RBX1 (ring-box 1)

2008-07-01   Lijun Jia , Yi Sun 

Division of Cancer Biology, Dept. of Radiation Oncology, University of Michigan, 4424B Medical Science I, 1301 Catherine Street, Ann Arbor, MI 48109-5637, USA




Atlas Image


RBX1 gene is evolutionarily conserved from plants to mammals with multiple family members in each species (Sun Y et al., 2001; Kamura T et al., 1999; Ohta T et al., 1999). Both Homo sapiens and Mus musculus genes are composed of five exons and four introns.


About 0.5 kb mRNA; regulated in mouse embryonic development with the strongest expression at 7 day-old followed by progressively decrease; ubiquitously distributed in adult mouse tissue and prevalent in the genital tract (ovary, testis, prostate and uterus) (Perin JP et al., 1999). RBX1 is also ubiquitously expressed in human tissues with the highest expression in heart, muscle, kidney and placenta (Swaroop M et al., 2001).


Atlas Image


The RBX1 family of proteins from different organisms have 108-121 amino acids with molecular weight about 12-16 kDa (Sun Y et al., 2001; Kamura T et al., 1999; Ohta T et al., 1999; Tan P et al., 1999). Human RBX1 contains a RING-H2 finger domain (Cys42 -X2- Cys45-X29- Cys75-X1- His77 -X2 - His80 -X2 - Cys83 -X10 - Cys94 -X2 - Asp97, see drawing above), which is required for zinc ion binding and ubiquitin ligation (Sun Y et al., 2001; Kamura T et al., 1999; Ohta T et al., 1999; Tan P et al., 1999; Chen A et al., 2000).


Ubiquitously expressed in human and mouse tissues and cell lines.


Both cytoplasm and nucleus.


RBX1, as an essential subunit of SCF, (Skp-1, cullins, F-box proteins) and VHL (von Hippel-Lindau) E3 ubiquitin ligases, interacts with different cullins and E2 ubiquitin-conjugating enzymes to catalyze ubiquitin polymerization of diverse substrates for proteasome-dependent degradation in numerous organisms (Kamura T et al., 1999; Nakayama KI et al., 2006; Petroski MD et al., 2005). Crystal structure study showed that RBX1, on one hand, complexes with cullin-F-box proteins which recognize a variety of protein substrates, and on the other hand, binds to E2 and transfers ubiquitin from E2 to substrates for proteasome-targeted degradation (Zheng N et al.,2002).
1) Binding with cullin family members for targeted protein degradation.
(A) Complexing with cullin1 in F-box protein/ SKP1/ Cullin 1/ RBX1, which is responsible for the degradation of a variety of substrates, including cell cycle regulators (e.g. cell cycle inhibitor p21/ p27/ p57 and cyclin A/ D/ E) , transcription factors (e.g. E2F1, FOXO1, Myc and c-Jun), signal transducers (e.g. Notch1/ 4 and BETA-catenin) and others (Nakayama KI et al., 2006; Petroski MD et al., 2005).
(B) Complexing with cullin 2 in VHL/ elongin BC/ Cullin 2/ RBX1, which is responsible for degradation of hypoxia-inducible factor-a (HIF-a) (Maxwell PH et al.,1999).
(C) Complexing with cullin 3 in BTB-domain protein/ Cullin 3/ RBX1, which is responsible for degradation of microtubule-severing protein MEI-1, Dishevelled (Dsh) and antioxidative transcription factor Nrf2 (Furukawa M et al., 2003; Furukawa M et al., 2005; Pintard L et al., 2003; Angers S et al., 2006).
(D) Complexing with cullin 4A in DDB1/ Cullin 4A/ RBX1, which is responsible for degradation of p53, TSC2, CDT1 and Merlin (Nag A et al., 2004; Banks D et al., 2006; Hu J et al., 2004; Hu J et al., 2008; Huang J et al., 2008).
(E) Complexing with cullin 5 in SOCS/ BC-box protein/ elongin BC/ Cullin 5/ RBX1, which is responsible for degradation of Disabled-1 (Dab1) (Feng L et al., 200721).
(F) Complexing with cullin 7 in Fbw8/ SKP1/ Cullin 7/ RBX1, which is responsible for degradation of insulin receptor substrate 1 ( IRS-1 ) (Xu X et al., 2008)
2) RBX1 activates Rub1 (also known as NEDD8) modification of cullin-1 and cullin-2 by E1 Rub1-activating enzyme Uba3/Ula1, and E2 Rub1-conjugating enzyme Ubc12, which is crucial for the activation of SCF ubiquitin ligase (Kamura T et al., 1999; Yamaguchi Y et al.,2007).
3) In yeast, RBX1 is a subunit of the Cdc53-containing SCF ubiquitin ligase required for ubiquitination of the cyclin-dependent kinase inhibitor Sic1 for the G1 to S cell cycle transition (Seol JH et al., 1999). RBX1 deletion causes yeast death, which can be rescued by human RBX1 and RBX2 (Ohta T et al., 1999; Swaroop M et al., 2000). Mutation of predicted zinc-binding residues in the conserved RING domain of RBX1 is lethal in S.cerevisiae and interferes with RBX1 activity in Rub1 conjugation and in ubiquitination of Cln2 (Ohta T et al., 1999; Kamura T et al., 1999; Swaroop M et al., 2000).
4) In Caenorhabditis elegans, RBX1 is essential for cell cycle progression and chromosome metabolism. Depletion of RBX1 by RNA-mediated interference (RNAi) causes pronounced defects in meiosis, mitotic chromosomal condensation and segregation, and cytokinesis (Sasagawa Y et al., 2005; Sasagawa Y et al., 2003).
5) In Drosophila, RBX1a is required for cell proliferation and embryo development. Deletion of RBX1a results in animal death, which cannot be rescued by overexpression of RBX1b, indicating a non-redundant function between the family members (Noureddine MA et al., 2003).
6) In mammalian cells, RBX1 is essential for normal cell cycle progression. Depletion of RBX1 by RNAi inhibits the proliferation of both normal and cancerous cells (Schlabach MR et al., 2008).
Atlas Image



