb to drive senescence.
- Loss of NORE1A allows Ras to bypass senescence induction and promote transformation.

The Ras genes are the most frequently mutated oncogenes in human cancer. However, Ras biology is quite complex. While Ras promotes tumorigenesis by regulating numerous growth promoting pathways, activated Ras can paradoxically also lead to cell cycle arrest, death, and Oncogene-Induced Senescence (OIS). OIS is thought to be a critical pathway that serves to protect cells against aberrant Ras signaling. Multiple reports have highlighted the importance of the p53 and Rb tumor suppressors in Ras mediated OIS. However, until recently, the molecular mechanisms connecting Ras to these proteins remained unknown. The RASSF family of tumor suppressors has recently been identified as direct effectors of Ras. One of these members, NORE1A (RASSF5), may be the missing link between Ras-induced senescence and the regulation of p53 and Rb. This occurs both quantitatively, by promoting protein stability, as well as qualitatively via promoting critical pro-senescent post-translational modifications. Here we review the mechanisms by which NORE1A can activate OIS as a barrier against Ras-mediated transformation, and how this could lead to improved therapeutic strategies against cancers having lost NORE1A expression.