Open Access

RBX1/ROC1-SCF E3 ubiquitin ligase is required for mouse embryogenesis and cancer cell survival

Cell Division20094:16

DOI: 10.1186/1747-1028-4-16

Received: 24 July 2009

Accepted: 06 August 2009

Published: 06 August 2009

Abstract

RBX1 (also known as ROC1) is a RING subunit of SCF (S kp1, C ullins, F-box proteins) E3 ubiquitin ligases, required for SCF to direct a timely degradation of diverse substrates, thereby regulating numerous cellular processes under both physiological and pathological conditions. Previous studies have shown that RBX1 is essential for growth in yeast, Caenorhabditis elegans and Drosophila. The role of RBX1 in mouse development and in regulation of cancer cell survival was unknown. Our recent work demonstrated that RBX1 is an essential gene for mouse embryogenesis, and targeted disruption of RBX1 causes embryonic lethality at E7.5 due to hypoproliferation as a result of p27 accumulation. We also showed that RBX1 is overexpressed in a number of human cancers, and siRNA silencing of RBX1 caused cancer cell death as a result of sequential induction of G2-M arrest, senescence and apoptosis. These findings reveal a physiological role of RBX1 during mouse development and a pathological role for the survival of human cancer cells. Differential outcomes between normal (growth arrest) and cancer cells (cell death) upon RBX1 disruption/silencing suggest RBX1 as a valid anticancer target.

Comments on:

Tan M, Davis SW, Saunders TL, Zhu Y, Sun Y. RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27. Proc Natl Acad Sci USA. 2009; 106:6203–6208

Jia L, Soengas MS, Sun Y. ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence. Cancer Res. 2009; 69:4974–82

Introduction

SCF (S kp1, C ullins, F-box proteins) E3 ubiquitin ligases, consist of S kp1, C ullins, F-box proteins, and the RING domain containing protein RBX1/ROC1 or its family member RBX2/ROC2/SAG. By promoting degradation of many short-lived proteins, including cell cycle regulators, transcription factors and signal transducers, RBX1-SCF E3 ligases regulate many biological processes. As an essential subunit of the SCF E3 ligase complex, RBX1, is evolutionarily conserved from plants to mammals with multiple family members in each species [1]. Human RBX1 gene consists of five exons and four introns and encodes a 108 amino acids-containing protein with a RING-H2 finger domain (C3H2C3) at the C-terminus, which is required for zinc ion binding and ubiquitin ligation. Human RBX1 is ubiquitously expressed in human tissues with the highest expression in heart, skeleton muscle, kidney and placenta [2]. Structurally, RBX1 binds to the C-terminus of cullin-1 via its N-terminus and to an E2 ubiquitin conjugating enzyme via its C-terminal RING domain. RBX1/Cullin-1 complex catalyzes the ubiquitin transfer from E2 to the substrates which are recognized by different F-box proteins, linked to the N-terminus of cullin-1 via an adaptor protein, Skp1 [3] (Fig 1).
Figure 1

Substrate ubiquitination by RBX1-SCF E3 ubiquitin ligase: Cullin-1 at its N-terminus binds to Skp1 and an F-box protein, which recognizes protein substrates, and at its C-terminus binds to RBX1. RBX1, on the other hand, binds to Cullin-1 using its N-terminus and an E2 ubiquitin conjugating enzyme using its C-terminal RING domain. Together, RBX1-cullin-1 catalyzes the ubiquitin transfer from E2 to protein substrates.

RBX1 binds to all seven cullin family members, including cullin-1, -2, -3, -4A, -4B, -5 and -7 [4]. By binding to and interaction with different cullins and cullin-associated proteins, RBX1, as an active RING component of the largest family of E3 ubiquitin ligases, plays an essential role in regulation of diverse biological processes by promoting the degradation of different protein substrates. Table 1 lists some known substrates targeted by different RBX1-cullins complexes. Over 350 potential RING-cullin substrates were recently identified by a global protein stability profiling analysis [5]. Further characterization and validation of these substrates will broaden our understanding of how RBX1-cullin-based E3 ligases regulate cellular processes under physiological and pathological conditions.
Table 1

