Introduction

Abstract

Cancer, medically termed as malignant neoplasm, is characterized by uncontrolled cell division and growth, resulting from genome instability or dysregulated responses to physiological cues that regulate normal cellular processes including proliferation, survival, and differentiation. Intensive investigations over the past decades have demonstrated that cancer can be considered largely a genetic disease, and typically multiple genetic alteration events are required in order for primary cells to become malignant, including loss of tumor suppressor functions combined with gain of oncoprotein functions (Fukasawa, Nat Rev Cancer 7(12):911–924, 2007; Crusio et al., Oncogene 29(35):4865–4873, 2010).

Recently, there has been a wealth of literature demonstrating that F-box proteins, complexed with other essential components (Skp1 and Cullin) to form SCF-type of E3 ubiquitin ligase complexes, play a pivotal role in the development and progression of human malignancies (Nakayama and Nakayama, Nat Rev Cancer 6(5):369–381, 2006; Welcker and Clurman, Nat Rev Cancer 8(2):83–93, 2008). Mechanistically, mounting evidence supports the notion that F-box proteins are involved in governing multiple cellular processes including cell proliferation, apoptosis, invasion, angiogenesis, and metastasis (Cardozo and Pagano, Nat Rev Mol Cell Biol 5(9):739–751, 2004). With many excellent studies in recent years regarding how F-box proteins contribute to human diseases such as cancer (Nakayama and Nakayama, Nat Rev Cancer 6(5):369–381, 2006; Welcker and Clurman, Nat Rev Cancer 8(2):83–93, 2008), now is a pertinent time to review our current understanding of how F-box proteins, including the well-established Fbw7, Skp2, and β-TRCP, are involved in tumorigenesis by controlling cell growth and apoptosis, regulation of invasion and metastasis, display of stem cell features, and establishment of drug resistance. Moreover, we also review the underlying mechanisms by which F-box proteins are regulated, and how these pathways when disrupted can promote tumorigenesis.

In addition to SCF ubiquitin ligases, the Anaphase Promoting Complex/Cyclosome (APC/C, also called APC) is also a major ubiquitin ligase, which is a driving force in governing proper cell cycle progression, especially regulating timely transitions during mitosis, and entry into S phase (Peters, Nat Rev Mol Cell Biol 7(9):644–656, 2006). The APC consists of a core holoenzyme and an adaptor protein, either Cdh1 or Cdc20. Recent genetic and biochemical studies revealed that APC^Cdc20 as a putative oncoprotein (Li et al., Mol Cell Biol 27(9):3481–3488, 2007; Manchado et al., Cancer Cell 18(6):641–654, 2010; Yin et al. Cell Cycle 6(23):2990–2992, 2007) while APC^Cdh1 likely functions as a tumor suppressor (Garcia-Higuera et al. Nat Cell Biol 10(7):802–811, 2008; Li et al. Nat Cell Biol 10(9):1083–1089, 2008), yet the underlying molecular mechanisms by which these two lases exert their effects on tumorigenesis remain largely undefined. Moreover, studies from various groups have revealed an intensive crosstalk between the APC and SCF E3 ligase complexes in coordinating the timely cell cycle transitions. Hence, it is critical to summarize recent advances in our genetic and biochemical understanding of how various APC and SCF complexes and their regulators function in tumorigenesis, which will be useful in guiding the development of specific inhibitors targeting ubiquitin ligase function as novel anticancer treatments.