Fbxw7β resides in the endoplasmic reticulum membrane and protects cells from oxidative stress

Oxidative stress has been implicated in cancer initiation and progression. Fbxw7 (also known as Fbw7, SEL-10, hCdc4, or hAgo) is the F-box protein subunit of an Skp1-Cul1-F-box (SCF)-type ubiquitin ligase complex that plays a central role in the degradation of oncoproteins such as c-Myc, c-Jun, Notch, and cyclin E. Fbxw7 is therefore thought to function as a tumor suppressor, and indeed the Fbxw7 gene is frequently mutated in many human malignancies. The Fbxw7 gene locus encodes three protein isoforms: Fbxw7 alpha, Fbxw7 beta, and Fbxw7 gamma. Whereas Fbxw7 alpha and Fbxw7 gamma are resident in the nucleus, Fbxw7 beta shows a cytoplasmic distribution suggestive of localization to the endoplasmic reticulum (ER). The specific function of Fbxw7 beta has remained unknown, however. We now show that Fbxw7 beta contains a putative transmembrane domain near its NH2-terminus, and topological analysis revealed that Fbxw7 beta is inserted in the ER membrane. Fbxw7 beta assembled with Skp1, Cul1, and Rbx1 to form an SCF complex, although the efficiency of this process appeared lower than that for Fbxw7 alpha or Fbxw7 gamma. To explore the physiological role of Fbxw7 beta, we generated mice specifically lacking this isoform of Fbxw7. Although these animals did not exhibit any apparent abnormalities in development, primary cultures of neurons prepared from the mutant mice were more vulnerable to oxidative stress than were those prepared from wild-type mice. Conversely, overexpression of Fbxw7 beta rendered cells resistant to oxidative stress, without affecting sensitivity to ER stress or other apoptosis-inducing agents. Our results thus suggest that Fbxw7 beta contributes to the protection of cells from oxidative stress. (Cancer Sci 2011; 102: 749-755)