RBX1-Cullins E3 ubiquitin ligases and their substrates in mammals

Name

Substrates

References

RBX1/Cullin-1/SKP1/F-Box proteins

e.g. p21, p27, p57, Cyclins A/D/E, E2F1, Cdc25A/B, PDCC4, FOXO1, Myc, p53, c-Jun, Notch 1/4, IκB, β-Catenin, Orc1, and many more. For near complete list, see cited references

[14, 25, 26]

RBX1/Cullin-2/Elongin BC/VHL

e.g. HIF-α, TEL-JAK2

[27, 28]

RBX1/Cullin-3/BTB-domain proteins

e.g. MEI-1, Dishevelled (Dsh), Nrf2, RhoBTB2, topoisomeraseI-DNA complex, and caspase 8

[2936]

RBX1/Cullin-4A/DDB1

e.g. p53, TSC2, Cdt1, c-Jun and Merlin

[3745]

RBX1/Cullin-5/elongin BC/BC-box proteins/SOCS

e.g. Disabled-1 (Dab1)

[46]

RBX1/Cullin-7/SKP1/Fbw8

e.g. Insulin receptor substrate 1 (IRS-1)

[47]

Discussion

RBX1 in development

RBX1-cullin complexes control the proteolysis of numerous substrates related to cell cycle progression, cell growth and cell death, suggesting that RBX1 may play an important role in development. Indeed, RBX1 is an essential gene in a number of species. In yeast, deletion of Hrt1, the yeast homologue of RBX1, via genetic manipulation, causes yeast death, which can be rescued by human RBX1 or RBX2/SAG [68]. In Caenorhabditis elegans, RBX1 is also crucial for cell cycle progression and chromosome metabolism, as evidenced by severe defects in meiosis, mitotic chromosomal condensation and segregation, and cytokinesis upon siRNA knockdown [9]. In Drosophila, ROC1a, the drosophila homologue of RBX1 is required for cell proliferation and embryo development, and deletion of ROC1a results in animal death [10]. In mouse, the level of RBX1 mRNA was regulated during embryonic development with the strongest expression at embryonic day 7 (E7), followed by a progressive decrease [11]. However, the physiological role of RBX1 in mouse development has not been previously characterized.

Most recently, we characterized the in vivo physiological function of RBX1 during mouse development using a conventional knockout study [12]. We found that homozygous disruption of mouse RBX1 via a gene trap strategy causes embryonic lethality at E7.5 as a result of reduced proliferation, but not enhanced apoptosis. Mechanistic studies revealed that RBX1 disruption induces significant accumulation of p27, a cyclin dependent kinase inhibitor, normally not expressed in early embryos. The p27 accumulation was further observed in mouse embryonic fibroblasts (MEF) or mouse embryonic stem cells (ESC) with RBX1 heterozygous background. In RBX1+/- MEF cells, p27 accumulation is associated with growth retardation and G1 arrest. Causal involvement of p27 accumulation in early death of RBX1-deficient embryos was clearly demonstrated by a rescue experiment in which simultaneous loss of p27 extends the life span of RBX1-deficient embryos from E6.5 to E9.5 [12]. 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 (Fig 2A). The fact that p27 loss cannot completely rescue RBX1-deficient embryos indicates that accumulation of other RBX1 substrates upon RBX1 disruption is detrimental to embryonic development beyond E9.5 (Fig 2A). A future challenge will be to define these physiologically relevant substrates to broaden our understanding of the in vivo physiological function of RBX1 in the later stages of mouse embryogenesis.
Figure 2

A working model for RBX1 targeting. (A) In mouse embryos. RBX1 disruption in mouse induces early embryonic lethality due to reduced proliferation as a result of p27 accumulation. Simultaneous deletion of p27 restores cell proliferation and causes a partial rescue of embryonic death by extending the embryo's life from E6.5 to E9.5. It is unclear, at the present time, if abnormal DNA damage response is involved in later stage death of RBX1/p27 double null embryos. (B) In human cancer cells: RBX1 silencing triggers DNA damage response and checkpoint controls via modulating the levels of oncogenes or DNA replication proteins (DRPs), leading to activation of multiple cell killing pathways, including G2-M arrest, senescence and apoptosis.

