The Ras effector NORE1A induces cell senescence and suppresses tumorigenesis by promoting the acetylation of p53, Donninger et al. reveal.
Activating mutations in the Ras GTPase drive cell proliferation, but their ability to promote tumorigenesis is limited by the fact that they also induce cells to exit the cell cycle and become senescent. How Ras induces senescence, and how this pathway is disrupted in cancer cells, is largely unknown. Donninger et al. examined the role of the tumor suppressor NORE1A, a scaffold protein that binds to active Ras.
Overexpressing NORE1A induced cell senescence, whereas knocking down the protein inhibited senescence and enhanced the transformation of cells expressing activated Ras. Donninger et al. found that Ras promoted NORE1A’s association with a kinase called HIPK2, and this interaction was required for senescence induction.
NORE1A, in turn, promoted HIPK2’s association with the tumor suppressor p53. HIPK2 can phosphorylate p53 to induce the transcription of proapoptotic genes such as Bax. But the kinase can also recruit enzymes that acetylate p53 and promote the expression of genes, like p21CIP1, that induce cell senescence. Donninger et al. found that NORE1A suppressed the former pathway and enhanced the latter. Accordingly, human tumors lacking NORE1A showed decreased levels of p53 acetylation.
NORE1A therefore mediates Ras-induced cell senescence, and the loss of this protein may be a critical step in tumorigenesis. Senior author Geoffrey Clark is now interested in whether NORE1A and related proteins allow Ras to regulate the acetylation of other proteins besides p53.
Text by Ben Short