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). "

    Full-text · Dataset · Jan 2015
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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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    ABSTRACT: The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.
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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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    ABSTRACT: Background Root bark of mulberry (Morus alba L.) has been used in herbal medicine as anti-phlogistic, liver protective, kidney protective, hypotensive, diuretic, anti-cough and analgesic agent. However, the anti-cancer activity and the potential anti-cancer mechanisms of mulberry root bark have not been elucidated. We performed in vitro study to investigate whether mulberry root bark extract (MRBE) shows anti-inflammatory and anti-cancer activity. Methods In anti-inflammatory activity, NO was measured using the griess method. iNOS and proteins regulating NF-κB and ERK1/2 signaling were analyzed by Western blot. In anti-cancer activity, cell growth was measured by MTT assay. Cleaved PARP, ATF3 and cyclin D1 were analyzed by Western blot. Results In anti-inflammatory effect, MRBE blocked NO production via suppressing iNOS over-expression in LPS-stimulated RAW264.7 cells. In addition, MRBE inhibited NF-κB activation through p65 nuclear translocation via blocking IκB-α degradation and ERK1/2 activation via its hyper-phosphorylation. In anti-cancer activity, MRBE deos-dependently induced cell growth arrest and apoptosis in human colorectal cancer cells, SW480. MRBE treatment to SW480 cells activated ATF3 expression and down-regulated cyclin D1 level. We also observed that MRBE-induced ATF3 expression was dependent on ROS and GSK3β. Moreover, MRBE-induced cyclin D1 down-regulation was mediated from cyclin D1 proteasomal degradation, which was dependent on ROS. Conclusions These findings suggest that mulberry root bark exerts anti-inflammatory and anti-cancer activity.
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