A critical role for FBXW8 and MAPK in cyclin D1 degradation and cancer cell proliferation. PLoS ONE 1, e128

Department of Pathology, School of Medicine, University of California San Francisco, San Francisco, California, United States of America
PLoS ONE (Impact Factor: 3.23). 02/2006; 1(1):e128. DOI: 10.1371/journal.pone.0000128
Source: PubMed


Cyclin D1 regulates G1 progression. Its transcriptional regulation is well understood. However, the mechanism underlying cyclin D1 ubiquitination and its subsequent degradation is not yet clear. We report that cyclin D1 undergoes increased degradation in the cytoplasm during S phase in a variety of cancer cells. This is mediated by phosphorylation at Thr286 through the activity of the Ras/Raf/MEK/ERK cascade and the F-box protein FBXW8, which is an E3 ligase. The majority of FBXW8 is expressed in the cytoplasm during G1 and S phase. In contrast, cyclin D1 accumulates in the nucleus during G1 phase and exits into the cytoplasm in S phase. Increased cyclin D1 degradation is linked to association with FBXW8 in the cytoplasm, and enhanced phosphorylation of cyclin D1 through sustained ERK1/2 signaling. Depletion of FBXW8 caused a significant accumulation of cyclin D1, as well as sequestration of CDK1 in the cytoplasm. This resulted in a severe reduction of cell proliferation. These effects could be rescued by constitutive nuclear expression of cyclin D1-T286A. Thus, FBXW8 plays an essential role in cancer cell proliferation through proteolysis of cyclin D1. It may present new opportunities to develop therapies targeting destruction of cyclin D1 or its regulator E3 ligase selectively.

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Available from: Hiroshi Okabe, Nov 04, 2014
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    • "Taken together, the emerging genetic evidence has strongly suggested a pivotal role for the CUL7 E3 ligase in growth control. CUL7 may have additional functions that include transformation mediated by simian virus-40 (SV40) large T antigen (Kohrman and Imperiale, 1992; Daud et al., 1993; Kasper et al., 2005), apoptosis (Tsai et al., 2000; Kim et al., 2007), p53 regulation (Andrews et al., 2006; Dowell et al., 2007; Kaustov et al., 2007; Jung et al., 2007), and the degradation of cyclin D1 (Okabe et al., 2006). "
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    • "Finally, activated ERK MAPK regulates its downstream targets in the positive or negative manners by phosphorylation (Fig. 4A). The downstream targets include transcription regulators (e.g., GATA-1) (Towatari et al., 2004), translational regulators (e.g., p90 ribosomal S6 kinases: RSK1, 2, 3) (Zhao et al., 1996), cell cycle regulators (e.g., Cyclin D1) (Okabe et al., 2006), and apoptosis regulators (e.g., BCL-2) (Tamura et al., 2004). Therefore, aberrant activation of Ras-ERK MAPK signaling contributes to abnormal gene expression, cell cycle progression, proliferation , and survival. "
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    • "Thus, we hypothesized that MRBE-induced decrease in cyclin D1 level may be mediated from its proteasomal degradation, and found that pretreatment of MG132 (proteasome inhibitor) suppresses MRBE-induced cyclin D1 down-regulation. There are some kinases reported to degrade cyclin D1 such as p38 [51], ERK1/2 [52], GSK3β [53] and ROS [54]. From using kinase inhibitor, we conclude that MRBE-induced cyclin D1 degradation requires ROS; however, p38, ERK1/2 and GSK3β are not involved in MRBE-induced cyclin D1 degradation. "
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