The ubiquitous nature of cancer: the role of the SCF(Fbw7) complex in development and transformation

Abstract

The ubiquitin-proteasome system (UPS) is a multi-subunit pathway that allows for ubiquitin modification of proteins and leads to either degradation or other non-proteolytic processes such as trafficking or transcriptional activation. Given its role as a regulator of cellular homeostasis it is not surprising that members of the UPS are frequently aberrantly expressed in a number of disease states including cancer. This review will focus on one member of the UPS, the F-box protein, Fbw7 (also known as Sel-10, Ago, hCDC4) and mechanisms by which Fbw7 interacts with its substrates in the context of development and tumorigenesis will be discussed. In addition, antagonists of this pathway as well as current and future therapeutics for the UPS will be examined.

Figure 1

Pathway of Fbw7-mediated degradation. A putative Fbw7 substrate either harbors a negatively charged amino acid in the +4 position or is phosphorylated by a kinase at this position. It is then phosphorylated by an additional priming kinase, which allows the interaction of the substrate with the SCF^Fbw7 complex. Fbw7 holds the substrate in close proximity to the E2 enzyme (ubc), which enables the covalent conjugation of ubiquitin. The addition of polyubiquitin targets the substrate for degradation by the proteasome. Alternatively, a deubiquitinating enzyme removes covalently bound ubiquitn from the substrate preventing its degradation effectively stabilizing the substrate. Data discussed in this review show that Fbw7 regulates the stability of proteins that have been associated with proliferation suggesting Fbw7-mediated proteasomal degradation is a mechanism important to the maintenance of cellular quiescence. Conversely, antagonists to this pathway lead to cellular proliferation.

Figure 2

Proposed mechanism of malignant transformation mediated by Fbw7 mutations. Somatic missense mutations in any of the three critical arginine residues (Arg⁴⁶⁵, Arg⁴⁷⁹ or Arg⁵⁰⁵) within the WD40 domain of Fbw7 abrogate its interaction with Cdc4 phospho degron (CPD) motifs on target substrates. Phosphorylated substrates are no longer bound and polyubiquitnated by SCF^Fbw7 and accumulate in the nucleus. Accumulation of Fbw7 targets, such a c-Myc, cyclin E and Notch-1, can trigger oncogene-induced apoptosis and senescence, which is largely dependent on p53 status. Cells harboring mutations in Fbw7 are selectively pressured to inactivate p53 for continued proliferation and survival, ultimately leading to increased genomic instability and tumorigenesis.