FBW7-Aurora B-p53 feedback loop regulates mitosis and cell growth

Abstract

FBW7 (F-box and WD repeat domain-containing 7, also known as FBXW7, CDC4, AGO and SEL10) is a well-characterized tumor suppressor and is frequently mutated in a variety of cancers. As a substrate recognition component of SCF (which is a complex of SKP1, CUL1 and F-box proteins) type ubiquitin ligase, FBW7 targets several well-known oncoproteins for ubiquitination and degradation, and therefore controls diverse cellular processes, including cell cycle progression, cell proliferation, cell differentiation and maintenance of genomic stability.1 However, the exact mechanism of FBW7-associated tumor suppression remains elusive. Although cyclin E and c-Myc have been identified as targets of FBW7, the downregulation of these two proteins cannot explain the polyploidy problems associated with FBW7 that are observed in many types of cancers. In a recent issue, Teng et al. showed that FBW7 regulated the ubiquitination and degradation of Aurora B, a mitotic checkpoint kinase that plays a critical role in chromosome alignment, segregation and cytokinesis during mitosis.2 Cancer cells frequently exhibit an unusually high level of Aurora B, leading to dysregulated mitosis and resulting in unequal chromosome segregation, which provides a growth advantage to cancer cells.3 Therefore, Aurora B is an attractive target for therapeutic cancer drugs. Teng et al. demonstrated that FBW7 was a negative regulator of Aurora B, and that the expression of FBW7 suppressed Aurora B-mediated cell growth and mitotic deregulation and reduced the percentage of multinucleated cells caused by Aurora B overexpression. By mapping the interaction region for the mutual association in FBW7 and Aurora B, Teng et al. further identified that R465 and R505 residues of WD 40 domain of FBW7 within the binding pockets are necessary for binding to Aurora B.2 Importantly, FBW7 R465 mutations are frequently observed in cancers.4 The mutant FBW7 would not be able to interact with Aurora B and mediate its degradation, which may lead to Aurora B accumulation and mitotic defects, thereby providing a growth advantage. It has been demonstrated that Aurora B is a negative regulator of p53, and it not only phosphorylates p53, leading to enhanced p53 degradation through MDM2-mediated ubiquitination, but also suppresses p53 transcriptional activity and function.5,6 Loss of p53 causes the downregulation of FBW7α.7 Taken together, these findings suggest the existence of a feedback loop between FBW7, Aurora B and p53. Clearly, a fine balance is critical for maintaining correct chromosome segregation and cell progression during mitosis in normal cells. Any signaling that breaks the balance, such as FBW7 mutations, Aurora B elevation or p53 mutations, may cause mitotic catastrophe and accelerate cancer cell growth. The findings of Teng et al. not only shed a new light on the tumor suppressive functions of FBW7 in oncogenesis, but also provide therapeutic strategy for cancer treatment. Figure 1. FBW7-Aurora B-p53 feedback loop regulates cell processes. FBW7 suppresses Aurora B expression through ubiquitination-mediated protein degradation. Loss of FBW7 leads to the accumulation of Aurora B; Aurora B phosphorylates p53 and enhances ...