Mutations in Fbx4 Inhibit Dimerization of the SCFFbx4 Ligase and Contribute to Cyclin D1 Overexpression in Human Cancer

Barbash, Olena; Zamfirova, Petia; Lin, Douglas I.; Chen, Xiangmei; Ke, Yang; Nakagawa, Hiroshi; Lu, Fengmin; Rustgi, Anil K.; Diehl, J. Alan

doi:10.1016/j.ccr.2008.05.017

Cited by 134 publications

(190 citation statements)

References 36 publications

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“…29 Remarkably, ASPP2 (D3/D3) MEFs had a prominent, fourfold higher number of nuclear cyclin D1-expressing cells in response to H-RasV12 induction compared with ASPP2 ( þ / þ ) MEFs (Figure 2e). In contrast, no difference was observed in the nuclear localization of p21 waf1/cip1 between ASPP2 ( þ / þ ) and ASPP2 (D3/D3) MEFs (Supplementary Figure 1).…”

Section: Resultsmentioning

confidence: 96%

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

et al. 2010

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Oncogene-induced senescence represents a key tumor suppressive mechanism. Here, we show that Ras oncogene-induced senescence can be mediated by the recently identified haploinsufficient tumor suppressor apoptosis-stimulating protein of p53 (ASPP) 2 through a novel and p53/p19 Arf /p21 waf1/cip1 -independent pathway. ASPP2 suppresses Ras-induced small ubiquitin-like modifier (SUMO)-modified nuclear cyclin D1 and inhibits retinoblastoma protein (Rb) phosphorylation. The lysine residue, K33, of cyclin D1 is a key site for this newly identified regulation. In agreement with the fact that its nuclear localization is required for its oncogenic activity, we show that nuclear cyclin D1 is far more potent than wild-type (WT) cyclin D1 in bypassing Ras-induced senescence. Thus, this study identifies SUMO modification as a positive regulator of nuclear cyclin D1, and reveals a new way by which cell cycle entry and senescence are regulated. Cell Death and Differentiation (2011) 18, 304-314; doi:10.1038/cdd.2010; published online 27 August 2010Cellular senescence is an irreversible cell cycle arrest and one of the major cellular processes that suppress tumor growth. Cyclin-dependent kinases (CDKs) are among the main regulators of cellular senescence, predominantly achieved through their phosphorylation of the retinoblastoma protein (Rb), preventing it from binding and inhibiting the E2F family of transcription factors that are involved in cell cycle progression. Deregulation of CDK pathways is common in the development of human cancers. Amplification and overexpression of cyclin D1, a regulatory subunit of CDK4/CDK6, has been observed in around 50% of human breast and esophageal cancers. 1,2 Interestingly, however, elevation of cyclin D1 alone is not sufficient to induce tumor growth in vivo, 3,4 partly owing to the fact that the cyclin D1/CDK4 or cyclin D1/CDK6 complex needs to locate in the nucleus to phosphorylate Rb during S-phase to promote cell proliferation. 5,6 Nuclear export, coupled with ubiquitin-dependent destruction of cyclin D1 in the cytoplasm during S-phase, is one of the best known mechanisms of cyclin D1/CDK4 kinase activity control. Hence, nuclear accumulation of cyclin D1 may be a key mechanism by which cyclin D1 exerts its oncogenic effects. In agreement with this, overexpression of mutant cyclin D1 (D1T286A), defective in phosphorylation-mediated nuclear export and subsequent proteolysis, induces cell transformation in vitro and triggers B-cell lymphoma in vivo. 6,7 Furthermore, transgenic mice overexpressing the same mutant, driven by mouse mammary tumor virus (MMTV) promoter (MMTV-D1T286A), developed mammary adenocarcinoma with a shorter latency relative to mice overexpressing wild-type (WT) cyclin D1 (MMTV-D1). 8 These observations support the notion that the subcellular localization of cyclin D1 is critical in controlling its tumorigenicity. Identifying the molecular mechanisms that regulate the nuclear localization of cyclin D1 is, therefore, vital for our better understanding of tumor development....

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Section: Resultsmentioning

confidence: 96%

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

et al. 2010

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“…For example, covalent modification of substrate proteins can regulate their interaction with E3 ligases so that they are appropriately targeted for ubiquitylation (8). In other cases, dimerization promotes the activity of RING E3 ligases (9,10). However, it is unclear how dimerization of the RING domain increases activity because even when the non-E3 ligase RING domains from Bard1, mouse double minute X (MDMX), and Bmi1 form heterodimers with their active partners they promote E3 ligase activity (10 -13).…”

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confidence: 99%

Smac Mimetics Activate the E3 Ligase Activity of cIAP1 Protein by Promoting RING Domain Dimerization