Functional characterization using various model systems from yeast to mouse clearly demonstrated that RBX1 is an essential gene for growth and development. Interestingly, some similarity and difference exist between the species with more than one family member of RBX1. For example, death phenotype induced by disruption of ROC1a in Drosophila or of RBX1 in mouse in the presence of their family member ROC2 or RBX2 [10, 12, 13] clearly indicated that these two RBX1 family members are not functionally redundant and are likely to target different sets of substrates during embryonic development. On the other hand, the mechanisms responsible for reduced proliferation as a result of ROC1a/RBX1 disruption seem different between Drosophila and mouse. In Drosophila, disruption of ROC1a, causes lethality due to proliferation failure as a result of accumulation of Ci (a Drosophila ortholog of mouse Gli2), a transcription factor that regulates Hedgehog signaling [10]. Whereas in mouse, disruption of RBX1 does not affect the levels of Gli2, but causes p27 accumulation to suppress proliferation [12]. Furthermore, although RBX1-p27 double null embryos at E9.5 are smaller than wild type littermates, no enhanced apoptosis was detected using the TUNEL assay (unpublished data). Thus, during mouse embryogenesis, RBX1 disruption appears not to induce apoptosis. These observations in normal tissues are strikely different from those seen in human cancer cells (see below) in which RBX1 silencing induces significant levels of apoptosis and senescence.

RBX1 in human cancer cell survival

RBX1-SCF E3 ubiquitin ligases regulate numerous cellular processes. It is not surprising that their dysfunction is associated with a variety of diseases including cancer [14]. For example, an oncogenic F-box protein Skp2, which promotes p27 degradation, is overexpressed in a number of human cancers [15], whereas a tumor suppressive F-box protein FBW7, which promotes the degradation of several proto-oncogenes, including c-Jun, c-Myc, cyclin E and mTOR undergoes numerous cancer-associated mutations [16]. To define potential roles of RBX1 in human cancers, we recently measured expression of RBX1 in human primary cancer tissues and in cancer cell lines with different tissue origins. We found that RBX1 is overexpressed in a number of human primary cancer tissues, including carcinoma of lung, liver, breast, colon, and ovary, and in many cancer cell lines [17]. We then determined potential biological consequences of reducing RBX1 levels via siRNA silencing. Significantly, RBX1 knockdown inhibited the growth of several human cancer cell lines by sequential induction of G2-M arrest, senescence and apoptosis. Further characterization revealed that G2-M arrest is associated with accumulation of 14-3-3σ and down-regulation of cyclin B1 and Cdc2, whereas apoptosis is associated with modest accumulation of PUMA and significant reduction of Bcl-2, Mcl-1, and survivin. Interestingly, senescence is p53/p21- and p16/pRB-independent [17]. Recently a shRNA library-based functional genomic screen also identified RBX1 as a growth essential gene in a number of human cancer cell lines, although no characterization was further pursued [18].

Mechanistic studies revealed that RBX1 silencing triggers DNA damage response at the early stage, as demonstrated by induced phosphoralytion of H2AX, Chk1 and Chk2 [17] (and unpublished data), which eventually leads to G2-M arrest, followed by apoptosis and senescence. We hypothesize that either or both sets of RBX1 substrates, which start to accumulate upon RBX1 silencing, are likely involved in the process, leading to phenotypic changes. The first set includes oncogenes (e.g. c-Myc, c-Jun, cyclin E/D), since oncogene activation triggers DNA damage response to induce senescence and apoptosis under certain circumstances [19, 20]. The second set of RBX1-cullin substrates could be DNA replication proteins, such as Orc-1 and Cdt-1, since the accumulation of DNA replication proteins (e.g. Cdt-1) induces DNA rereplication stress and triggers DNA damage [21] (Fig 2B). Our laboratory is currently testing the hypothesis to further elucidate the mechanism(s) by which RBX1 silencing induces cancer cell killing via induction of G2-M arrest, senescence and apoptosis.

