Gene Symbol: Huwe1
Description: HECT, UBA and WWE domain containing 1
Alias: 5430439H10Rik, AU041296, Arf-bp1, C430014N20Rik, C80292, Gm1718, Ib772, LASU1, Mule, Ureb1, E3 ubiquitin-protein ligase HUWE1, E3Histone, HECT, UBA and WWE domain-containing protein 1, HECT-type E3 ubiquitin transferase HUWE1, Mcl-1 ubiquitin ligase, URE-B1, URE-binding protein 1, upstream regulatory element binding protein 1
Species: mouse
Products:     Huwe1

Top Publications

  1. Yin L, Joshi S, Wu N, Tong X, Lazar M. E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb alpha. Proc Natl Acad Sci U S A. 2010;107:11614-9 pubmed publisher
    ..Thus, Arf-bp1 and Pam are novel regulators of circadian gene expression that target Rev-erb alpha for degradation. ..
  2. Kon N, Zhong J, Qiang L, Accili D, Gu W. Inactivation of arf-bp1 induces p53 activation and diabetic phenotypes in mice. J Biol Chem. 2012;287:5102-11 pubmed publisher
    ..These findings underscore an important role of ARF-BP1 in maintaining ?-cell homeostasis in aging mice and reveal that the stability of p53 is critically regulated by ARF-BP1 in vivo. ..
  3. Inoue S, Hao Z, Elia A, Cescon D, Zhou L, Silvester J, et al. Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15. Genes Dev. 2013;27:1101-14 pubmed publisher
    ..Many gene products involved in these processes are substrates of the E3 ubiquitin ligase Mule/Huwe1/Arf-BP1 (Mule), but whether Mule acts as an oncogene or tumor suppressor in vivo remains controversial...
  4. Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005;121:1085-95 pubmed
    ..fractionation of cell extracts allowed us to identify a 482 kDa HECT-domain-containing ubiquitin ligase named Mule (Mcl-1 ubiquitin ligase E3) that is both required and sufficient for the polyubiquitination of Mcl-1...
  5. Liu Z, Oughtred R, Wing S. Characterization of E3Histone, a novel testis ubiquitin protein ligase which ubiquitinates histones. Mol Cell Biol. 2005;25:2819-31 pubmed
    ..Indeed, a novel enzyme, E3Histone, which could conjugate ubiquitin to histones H1, H2A, H2B, H3, and H4 in vitro, was found...
  6. Hao Z, Duncan G, Su Y, Li W, Silvester J, Hong C, et al. The E3 ubiquitin ligase Mule acts through the ATM-p53 axis to maintain B lymphocyte homeostasis. J Exp Med. 2012;209:173-86 pubmed publisher
    Cellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation...
  7. Chen D, Kon N, Li M, Zhang W, Qin J, Gu W. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell. 2005;121:1071-83 pubmed
    ..As such, ARF-BP1 may serve as a potential target for therapeutic intervention in tumors regardless of p53 status. ..
  8. Zhao X, Heng J, Guardavaccaro D, Jiang R, Pagano M, Guillemot F, et al. The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat Cell Biol. 2008;10:643-53 pubmed publisher
    ..Here we report that the HECT-domain ubiquitin ligase Huwe1 ubiquitinates the N-Myc oncoprotein through Lys 48-mediated linkages and targets it for destruction by the ..
  9. Dominguez Brauer C, Hao Z, Elia A, Fortin J, Nechanitzky R, Brauer P, et al. Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation. Cell Stem Cell. 2016;19:205-216 pubmed publisher
    The E3 ubiquitin ligase Mule is often overexpressed in human colorectal cancers, but its role in gut tumorigenesis is unknown...

More Information


  1. Urbán N, van den Berg D, Forget A, Andersen J, Demmers J, Hunt C, et al. Return to quiescence of mouse neural stem cells by degradation of a proactivation protein. Science. 2016;353:292-5 pubmed publisher
    ..Here, we show that the E3-ubiquitin ligase Huwe1 (HECT, UBA, and WWE domain-containing 1) is required for proliferating stem cells of the adult mouse hippocampus ..
