Drosophila Roc1a Encodes a RING-H2 Protein with a Unique Function in Processing the Hh Signal Transducer Ci by the SCF E3 Ubiquitin Ligase

Noureddine, Maher; Donaldson, Timothy D.; Thacker, Stephen A.; Duronio, Robert J.

doi:10.1016/s1534-5807(02)00164-8

Cited by 60 publications

(89 citation statements)

References 79 publications

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“…3I), and Gli2 (Fig. 3J), a mouse ortholog of Drosophila Cubitus interruptus (Ci) protein, which accumulates on deletion of Rbx1a in Drosophila (22). Thus, it appears that at the early stage of embryogenesis, Rbx1 disrupted embryos fail to degrade p27, a cyclin dependent kinase inhibitor that blocks G1 to S phase progression (23).…”

Section: Remarkable Reduction Of Cell Proliferation In E65 Rbx1 Gt/gmentioning

confidence: 99%

“…In Caenorhabditis elegans, siRNA knockdown of RBX1 causes pronounced defects in the first meiotic division, in mitotic chromosomal condensation, and in germ cell proliferation, indicating its role in chromosome metabolism and cell cycle control (32). In Drosophila, disruption of ROC1a, the homologue of RBX1, causes the lethality due to a proliferation failure as a result of accumulation of Ci (a Drosophila ortholog of mouse Gli2), a transcription factor that regulates Hedgehog signaling (22). This observation is strikingly different from the disruption of Rbx1 in mouse; no Gli accumulation was found (Fig.…”

Section: Primary Mef Cells (C) or Es Cells (D)mentioning

confidence: 99%

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RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27

Tan

Davis

Saunders

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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RBX1 (RING box protein-1) or ROC1 (regulator of cullins-1) is the RING component of SCF (Skp1, Cullins, F-box proteins) E3 ubiquitin ligases, which regulate diverse cellular processes by targeting various substrates for degradation. However, the in vivo physiological function of RBX1 remains uncharacterized. Here, we show that a gene trap disruption of mouse Rbx1 causes embryonic lethality at embryonic day (E)7.5, mainly due to a failure in proliferation; p27, a cyclin dependent kinase inhibitor, normally undetectable in the early embryos, accumulates at high levels in the absence of Rbx1. Although mice heterozygous for the Rbx1 gene trap appear viable and fertile without obvious abnormalities, the Rbx1 ؉/Gt MEFs do show retarded growth with G1 arrest and p27 accumulation. Simultaneous loss of p27 extended the life span of Rbx1 Gt/Gt embryos from E6.5 to E9.5, indicating that p27-mediated cell cycle inhibition contributes to the early embryonic lethality in the Rbx1-deficient embryos. Our study demonstrates that the in vivo physiological function of RBX1 is to ensure cell proliferation by preventing p27 accumulation during the early stage of embryonic development.SCF E3 ubiquitin ligase ͉ protein degradation ͉ growth suppression

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Section: Remarkable Reduction Of Cell Proliferation In E65 Rbx1 Gt/gmentioning

confidence: 99%

Section: Primary Mef Cells (C) or Es Cells (D)mentioning

confidence: 99%

RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27

Tan

Davis

Saunders

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Mosaic analysis reveals accumulation of full-length Ci, decrease of Ci 75 , and up-regulation of the TGF-β homologue, decapentaplegic (dpp), in clones of cells lacking Slimb, GSK3β or CK1δ [57,59,61]. Genetic evidence also reveals the ring finger protein Roc1α as a putative component in Ci processing [62]. Roc1α is a member of the SCF E3 complex, which facilitates substrate recognition for the proteolytic machinery (reviewed in [63]).…”

Section: Cubitus Interruptusmentioning

confidence: 99%

“…Roc1α is a member of the SCF E3 complex, which facilitates substrate recognition for the proteolytic machinery (reviewed in [63]). Disruption of Roc1α function results in accumulation of full-length Ci and activation of dpp [62].…”

Section: Cubitus Interruptusmentioning

confidence: 99%

Regulation of Hedgehog signaling: a complex story

Ogden

Ascano

Stegman

et al. 2004

Biochemical Pharmacology

102

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The Hedgehog (Hh) signal transduction pathway plays critical instructional roles during development. Activating mutations in human Hh signaling components predispose to a variety of tumor types, and have been observed in sporadic tumors occurring in a wide range of organs. Multiple insights into the regulation of Hh signaling have been achieved through studies using Drosophila melanogaster as a model organism. In Drosophila, regulation of the transcription factor

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“…In Caenorhabditis elegans, RBX-1 is crucial for cell cycle progression and chromosome metabolism, and RBX-1 silencing results in embryonic death (14,15). In Drosophila, Roc1a, the Drosophila homolog of RBX1, is required for cell proliferation and embryonic development, and deletion of Roc1a results in animal death (16). Recently, we reported that mouse Rbx1 disruption causes early embryonic lethality due to significant accumulation of p27 to suppress proliferation, which can be partially rescued by a simultaneous deletion of p27 (17).…”

mentioning

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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Drosophila Roc1a Encodes a RING-H2 Protein with a Unique Function in Processing the Hh Signal Transducer Ci by the SCF E3 Ubiquitin Ligase

Cited by 60 publications

References 79 publications

RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27

RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27

Regulation of Hedgehog signaling: a complex story

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

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