It is rather clear that the mechanism responsible for early embryonic lethality upon RBX1 disruption is quite different from that responsible for cancer cell killing upon RBX1 silencing, although it is not a typically paired comparison. Nevertheless, in mouse, RBX1 knockout leads to p27 accumulation, reduced proliferation and prolonged G1 arrest, whereas in human cancer cells, p27 accumulation and G1 arrest were not observed upon RBX1 silencing [17]. Future studies should be directed to determine if the altered DNA damage response commonly seen in cancer cells after RBX1 silencing can also be observed in RBX1-p27 double null embryos and if so, its contribution to the embryonic lethality in the later stages of development (Fig 2, crosstalk between panel A and B).

Conclusion

The findings from our laboratory demonstrated that RBX1 is an essential gene not only for mouse development but also for human cancer cell survival. The fact that RBX1 is overexpressed in a number of human cancers suggests that abnormal regulation of RBX1 is involved either in human carcinogenesis or in the maintenance of the cancer cell phenotype. Differential response to RBX1 disruption/silencing between normal tissues (reduced proliferation, but no induction of apoptosis during mouse embryogenesis) and cancer cells (enhanced cell killing) may provide a reasonable therapeutic window for cancer cell-specific killing via RBX1 targeting. Thus, future development of siRNA-based therapy by RBX1 silencing or small molecule inhibitors against RBX1 E3 ubiquitin ligases may hold great promise for the treatment of human cancer [2224].

Declarations

Acknowledgements

This work is supported by the National Cancer Institute grants CA111554 and CA116982 to YS.

