The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein

Zhao, Xudong; Heng, Julian Ik‐Tsen; Guardavaccaro, Daniele; Jiang, Richeng; Pagano, Michele; Guillemot, François; Iavarone, Antonio; Lasorella, Anna

doi:10.1038/ncb1727

Cited by 233 publications

(285 citation statements)

References 44 publications

(5 reference statements)

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“…Mule belongs to the HECT-domain-containing E3 ligase family, which is known to catalyze only one type of polyubiquitination linkages (43), K48-linked polyubiquitination of substrates including p53, Mcl-1, N-Myc, and Cdc6 (33,(35)(36)(37). To determine whether Mule catalyzes K48-linked polyubiquitination of Miz1, we performed the in vitro ubiquitination assay in the presence of Ub (K48O), in which all lysines in ubiquitin were mutated to arginines except K48, or Ub (K63O).…”

Section: Resultsmentioning

confidence: 99%

“…The HECT domain-containing ubiquitin ligase (E3) Mule (also known as Ureb1, LASU1, HUWE1, ARF-BP1, or HectH9) plays a critical role in proteasomal degradation of several proteins (33)(34)(35)(36)(37), and is involved in regulation of apoptosis (33). Mule has two Armadillo (ARM) repeat-like domains (ARLD1 spanning amino acids 104-374, and ARLD2 spanning amino acids 424-815), a ubiquitin-associated (UBA) domain (amino acids 1317-1355), a WWE (amino acids 1617-1678), and a well-conserved BH3 domain (amino acids 1972-1994) at its N terminus, and a HECT domain (amino acids 4016-4374) is at its C terminus (33,(38)(39)(40).…”

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confidence: 99%

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E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFα-induced JNK activation

Yang

Chi

Tian

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The zinc finger transcription factor Miz1 is a negative regulator of TNFα-induced JNK activation and cell death through inhibition of TRAF2 K63-polyubiquitination in a transcription-independent manner. Upon TNFα stimulation, Miz1 undergoes K48-linked polyubiquitination and proteasomal degradation, thereby relieving its inhibition. However, the underling regulatory mechanism is not known. Here, we report that HECT-domain-containing Mule is the E3 ligase that catalyzes TNFα-induced Miz1 polyubiquitination. Mule is a Miz1-associated protein and catalyzes its K48-linked polyubiquitination. TNFα-induced polyubiquitination and degradation of Miz1 were inhibited by silencing of Mule and were promoted by ectopic expression of Mule. The interaction between Mule and Miz1 was promoted by TNFα independently of the pox virus and zinc finger domain of Miz1. Silencing of Mule stabilized Miz1, thereby suppressing TNFα-induced JNK activation and cell death. Thus, our study reveals a molecular mechanism by which Mule regulates TNFα-induced JNK activation and apoptosis by catalyzing the polyubiquitination of Miz1.Mule/ARF-BP1 | TNFα signaling | Miz1 ubiquitination

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFα-induced JNK activation

Yang

Chi

Tian

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…32,33 Recently, the HectH9/Huwe1 ubiquitin-protein ligase has been shown to degrade N-Myc protein during neuronal differentiation. 34 In the current study, we have identified the ubiquitin-protein ligase NEDD4, which is a member of the HECT ubiquitin-protein ligase family, 25,26 as a novel regulator of Myc protein ubiquitination and degradation. Our data demonstrate that NEDD4 directly binds to N-Myc protein, and targets N-Myc protein for ubiquitination by the ubiquitin conjugating enzymes (E2) UbcH5a and UbcH5b.…”

Section: Discussionmentioning

confidence: 99%

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

et al. 2012

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Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin-proteasome pathway-mediated proteolysis, and exert oncogenic effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin-protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies. The Myc family of oncoproteins are commonly upregulated in human cancer. MYCN oncogene amplification and consequent N-Myc oncoprotein overexpression occur in 20-25% of neuroblastoma and correlate with a poor patient outcome. 1-3 MYC oncogene amplification occurs in 54% of human pancreatic cancer cell lines 4 and 33% of human primary pancreatic tumors, 5 and significant c-Myc oncoprotein overexpression is seen in B50% of human primary pancreatic tumors. 6 Stabilization and degradation of Myc oncoproteins are controlled by ordered phosphorylation at serine 62 (S62) and threonine 58 (T58) and consequent ubiquitinproteasome pathway-mediated proteolysis. 7-9 Aurora A interacts with both N-Myc and ubiquitin, and blocks ubiquitin-regulated N-Myc protein degradation. 8 Myc oncoproteins induce malignant transformation by binding to cognate DNA sequences and consequently modulating gene transcription 10-13 as well as by enhancing ribosome biogenesis and consequently upregulating protein expression, 14,15 leading to cell proliferation.Recruitment of histone deacetylase (HDACs) to gene promoters induces histone hypoacetylation and transcriptional repression, particularly of tumor suppressor genes. 16 In a comprehensive panel of normal cells, cancer cell lines, normal tissues, and primary tumors, global loss of monoacetylation of histone H4 at lysine 16 (H4K16) is seen only in cancer cells and is associated with early stages of tumorigenesis. 17 One of the HDACs that cause H4K16 deacetylation is the class III HDAC SIRT2, which shows a strong preference for acetylated H4K16. 18 Mo...

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“…Mule was first identified as a ubiquitin ligase for an anti-apoptotic Bcl-2 family protein, Mcl-1 (Zhong et al 2005). Mule is also known as ARF-BP1, Ureb1, LASU1, HUWE1, or HectH9, and promotes ubiquitin-proteasomal degradation of multiple substrates, including p53, c-Myc, Cdc6, histones, N-Myc, Miz1, TopBP1, and Polb (Adhikary et al 2005;Chen et al 2005;Zhong et al 2005;Hall et al 2007;Liu et al 2007;Herold et al 2008;Zhao et al 2008;Parsons et al 2009;Yang et al 2010). However, whether any of these existing or unidentified substrates mediate the major function of Mule in the DNA damage response remains elusive.…”

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confidence: 99%

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

Zhang¹,

Kan²,

Huang³

et al. 2011

Genes Dev.

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Histone deacetylases (HDACs) are major epigenetic modulators involved in a broad spectrum of human diseases including cancers. Administration of HDAC inhibitors (HDACis) leads to growth inhibition, differentiation, and apoptosis of cancer cells. Understanding the regulatory mechanism of HDACs is imperative to harness the therapeutic potentials of HDACis. Here we show that HDACi-and DNA damage-induced 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. Accumulation of HDAC2 in Mule-deficient cells leads to compromised p53 acetylation as well as crippled p53 transcriptional activation, accumulation, and apoptotic response upon DNA damage and Nutlin-3 treatments. These defects in Mule-null cells can be partially reversed by HDACis and fully rescued by lowering the elevated HDAC2 in Mule-null cells to the normal levels as in wild-type cells. Taken together, our results reveal a critical regulatory mechanism of HDAC2 by Mule and suggest this pathway determines the cellular response to HDACis and DNA damage.

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The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein

Cited by 233 publications

References 44 publications

E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFα-induced JNK activation

E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFα-induced JNK activation

The histone deacetylase SIRT2 stabilizes Myc oncoproteins

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

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