James et al. Page 649

Neurofibromatosis 2 tumor suppressor gene (NF2) inactivation is the initiating event in most meningiomas and almost all schwannomas, for which no medical therapies are available. Extending their initial findings that identified the NF2 protein merlin as a novel negative regulator of mTORC1, James and colleagues now show the regulation of mTORC2 signaling by NF2. The authors show the differences between acute and chronic loss of merlin. More importantly, preclinical treatment of meningioma cells indicates that an mTOR kinase inhibitor may be better than rapamycin for meningiomas. These findings have wider implications for tumors with aberrant mTOR signaling.

Ferrari et al. Page 605

VEGF, the major tumor angiogenesis inducer, protects endothelial cells from apoptosis. Ferrari and colleagues report that TGF-β1 converts VEGF into a proapoptotic activity for endothelial cells through the activation of distinct isoforms of p38 mitogen-activated kinase (MAPK). The α and β isoforms of p38 have opposing roles in endothelial cells: p38β transduces survival signaling, whereas p38α mediates apoptosis. TGF-β1 induces endothelial cell apoptosis by switching VEGF activation of p38 from the β to the α isoform. This mechanism could be exploited for the development of novel pharmacologic tools. Agents that can switch VEGF activation of p38MAPK from the β to the α isoform could induce endothelial cell apoptosis and thus provide a potent antitumor angiogenesis treatment.

Cho et al. Page 615

In this study, Cho and colleagues show that RAP80 protein levels fluctuate during the cell cycle. Also, RAP80 is polyubiquitinated and degraded by the anaphase-promoting complex (APC/C)Cdc20 or (APC/C)Cdh1. Consistent with this observation, knockdown of Cdc20 or Cdh1 expression by transfection with small interfering RNAs blocked RAP80 degradation during mitosis or the G1 phase. A conserved destruction box in RAP80 affected its stability and ubiquitination, which was dependent on APC/CCdc20 or APC/CCdh1. In addition, overexpression of RAP80 destruction box1 deletion mutant attenuated mitotic progression. Thus, APC/CCdc20 or APC/CCdh1 complexes regulate RAP80 stability during mitosis to the G1 phase, representing critical events for a novel function of RAP80 in mitotic progression.

Schultz et al. Page 660

In this study, Shultz and colleagues explore the molecular mechanisms that regulate the alternative splicing of Bcl-x pre-mRNA in non–small cell lung cancer (NSCLC). Specifically, they identify the NSCLC proto-oncogene, protein kinase C iota (PKCι), as a major regulator of the alternative splicing of Bcl-x pre-mRNA, acting downstream of the major survival/oncogenic enzyme phosphoinositide 3-kinase (PI3K). Furthermore, this study provides evidence that PKCι regulates this distal mechanism via the expression of the RNA trans-factor, SAP155. Finally, the authors show that antiapoptotic Bcl-x(L) plays an important role in the survival function of PKCι in NSCLC cells. These findings provide new therapeutic targets for NSCLC.