NORE1A erects a senescence barrier to tumorigenesis

Sohet et al. demonstrate that the tricellular tight junction protein LSR helps form the blood–brain barrier during embryogenesis. The blood–brain barrier protects neurons from the contents of the circulatory system and relies, in part, on the formation of tight junctions between the endothelial cells lining the blood vessels of the central nervous system. Mice lacking the tight junction protein claudin 5, for example, develop a leaky blood–brain barrier and die shortly after birth. But, because claudin 5 is expressed in all endothelial cells, it remains unclear why blood vessels in the brain are so much more impermeable than the blood vessels supplying other tissues. Sohet et al. were interested in a protein called LSR that, in epithelial tissues, localizes to tight junctions at the points where three neighboring cells contact one another. LSR was also enriched at the tricellular tight junctions of central nervous system endo-thelial cells, the researchers found, but wasn't expressed in the blood vessels of other mouse tissues. LSR was expressed in brain endothelial cells at the time—embryonic day E14.5—that the blood–brain barrier became impermeable to small molecules. In mice lacking LSR, however, the barrier failed to seal before the animals died at E15.5. The blood–brain barrier is often disrupted by neurological injury or disease. Sohet et al. found that LSR was down-regulated in the leaky brain blood vessels generated in mouse models of both multiple sclerosis and stroke. The authors now want to investigate how this down-regulation occurs and whether preventing it can help maintain the blood–brain barrier's integrity. The Ras effector NORE1A induces cell senescence and suppresses tumorigenesis by promoting the acety-lation of p53, Don-ninger 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 senes-cence induction. NORE1A, in turn, promoted HIPK2's association with the tumor suppressor p53. HIPK2 can phosphorylate p53 to …