  2. Corbel C, Diabangouaya P, Gendrel A, Chow J, Heard E. Unusual chromatin status and organization of the inactive X chromosome in murine trophoblast giant cells. Development. 2013;140:861-72 pubmed publisher
    ..This unusual combination of silent and active features is likely to reflect, and might underlie, the partial activity of the X chromosome in TGCs...
  3. Zhang X, Berger F, Yang J, Lu X. USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1. EMBO J. 2011;30:2177-89 pubmed publisher
    ..Finally, we showed that USP4 is overexpressed in several types of human cancer, suggesting that USP4 is a potential oncogene. ..
  4. Xu B, Mao Z, Ji X, Yao M, Chen M, Zhang X, et al. miR-98 and its host gene Huwe1 target Caspase-3 in Silica nanoparticles-treated male germ cells. Sci Rep. 2015;5:12938 pubmed publisher
    ..Accordingly, the expression level of miR-98, which can regulate Caspase-3, was significantly decreased. Huwe1, the host gene of miR-98, was positively associated with miR-98 expression after Silica NP exposure...
  5. D Arca D, Zhao X, Xu W, Ramirez Martinez N, Iavarone A, Lasorella A. Huwe1 ubiquitin ligase is essential to synchronize neuronal and glial differentiation in the developing cerebellum. Proc Natl Acad Sci U S A. 2010;107:5875-80 pubmed publisher
    We have generated a knockout mouse strain in which the gene coding for the ubiquitin ligase Huwe1 has been inactivated in cerebellar granule neuron precursors (CGNPs) and radial glia...
  6. Zhao X, D Arca D, Lim W, Brahmachary M, Carro M, Ludwig T, et al. The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain. Dev Cell. 2009;17:210-21 pubmed publisher
    ..Here we show that the ubiquitin ligase Huwe1 operates upstream of the N-Myc-DLL3-Notch pathway to control neural stem cell activity and promote neurogenesis...
  7. Lee C, Yang Y, Chen C, Liu J. Syk-mediated tyrosine phosphorylation of mule promotes TNF-induced JNK activation and cell death. Oncogene. 2016;35:1988-95 pubmed publisher
    ..and cell death by suppressing TRAF2 K63-polyubiquitination; upon TNF stimulation, the suppression is relieved by Mule/ARF-BP1-mediated Miz1 ubiquitination and subsequent degradation. It is not known how Mule is activated by TNF...
  8. Zhang J, Kan S, Huang B, Hao Z, Mak T, Zhong Q. Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2. Genes Dev. 2011;25:2610-8 pubmed publisher
    ..apoptosis are severely compromised in mouse embryonic fibroblasts lacking a HECT domain ubiquitin ligase, Mule (Mcl-1 ubiquitin ligase E3). Mule specifically targets HDAC2 for ubiquitination and degradation...
  9. Myant K, Cammareri P, Hodder M, Wills J, von Kriegsheim A, Győrffy B, et al. HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. EMBO Mol Med. 2017;9:181-197 pubmed publisher
    ..One exemplar gene is HUWE1, which has been found to be mutated in numerous studies...
  10. Qi C, Kim Y, Xiang S, Abdullaev Z, Torrey T, Janz S, et al. Characterization of ARF-BP1/HUWE1 interactions with CTCF, MYC, ARF and p53 in MYC-driven B cell neoplasms. Int J Mol Sci. 2012;13:6204-19 pubmed publisher
    ..The E3 ubiquitin ligase, ARF-BP1, encoded by HUWE1, modulates the activity of both the MYC and the ARF-p53 signaling pathways, prompting us to determine if it is ..
  11. Dominguez Brauer C, Khatun R, Elia A, Thu K, Ramachandran P, Baniasadi S, et al. E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling. Proc Natl Acad Sci U S A. 2017;114:E1148-E1157 pubmed publisher
    ..We previously showed that Mule/Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via ..
  12. Tsuchiya K, Willard H. Chromosomal domains and escape from X inactivation: comparative X inactivation analysis in mouse and human. Mamm Genome. 2000;11:849-54 pubmed
    ..Possible mechanisms responsible for the differing inactivation status between genes in the escape domain in human Xp11. 21-p11.22 and the corresponding mouse region are discussed. ..