Authors’ Affiliations

(1)
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center

References

  1. Sun Y, Tan M, Duan H, Swaroop M: SAG/ROC/Rbx/Hrt, a zinc RING finger gene family: molecular cloning, biochemical properties, and biological functions. Antioxid Redox Signal 2001, 3: 635–650. 10.1089/15230860152542989View ArticlePubMedGoogle Scholar
  2. Swaroop M, Gosink M, Sun Y: SAG/ROC2/Rbx2/Hrt2, a component of SCF E3 ubiquitin ligase: genomic structure, a splicing variant, and two family pseudogenes. DNA Cell Biol 2001, 20: 425–434. 10.1089/104454901750361488View ArticlePubMedGoogle Scholar
  3. Zheng N, Schulman BA, Song L, et al.: Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 2002, 416: 703–709. 10.1038/416703aView ArticlePubMedGoogle Scholar
  4. Ohta T, Michel JJ, Xiong Y: Association with cullin partners protects ROC proteins from proteasome-dependent degradation. Oncogene 1999, 18: 6758–6766. 10.1038/sj.onc.1203115View ArticlePubMedGoogle Scholar
  5. Yen HC, Elledge SJ: Identification of SCF ubiquitin ligase substrates by global protein stability profiling. Science 2008, 322: 923–929. 10.1126/science.1160462View ArticlePubMedGoogle Scholar
  6. Ohta T, Michel JJ, Schottelius AJ, Xiong Y: ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Mol Cell 1999, 3: 535–541. 10.1016/S1097-2765(00)80482-7View ArticlePubMedGoogle Scholar
  7. Seol JH, Feldman RMR, Zachariae WZ, et al.: Cdc53/cullin and the essential Hrt1 RING-H2 subunit of SCF define a ubiquitin ligase module that activates the E2 enzyme Cdc34. Genes & Dev 1999, 13: 1614–1626. 10.1101/gad.13.12.1614View ArticleGoogle Scholar
  8. Swaroop M, Wang Y, Miller P, et al.: Yeast 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. Oncogene 2000, 19: 2855–2866. 10.1038/sj.onc.1203635View ArticlePubMedGoogle Scholar
  9. Sasagawa Y, Urano T, Kohara Y, Takahashi H, Higashitani A: Caenorhabditis elegans RBX1 is essential for meiosis, mitotic chromosomal condensation and segregation, and cytokinesis. Genes Cells 2003, 8: 857–872. 10.1046/j.1365-2443.2003.00682.xView ArticlePubMedGoogle Scholar
  10. Noureddine MA, Donaldson TD, Thacker SA, Duronio RJ: Drosophila Roc1a encodes a RING-H2 protein with a unique function in processing the Hh signal transducer Ci by the SCF E3 ubiquitin ligase. Dev Cell 2002, 2: 757–770. 10.1016/S1534-5807(02)00164-8View ArticlePubMedGoogle Scholar
  11. Perin JP, Seddiqi N, Charbonnier F, et al.: Genomic organization and expression of the ubiquitin-proteasome complex-associated protein Rbx1/ROC1/Hrt1. Cell Mol Biol 1999, 45: 1131–1137.Google Scholar
  12. Tan M, Davis SW, Saunders TL, Zhu Y, Sun Y: RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27. Proc Natl Acad Sci USA 2009, 106: 6203–6208. 10.1073/pnas.0812425106PubMed CentralView ArticlePubMedGoogle Scholar
  13. Donaldson TD, Noureddine MA, Reynolds PJ, Bradford W, Duronio RJ: Targeted disruption of Drosophila Roc1b reveals functional differences in the Roc subunit of Cullin-dependent E3 ubiquitin ligases. Mol Biol Cell 2004, 15: 4892–4903. 10.1091/mbc.E04-03-0180PubMed CentralView ArticlePubMedGoogle Scholar
  14. Nakayama KI, Nakayama K: Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 2006, 6: 369–381. 10.1038/nrc1881View ArticlePubMedGoogle Scholar
  15. Frescas D, Pagano M: Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 2008, 8: 438–449. 10.1038/nrc2396PubMed CentralView ArticlePubMedGoogle Scholar
  16. Welcker M, Clurman BE: FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer 2008, 8: 83–93. 10.1038/nrc2290View ArticlePubMedGoogle Scholar
  17. Jia L, Soengas MS, Sun Y: ROC1/RBX1 E3 ubiquitin ligase silencing suppresses tumor cell growth via sequential induction of G2-M arrest, apoptosis, and senescence. Cancer Res 2009, 69: 4974–4982. 10.1158/0008-5472.CAN-08-4671PubMed CentralView ArticlePubMedGoogle Scholar
  18. Schlabach MR, Luo J, Solimini NL, et al.: Cancer proliferation gene discovery through functional genomics. Science 2008, 319: 620–624. 10.1126/science.1149200PubMed CentralView ArticlePubMedGoogle Scholar
  19. Schmitt CA: Senescence, apoptosis and therapy – cutting the lifelines of cancer. Nat Rev Cancer 2003, 3: 286–295. 10.1038/nrc1044View ArticlePubMedGoogle Scholar
  20. Wahl GM, Carr AM: The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nat Cell Biol 2001, 3: E277–286. 10.1038/ncb1201-e277View ArticlePubMedGoogle Scholar
  21. Liu E, Lee AY, Chiba T, Olson E, Sun P, Wu X: The ATR-mediated S phase checkpoint prevents rereplication in mammalian cells when licensing control is disrupted. J Cell Biol 2007, 179: 643–657. 10.1083/jcb.200704138PubMed CentralView ArticlePubMedGoogle Scholar
