RBX1/ROC1 Disruption Results in Early Embryonic Lethality Due to Proliferation Failure, Partially Rescued by Simultaneous Loss of P27

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Mar 28

PMID 19325126

Citations 51

Authors

Mingjia Tan

Shannon W Davis

Thomas L Saunders

Yuan Zhu

Yi Sun

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The Cullin-RING Ligase Family in Immune Regulation.

Wu D Adv Exp Med Biol. 2024; 1466:81-87.

PMID: 39546136 DOI: 10.1007/978-981-97-7288-9_5.

Protein neddylation and its role in health and diseases.

Zhang S, Yu Q, Li Z, Zhao Y, Sun Y Signal Transduct Target Ther. 2024; 9(1):85.

PMID: 38575611 PMC: 10995212. DOI: 10.1038/s41392-024-01800-9.

Emerging Roles of Cullin-RING Ubiquitin Ligases in Cardiac Development.

Zambrano-Carrasco J, Zou J, Wang W, Sun X, Li J, Su H Cells. 2024; 13(3.

PMID: 38334627 PMC: 10854628. DOI: 10.3390/cells13030235.

RING box protein-1(RBX1), a key component of SCF E3 ligase, induced multiple myeloma cell drug-resistance though suppressing p27.

Bao E, Zhou Y, He S, Tang J, He Y, Zhu M Cancer Biol Ther. 2023; 24(1):2231670.

PMID: 37639640 PMC: 10464534. DOI: 10.1080/15384047.2023.2231670.

The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells.

Wu D, Sun Y Research (Wash D C). 2023; 6:0212.

PMID: 37600496 PMC: 10437198. DOI: 10.34133/research.0212.

References

Li B, Ruiz J, Chun K . CUL-4A is critical for early embryonic development. Mol Cell Biol. 2002; 22(14):4997-5005. PMC: 139768. DOI: 10.1128/MCB.22.14.4997-5005.2002. View

Sherr C, Roberts J . Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995; 9(10):1149-63. DOI: 10.1101/gad.9.10.1149. View

Ciemerych M, Yu Q, Szczepanska K, Sicinski P . CDK4 activity in mouse embryos expressing a single D-type cyclin. Int J Dev Biol. 2008; 52(2-3):299-305. DOI: 10.1387/ijdb.072336mc. View

Noureddine M, Donaldson T, Thacker S, Duronio R . 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(6):757-70. DOI: 10.1016/s1534-5807(02)00164-8. View

Seddiqi N, Charbonnier F, Goudou D, Belkadi L, Rieger F, Alliel P . Genomic organization and expression of the ubiquitin-proteasome complex-associated protein Rbx1/ROC1/Hrt1. Cell Mol Biol (Noisy-le-grand). 2000; 45(8):1131-7. View

Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U . p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol. 1999; 1(4):207-14. DOI: 10.1038/12027. View

Carrano A, Eytan E, Hershko A, Pagano M . SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999; 1(4):193-9. DOI: 10.1038/12013. View

Zheng N, Schulman B, Song L, Miller J, Jeffrey P, Wang P . Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 2002; 416(6882):703-9. DOI: 10.1038/416703a. View

Arai T, Kasper J, Skaar J, Ali S, Takahashi C, DeCaprio J . Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis. Proc Natl Acad Sci U S A. 2003; 100(17):9855-60. PMC: 187864. DOI: 10.1073/pnas.1733908100. View

10.

Kiyokawa H, Kineman R, Soares V, HOFFMAN E, Ono M, Khanam D . Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell. 1996; 85(5):721-32. DOI: 10.1016/s0092-8674(00)81238-6. View

11.

Pan Z, Kentsis A, Dias D, Yamoah K, Wu K . Nedd8 on cullin: building an expressway to protein destruction. Oncogene. 2004; 23(11):1985-97. DOI: 10.1038/sj.onc.1207414. View

12.

Petroski M, Deshaies R . Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol. 2005; 6(1):9-20. DOI: 10.1038/nrm1547. View

13.

Seol J, Feldman R, Zachariae W, Correll C, Lyapina S, Chi Y . 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(12):1614-26. PMC: 316801. DOI: 10.1101/gad.13.12.1614. View

14.

Swaroop M, Wang Y, Miller P, Duan H, Jatkoe T, Madore S . 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(24):2855-66. DOI: 10.1038/sj.onc.1203635. View

15.

Willems A, Schwab M, Tyers M . A hitchhiker's guide to the cullin ubiquitin ligases: SCF and its kin. Biochim Biophys Acta. 2004; 1695(1-3):133-70. DOI: 10.1016/j.bbamcr.2004.09.027. View

16.

Gu Q, Tan M, Sun Y . SAG/ROC2/Rbx2 is a novel activator protein-1 target that promotes c-Jun degradation and inhibits 12-O-tetradecanoylphorbol-13-acetate-induced neoplastic transformation. Cancer Res. 2007; 67(8):3616-25. DOI: 10.1158/0008-5472.CAN-06-4020. View

17.

Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, HORII I . Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell. 1996; 85(5):707-20. DOI: 10.1016/s0092-8674(00)81237-4. View

18.

Duan H, Wang Y, Aviram M, Swaroop M, Loo J, Bian J . SAG, a novel zinc RING finger protein that protects cells from apoptosis induced by redox agents. Mol Cell Biol. 1999; 19(4):3145-55. PMC: 84108. DOI: 10.1128/MCB.19.4.3145. View

19.

Nakayama K, Nakayama K . Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 2006; 6(5):369-81. DOI: 10.1038/nrc1881. View

20.

Dealy M, Nguyen K, Lo J, Gstaiger M, Krek W, Elson D . Loss of Cul1 results in early embryonic lethality and dysregulation of cyclin E. Nat Genet. 1999; 23(2):245-8. DOI: 10.1038/13886. View