SnapShot: F Box Proteins II

Skaar, Jeffrey R.; Pagan, Julia K.; Pagano, Michele

doi:10.1016/j.cell.2009.05.040

Cited by 116 publications

(118 citation statements)

References 14 publications

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“…Fbxl17 belongs to a family of E3 ubiquitin ligases containing a leucine‐rich repeat and an F‐box motif, which mediate binding to Skp1 (S‐phase kinase‐associated protein 1) (Skaar et al , 2009). Skp1 in turn recruits Cul1 (Cullin 1) and Rbx1 (RING‐box protein 1) for the formation of an SCF (Skp1‐Cul1‐F‐box protein) complex.…”

Section: Introductionmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

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Section: Introductionmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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“…Because many oncoproteins (such as c-MYC, c-JUN, cyclin D, and H-RAS) are known substrates of RBX1-SCF E3 ligases (2,32) and may accumulate upon RBX1 silencing to trigger DDR, we measured the level of these oncoproteins in U87 cells. We found none of them to be accumulated in response to RBX1 siRNA (Fig.…”

Section: Rbx1 Silencing Activates G 2 Checkpoint Controls Induces Anmentioning

confidence: 99%

RBX1 (RING Box Protein 1) E3 Ubiquitin Ligase Is Required for Genomic Integrity by Modulating DNA Replication Licensing Proteins

Jia

Bickel

et al. 2011

Journal of Biological Chemistry

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RBX1 (RING box protein 1), also known as ROC1 (Regulator of Cullin 1), is an essential component of SCF (Skp1/Cullins/Fbox) E3 ubiquitin ligases, which target diverse proteins for proteasome-mediated degradation. Our recent study showed that RBX1 silencing triggered a DNA damage response (DDR) leading to G 2 -M arrest, senescence, and apoptosis, with the mechanism remaining elusive. Here, we show that, in human cancer cells, RBX1 silencing causes the accumulation of DNA replication licensing proteins CDT1 and ORC1, leading to DNA double-strand breaks, DDR, G 2 arrest, and, eventually, aneuploidy. Whereas CHK1 activation by RBX1 silencing is responsible for the G 2 arrest, enhanced DNA damage renders cancer cells more sensitive to radiation. In Caenorhabditis elegans, RBX-1 silencing causes CDT-1 accumulation, triggering DDR in intestinal cells, which is largely abrogated by simultaneous CDT-1 silencing. RBX-1 silencing also induces lethality during development of embryos and in adulthood. Thus, RBX1 E3 ligase is essential for the maintenance of mammalian genome integrity and the proper development and viability in C. elegans. SCF (Skp1/Cullins/F-box; also known as CRL (Cullin-RING Ligase) E3 ubiquitin ligases are the largest multiunit E3 ligases that promote the degradation of numerous short-lived cellular proteins, including cell cycle regulators, transcription factors, signal transducers, and oncogene/tumor suppressors (1, 2). A recent global protein stability profiling analysis identified ϳ350 potential SCF substrates, the majority of which were previously unidentified (3). Most recently, a study of SCF inactivation by a small molecule inhibitor of cullin neddylation suggested that up to 20% of ubiquitinated cellular proteins are mediated by SCF E3 for proteasome degradation (4). Thus, SCF E3 ubiquitin ligases regulate many aspects of cellular functions and biological processes under physiological conditions. Dysfunction of SCF is involved in the pathogenesis of a variety of diseases, including cancer (2, 5).The core of SCF ubiquitin ligases is a complex of RBX1-cullins (6). RBX1 consists of 108 amino acids with a C-terminal RING-H2 finger domain required for zinc ion binding and ligase activity (7-9). Crystal structure studies revealed that RBX1 complexes with cullin/F-box proteins form functional SCF E3 ligases that transfer ubiquitin from E2 to specific substrates for proteasome-targeted degradation (10). Previous studies have shown that RBX1 interacts with all seven cullin family members to activate E3 ubiquitin ligases and regulate numerous biological processes by promoting timely degradation of cellular substrates (9, 11).As an essential component of SCF E3 ligase, RBX1 plays a critical role in development. In yeast, deletion of Hrt1, the yeast homolog of RBX1, causes lethality, which can be rescued by human RBX1 or RBX2/SAG (Sensitive to Apoptosis gene) (9,12,13). In Caenorhabditis elegans, RBX-1 is crucial for cell cycle progression and chromosome metabolism, and RBX-1 silencing results in embryonic d...

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“…5,6 Thus, targeting a specific E3 ligase associated with a particular cancer could reduce the likelihood of off-target toxicity.…”

Section: By Tim Fulmer Senior Writermentioning

confidence: 99%

Inhibiting E3 ligases

Fulmer¹

2010

Science-Business eXchange

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SnapShot: F Box Proteins II

Cited by 116 publications

References 14 publications

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

RBX1 (RING Box Protein 1) E3 Ubiquitin Ligase Is Required for Genomic Integrity by Modulating DNA Replication Licensing Proteins

Inhibiting E3 ligases

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