  13. Qi C, Zhang R, Sun J, Li Z, Shin D, Wang H, et al. Homeostatic defects in B cells deficient in the E3 ubiquitin ligase ARF-BP1 are restored by enhanced expression of MYC. Leuk Res. 2013;37:1680-9 pubmed publisher
    ..These findings indicate that the dynamic balance between MYC and p53 required for normal B cell maturation and function is finely tuned and critically dependent on the activities of ARF-BP1. ..
  14. Wang L, Luk C, Schroer S, Smith A, Li X, Cai E, et al. Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions. Diabetologia. 2014;57:1889-98 pubmed publisher
    ..A newly discovered ubiquitination molecule HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1 [also known as MULE or ARF-BP1]) is a critical regulator of p53-dependent apoptosis...
  15. Plafker S, Macara I. Ribosomal protein L12 uses a distinct nuclear import pathway mediated by importin 11. Mol Cell Biol. 2002;22:1266-75 pubmed
    ..Taken together, these results indicate that rpL12 uses a distinct nuclear import pathway that may contribute to a mechanism for regulating ribosome synthesis and/or maturation. ..
  16. Markkanen E, van Loon B, Ferrari E, Parsons J, Dianov G, Hubscher U. Regulation of oxidative DNA damage repair by DNA polymerase ? and MutYH by cross-talk of phosphorylation and ubiquitination. Proc Natl Acad Sci U S A. 2012;109:437-42 pubmed publisher
    ..Here, we show that the E3 ligase Mule mediates the degradation of Pol ? and that the control of Pol ? levels by Mule has functional consequences for the ..
  17. Warr M, Mills J, Nguyen M, Lemaire Ewing S, Baardsnes J, Sun K, et al. Mitochondrion-dependent N-terminal processing of outer membrane Mcl-1 protein removes an essential Mule/Lasu1 protein-binding site. J Biol Chem. 2011;286:25098-107 pubmed publisher
    ..outer membrane, is subject to constitutive ubiquitylation by the Bcl-2 homology 3-only E3 ligase, Mule/Lasu1, resulting in rapid steady-state degradation via the proteasome...
  18. Liu Z, Miao D, Xia Q, Hermo L, Wing S. Regulated expression of the ubiquitin protein ligase, E3(Histone)/LASU1/Mule/ARF-BP1/HUWE1, during spermatogenesis. Dev Dyn. 2007;236:2889-98 pubmed
    A ubiquitin protein ligase (E3), E3(Histone)/LASU1 (Mule/ARF-BP1/HUWE1), was recently identified that mediates ubiquitination of core histones, the Mcl-1 anti-apoptotic protein, and the p53 tumor suppressor protein...
  19. Li L, Martinez S, Hu W, Liu Z, Tjian R. A specific E3 ligase/deubiquitinase pair modulates TBP protein levels during muscle differentiation. elife. 2015;4:e08536 pubmed publisher
    ..Using an in vitro ubiquitination assay coupled with biochemical fractionation, we identified Huwe1 as an E3 ligase targeting TBP for K48-linked ubiquitination and proteasome-mediated degradation...
  20. Hao Z, Sheng Y, Duncan G, Li W, Dominguez C, Sylvester J, et al. K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression. Nat Commun. 2017;8:14003 pubmed publisher
    ..Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase...
  21. Yang Y, Do H, Tian X, Zhang C, Liu X, Dada L, et al. E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFalpha-induced JNK activation. Proc Natl Acad Sci U S A. 2010;107:13444-9 pubmed publisher
    ..However, the underling regulatory mechanism is not known. Here, we report that HECT-domain-containing Mule is the E3 ligase that catalyzes TNFalpha-induced Miz1 polyubiquitination...
  22. Fok K, Bose R, Sheng K, Chang C, Katz Egorov M, Culty M, et al. Huwe1 Regulates the Establishment and Maintenance of Spermatogonia by Suppressing DNA Damage Response. Endocrinology. 2017;158:4000-4016 pubmed publisher
    ..In this study, we report that inactivation of the ubiquitin ligase Huwe1 in male germ cells in mice led to the degeneration of spermatogonia in neonates and resulted in a Sertoli cell-..