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Description | 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). |
Expression | Ubiquitously expressed in human and mouse tissues and cell lines. |
Localisation | Both cytoplasm and nucleus. |
Function | 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). |
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