Feltham

Bettjeman

Budhidarmo

et al. 2011

Journal of Biological Chemistry

145

152

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The inhibitor of apoptosis (IAP) proteins are important ubiquitin E3 ligases that regulate cell survival and oncogenesis. The cIAP1 and cIAP2 paralogs bear three N-terminal baculoviral IAP repeat (BIR) domains and a C-terminal E3 ligase RING domain. IAP antagonist compounds, also known as Smac mimetics, bind the BIR domains of IAPs and trigger rapid RING-dependent autoubiquitylation, but the mechanism is unknown. We show that RING dimerization is essential for the E3 ligase activity of cIAP1 and cIAP2 because monomeric RING mutants could not interact with the ubiquitin-charged E2 enzyme and were resistant to Smac mimetic-induced autoubiquitylation. Unexpectedly, the BIR domains inhibited cIAP1 RING dimerization, and cIAP1 existed predominantly as an inactive monomer. However, addition of either mono-or bivalent Smac mimetics relieved this inhibition, thereby allowing dimer formation and promoting E3 ligase activation. In contrast, the cIAP2 dimer was more stable, had higher intrinsic E3 ligase activity, and was not highly activated by Smac mimetics. These results explain how Smac mimetics promote rapid destruction of cIAP1 and suggest mechanisms for activating cIAP1 in other pathways.The attachment of ubiquitin and ubiquitin-like molecules to intracellular proteins is a key process that regulates many cellular events (1). A hierarchical multienzyme cascade brings about the attachment of ubiquitin to substrate proteins. Ubiquitin is first activated by the ubiquitin-activating enzyme (E1) and then is transferred to the active site cysteine of the ubiquitin-conjugating enzyme (E2). Subsequently, ubiquitin-protein ligases (E3s) promote the transfer of ubiquitin from the E2 to lysine residues in target proteins. The RING 4 domain-containing E3 ligases, which are prevalent in mammals (Ͼ300), do not directly interact with ubiquitin; instead, the RING domain binds to the E2 and promotes the transfer of ubiquitin from the E2ϳubiquitin (E2ϳUb) thioester conjugate to the target protein (2). The mechanism by which the RING domain promotes ubiquitin transfer is not obvious because the RING-binding site on the E2 is distant from the active site. It has been proposed that the RING domain simply brings the E2ϳUb conjugate into close proximity with the substrate and that the increased availability of E2s promotes transfer of ubiquitin to the substrate. However, interactions between RING domains and E2s are generally transient and have modest affinity, and tighter binding does not always correlate with increased activity. In addition, not all RING-E2 complexes promote transfer, demonstrating that proximity alone is insufficient (3). Notably, the RING domains of Brca1 and c-Cbl interact with UbcH7 and UbcH5b, but only interaction with UbcH5b results in ubiquitin transfer (3, 4). Others have suggested that an allosteric mechanism is important whereby interaction of the RING domain with the E2 leads to changes at its active site that promote release of ubiquitin (5, 6). Consistent with this, binding of the G2BR domain of the E3 gp78...

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“…Deregulations of cyclin D1 proteolysis can lead to aberrant accumulation of cyclin D1 independent of alterations in CCND1 gene expression and translation. Indeed, mutations that directly disrupt on the phosphorylation of Thr286 (25,26) or inactivate SCF Fbx4-aB-crystallin ligase have been identified in esophageal cancer and endometrial cancer (9,27). In addition to these mutations, an alternative splice variant of cyclin D1, cyclin D1b, was identified in human cancer-derived cell lines.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus X Protein Stabilizes Cyclin D1 and Increases Cyclin D1 Nuclear Accumulation through ERK-Mediated Inactivation of GSK-3β

Chen

Zhang

Zheng

et al. 2015

Cancer Prevention Research

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The Hepatitis B virus X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). It has been suggested that the transcriptional activation of cyclin D1 by HBx is implicated in the development of HCC. However, numerous studies have shown that overexpression of cyclin D1 alone is not sufficient to drive oncogenic transformation. Herein, we investigated whether HBx can stabilize cyclin D1 and induce cyclin D1 protein nuclear accumulation, and thereby accelerate hepatocarcinogenesis. The effects of HBx on cyclin D1 stabilization were assessed in cell-based transfection, Western blot, immunoprecipitation, immunocytofluorescence staining, and flow-cytometric assays. The results demonstrated that ectopic expression of HBx in HCC cells could extend the half-life of cyclin D1 protein from 40-60 minutes to 80-110 minutes. HBx stabilized cyclin D1 primarily in the S phase of the cell cycle, in a manner dependent on the inactivation of GSK-3b, which was mediated by ERK activation. HBx also prompted the nuclear accumulation of cyclin D1, and cotransfection of the constitutively active mutant of GSK-3b along with HBx could reverse the nuclear accumulation and subsequent cell proliferation induced by HBx. Further, a positive correlation between HBx and nuclear cyclin D1 level was established in HCC specimens detected by an immunohistochemical assay. Taken together, our results indicated that HBx could stabilize and increase cyclin D1 nuclear accumulation through ERK-mediated inactivation of GSK-3b. This HBx-induced cyclin D1 upregulation might play an important role in HCC development and progression. Cancer Prev Res; 8(5); 455-63. Ó2015 AACR.

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Mutations in Fbx4 Inhibit Dimerization of the SCFFbx4 Ligase and Contribute to Cyclin D1 Overexpression in Human Cancer

Cited by 134 publications

References 36 publications

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

Smac Mimetics Activate the E3 Ligase Activity of cIAP1 Protein by Promoting RING Domain Dimerization

Hepatitis B Virus X Protein Stabilizes Cyclin D1 and Increases Cyclin D1 Nuclear Accumulation through ERK-Mediated Inactivation of GSK-3β

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