Not known


Not known

Implicated in

Entity name
Various cancers
RBX1 is ubiquitously expressed in many human cancer cells (Swaroop M et al., 2001; Schlabach MR et al., 2008).
Not known
Not known


Pubmed IDLast YearTitleAuthors
165475212006The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation.Angers S et al
168618902006L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes.Banks D et al
107480832000The conserved RING-H2 finger of ROC1 is required for ubiquitin ligation.Chen A et al
179749152007Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development.Feng L et al
156018392005BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.Furukawa M et al
154486972004Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage.Hu J et al
183818902008WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase.Hu J et al
183328682008VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation.Huang J et al
105799991999The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2.Kamura T et al
102136911999Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase.Kamura T et al
103532511999The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.Maxwell PH et al
155486782004Cul4A physically associates with MDM2 and participates in the proteolysis of p53.Nag A et al
166333652006Ubiquitin ligases: cell-cycle control and cancer.Nakayama KI et al
120620882002Drosophila Roc1a encodes a RING-H2 protein with a unique function in processing the Hh signal transducer Ci by the SCF E3 ubiquitin ligase.Noureddine MA et al
102304071999ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity.Ohta T et al
106439621999Genomic organization and expression of the ubiquitin-proteasome complex-associated protein Rbx1/ROC1/Hrt1.Périn J-P et al
156880632005Function and regulation of cullin-RING ubiquitin ligases.Petroski MD et al
136799212003The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase.Pintard L et al
172061472007Direct interactions between NEDD8 and ubiquitin E2 conjugating enzymes upregulate cullin-based E3 ligase activity.Sakata E et al
159735012005Caenorhabditis elegans Elongin BC complex is essential for cell proliferation and chromosome condensation and segregation during mitosis and meiotic division II.Sasagawa Y et al
182391262008Cancer proliferation gene discovery through functional genomics.Schlabach MR et al
103856291999Cdc53/cullin and the essential Hrt1 RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34.Seol JH et al
115544502001SAG/ROC/Rbx/Hrt, a zinc RING finger gene family: molecular cloning, biochemical properties, and biological functions.Sun Y et al
115067062001SAG/ROC2/Rbx2/Hrt2, a component of SCF E3 ubiquitin ligase: genomic structure, a splicing variant, and two family pseudogenes.Swaroop M et al
108510892000Yeast homolog of human SAG/ROC2/Rbx2/Hrt2 is essential for cell growth, but not for germination: chip profiling implicates its role in cell cycle regulation.Swaroop M et al
102304061999Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha.Tan P et al
184987452008The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation.Xu X et al
119615462002Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex.Zheng N et al

Other Information

Locus ID:

NCBI: 9978
MIM: 603814
HGNC: 9928
Ensembl: ENSG00000100387


dbSNP: 9978
ClinVar: 9978
TCGA: ENSG00000100387


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Nucleotide excision repairKEGGko03420
Cell cycleKEGGko04110
Ubiquitin mediated proteolysisKEGGko04120
Wnt signaling pathwayKEGGko04310
TGF-beta signaling pathwayKEGGko04350
Circadian rhythmKEGGko04710
Renal cell carcinomaKEGGko05211
Nucleotide excision repairKEGGhsa03420
Cell cycleKEGGhsa04110
Ubiquitin mediated proteolysisKEGGhsa04120
Wnt signaling pathwayKEGGhsa04310
TGF-beta signaling pathwayKEGGhsa04350
Circadian rhythmKEGGhsa04710
Pathways in cancerKEGGhsa05200
Renal cell carcinomaKEGGhsa05211
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114
Protein processing in endoplasmic reticulumKEGGko04141
Protein processing in endoplasmic reticulumKEGGhsa04141
SCF-BTRC complexKEGGhsa_M00380
SCF-SKP2 complexKEGGhsa_M00381
SCF-FBS complexKEGGhsa_M00382
ECV complexKEGGhsa_M00383
Cul3-SPOP complexKEGGhsa_M00384
Cul4-DDB1-DDB2 complexKEGGhsa_M00385
Cul4-DDB1-CSA complexKEGGhsa_M00386
SCF-FBW7 complexKEGGhsa_M00387
SCF-FBS complexKEGGM00382
HIF-1 signaling pathwayKEGGhsa04066
SCF-BTRC complexKEGGM00380
SCF-SKP2 complexKEGGM00381
ECV complexKEGGM00383
Cul3-SPOP complexKEGGM00384
Cul4-DDB1-DDB2 complexKEGGM00385
Cul4-DDB1-CSA complexKEGGM00386
SCF-FBW7 complexKEGGM00387
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by NOTCH1 in CancerREACTOMER-HSA-2644603
Signaling by NOTCH1 PEST Domain Mutants in CancerREACTOMER-HSA-2644602
Constitutive Signaling by NOTCH1 PEST Domain MutantsREACTOMER-HSA-2644606
Signaling by NOTCH1 HD+PEST Domain Mutants in CancerREACTOMER-HSA-2894858
Constitutive Signaling by NOTCH1 HD+PEST Domain MutantsREACTOMER-HSA-2894862
FBXW7 Mutants and NOTCH1 in CancerREACTOMER-HSA-2644605
Loss of Function of FBXW7 in Cancer and NOTCH1 SignalingREACTOMER-HSA-2644607
Infectious diseaseREACTOMER-HSA-5663205
HIV InfectionREACTOMER-HSA-162906
Host Interactions of HIV factorsREACTOMER-HSA-162909
Vif-mediated degradation of APOBEC3GREACTOMER-HSA-180585
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Class I MHC mediated antigen processing & presentationREACTOMER-HSA-983169
Antigen processing: Ubiquitination & Proteasome degradationREACTOMER-HSA-983168
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Regulation of RAS by GAPsREACTOMER-HSA-5658442
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Prolactin receptor signalingREACTOMER-HSA-1170546
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by NOTCHREACTOMER-HSA-157118
Signaling by NOTCH1REACTOMER-HSA-1980143
NOTCH1 Intracellular Domain Regulates TranscriptionREACTOMER-HSA-2122947
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by WntREACTOMER-HSA-195721
Degradation of beta-catenin by the destruction complexREACTOMER-HSA-195253
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Degradation of DVLREACTOMER-HSA-4641258
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Signaling by HedgehogREACTOMER-HSA-5358351
Hedgehog 'off' stateREACTOMER-HSA-5610787
GLI3 is processed to GLI3R by the proteasomeREACTOMER-HSA-5610785
Degradation of GLI2 by the proteasomeREACTOMER-HSA-5610783
Degradation of GLI1 by the proteasomeREACTOMER-HSA-5610780
Hedgehog 'on' stateREACTOMER-HSA-5632684
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G2-G2/M phasesREACTOMER-HSA-453274
G2/M TransitionREACTOMER-HSA-69275
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
DNA Damage BypassREACTOMER-HSA-73893
Recognition of DNA damage by PCNA-containing replication complexREACTOMER-HSA-110314
Cellular responses to stressREACTOMER-HSA-2262752
Cellular response to hypoxiaREACTOMER-HSA-2262749
Regulation of Hypoxia-inducible Factor (HIF) by oxygenREACTOMER-HSA-1234174
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor AlphaREACTOMER-HSA-1234176
Nucleotide Excision RepairREACTOMER-HSA-5696398
Global Genome Nucleotide Excision Repair (GG-NER)REACTOMER-HSA-5696399
DNA Damage Recognition in GG-NERREACTOMER-HSA-5696394
Formation of Incision Complex in GG-NERREACTOMER-HSA-5696395
Dual Incision in GG-NERREACTOMER-HSA-5696400
Transcription-Coupled Nucleotide Excision Repair (TC-NER)REACTOMER-HSA-6781827
Formation of TC-NER Pre-Incision ComplexREACTOMER-HSA-6781823
Dual incision in TC-NERREACTOMER-HSA-6782135
Gap-filling DNA repair synthesis and ligation in TC-NERREACTOMER-HSA-6782210
RET signalingREACTOMER-HSA-8853659
FBXL7 down-regulates AURKA during mitotic entry and in early mitosisREACTOMER-HSA-8854050


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociatedPD


Pubmed IDYearTitleCitations
145640142003Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex.579
119615462002Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex.546
156018392005BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase.248
166781102006Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage.196
147394642004Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase.139
183818902008WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase.73
195570012009REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 ubiquitin ligase.62
187236772008Autoinhibitory regulation of SCF-mediated ubiquitination by human cullin 1's C-terminal tail.59
195092292009ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence.56
172176222006SAG/ROC-SCF beta-TrCP E3 ubiquitin ligase promotes pro-caspase-3 degradation as a mechanism of apoptosis protection.48


Lijun Jia ; Yi Sun

RBX1 (ring-box 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-07-01

Online version: http://atlasgeneticsoncology.org/gene/42075/rbx1-(ring-box-1)