  22. Nalepa G, Rolfe M, Harper JW: Drug discovery in the ubiquitin-proteasome system. Nat Rev Drug Discov 2006, 5: 596–613. 10.1038/nrd2056View ArticlePubMedGoogle Scholar
  23. Sun Y: Targeting E3 ubiquitin ligases for cancer therapy. Cancer Biol Therapy 2003, 2: 623–629.Google Scholar
  24. Sun Y: E3 ubiquitin ligases as cancer targets and biomarkers. Neoplasia 2006, 8: 645–654. 10.1593/neo.06376PubMed CentralView ArticlePubMedGoogle Scholar
  25. Petroski MD, Deshaies RJ: Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 2005, 6: 9–20. 10.1038/nrm1547View ArticlePubMedGoogle Scholar
  26. Skaar JR, D'Angiolella V, Pagan JK, Pagano M: SnapShot: F Box Proteins II. Cell 2009, 137: 1358.View ArticlePubMedGoogle Scholar
  27. Maxwell PH, Wiesener MS, Chang GW, et al.: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999, 399: 271–275. 10.1038/20459View ArticlePubMedGoogle Scholar
  28. Kamizono S, Hanada T, Yasukawa H, et al.: The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2. J Biol Chem 2001, 276: 12530–12538. 10.1074/jbc.M010074200View ArticlePubMedGoogle Scholar
  29. Furukawa M, He YJ, Borchers C, Xiong Y: Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases. Nat Cell Biol 2003, 5: 1001–1007. 10.1038/ncb1056View ArticlePubMedGoogle Scholar
  30. Furukawa M, Xiong Y: BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol 2005, 25: 162–171. 10.1128/MCB.25.1.162-171.2005PubMed CentralView ArticlePubMedGoogle Scholar
  31. Pintard L, Willis JH, Willems A, et al.: The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature 2003, 425: 311–316. 10.1038/nature01959View ArticlePubMedGoogle Scholar
  32. Angers S, Thorpe CJ, Biechele TL, et al.: The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation. Nat Cell Biol 2006, 8: 348–357. 10.1038/ncb1381View ArticlePubMedGoogle Scholar
  33. Niture SK, Jaiswal AK: Prothymosin-alpha mediates nuclear import of the INrf2/Cul3 Rbx1 complex to degrade nuclear Nrf2. J Biol Chem 2009, 284: 13856–13868. 10.1074/jbc.M808084200PubMed CentralView ArticlePubMedGoogle Scholar
  34. Jin Z, Li Y, Pitti R, et al.: Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell 2009, 137: 721–735. 10.1016/j.cell.2009.03.015View ArticlePubMedGoogle Scholar
  35. Wilkins A, Ping Q, Carpenter CL: RhoBTB2 is a substrate of the mammalian Cul3 ubiquitin ligase complex. Genes Dev 2004, 18: 856–861. 10.1101/gad.1177904PubMed CentralView ArticlePubMedGoogle Scholar
  36. Zhang HF, Tomida A, Koshimizu R, Ogiso Y, Lei S, Tsuruo T: Cullin 3 promotes proteasomal degradation of the topoisomerase I-DNA covalent complex. Cancer Res 2004, 64: 1114–1121. 10.1158/0008-5472.CAN-03-2858View ArticlePubMedGoogle Scholar
  37. Nag A, Bagchi S, Raychaudhuri P: Cul4A physically associates with MDM2 and participates in the proteolysis of p53. Cancer Res 2004, 64: 8152–8155. 10.1158/0008-5472.CAN-04-2598View ArticlePubMedGoogle Scholar
  38. Banks D, Wu M, Higa LA, et al.: L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes. Cell Cycle 2006, 5: 1719–1729.View ArticlePubMedGoogle Scholar
  39. Hu J, McCall CM, Ohta T, Xiong Y: Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol 2004, 6: 1003–1009. 10.1038/ncb1172View ArticlePubMedGoogle Scholar
  40. Hu J, Zacharek S, He YJ, et al.: WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase. Genes Dev 2008, 22: 866–871. 10.1101/gad.1624008PubMed CentralView ArticlePubMedGoogle Scholar
  41. Huang J, Chen J: VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. Oncogene 2008, 27: 4056–4064. 10.1038/onc.2008.44View ArticlePubMedGoogle Scholar
  42. Wertz IE, O'Rourke KM, Zhang Z, et al.: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. Science 2004, 303: 1371–1374. 10.1126/science.1093549View ArticlePubMedGoogle Scholar
  43. Jin J, Arias EE, Chen J, Harper JW, Walter JC: A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell 2006, 23: 709–721. 10.1016/j.molcel.2006.08.010View ArticlePubMedGoogle Scholar
  44. Higa LA, Mihaylov IS, Banks DP, Zheng J, Zhang H: Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint. Nat Cell Biol 2003, 5: 1008–1015. 10.1038/ncb1061View ArticlePubMedGoogle Scholar
  45. Zhong W, Feng H, Santiago FE, Kipreos ET: CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing. Nature 2003, 423: 885–889. 10.1038/nature01747View ArticlePubMedGoogle Scholar
  46. Feng L, Allen NS, Simo S, Cooper JA: Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development. Genes Dev 2007, 21: 2717–2730. 10.1101/gad.1604207PubMed CentralView ArticlePubMedGoogle Scholar
  47. Xu X, Sarikas A, Dias-Santagata DC, et al.: The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation. Mol Cell 2008, 30: 403–414. 10.1016/j.molcel.2008.03.009PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Jia and Sun; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement