A Novel RING-Type Ubiquitin Ligase <i>Breast Cancer-Associated Gene 2</i> Correlates with Outcome in Invasive Breast Cancer

Burger, Angelika M.; Gao, Yanfang; Amemiya, Yutaka; Kahn, Harriette J.; Kitching, Richard; Yang, Yili; Park, Sun; Narod, Steven A.; Hanna, Wedad; Seth, Arun

doi:10.1158/0008-5472.can-05-2103

Cited by 90 publications

(179 citation statements)

References 26 publications

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“…Growing evidence indicates that EGFR-PTK-mediated tyrosine phosphorylation is a prerequisite for ubiquitination of cellular proteins that are targeted for proteasome-mediated degradation (17)(18)(19)(20). Tyr23 is one of a series of small molecular weight specific inhibitors of EGFR-PTK that can decrease ubiquitination of cellular proteins by binding to the substrate subsite of the EGFR-PTK domain (21).…”

Section: Resultsmentioning

confidence: 99%

Pyruvate Dehydrogenase Complex Deficiency Caused by Ubiquitination and Proteasome-mediated Degradation of the E1β Subunit

Han¹,

Zhong²,

Srivastava

et al. 2008

Journal of Biological Chemistry

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Congenital deficiencies of the human pyruvate dehydrogenase (PDH) complex are considered to be due to loss of function mutations in one of the component enzymes. Here we describe a case of PDH deficiency associated with the PDH E1␤ subunit (PDHB) gene. The clinical phenotype of the patient was consistent with reported cases of PDH deficiency. Cultured skin fibroblasts demonstrated a 55% reduction in PDH activity and markedly decreased immunoreactivity for PDHB protein, compared with healthy controls. Surprisingly, nucleotide sequence analyses of cDNAs corresponding to the patient PDH E1␣ (PDHA1) and PDHB genes revealed no pathological mutations. Moreover, the relative expression level of PDHB mRNA and the rates of transcription and translation of the PDHB gene were normal. However, PDC activity could be restored in cells from this patient following treatment with MG132, a specific proteasome inhibitor, and normal levels of E1␤ could be detected in MG132-treated cells. Similar results were obtained following treatment with Tyrphostin 23 (Tyr23), a specific inhibitor of epidermal growth factor receptor-protein-tyrosine kinase (EGFR-PTK), which also restored E1␤ protein levels to those in cells from healthy subjects or from patients with PDHA1 deficiency. The index patient's cells contained a high basal level of EGFR-PTK activity that correlated with the high level of ubiquitination of cellular proteins, although the total EGFR protein levels were similar to those in cells from El␣-deficient subjects and healthy subjects. These data indicate that PDH deficiency in our patient involves a post-translational modification in which EGFR-PTK-mediated tyrosine phosphorylation of the E1␤ protein leads to enhanced ubiquitination followed by proteasome-mediated degradation. They also provide a novel mechanism accounting for congenital deficiency of the PDH complex and perhaps other inborn errors of metabolism.The nuclear encoded mitochondrial pyruvate dehydrogenase (PDH) 2 complex plays major roles in regulating cellular fuel metabolism, acid-base equilibrium and energetics (1, 2). The complex consists of three catalytic components: pyruvate dehydrogenase (E1; EC 1.2.4.1), dihydrolipoamide transacetylase (E2; EC 2.3.1.12), and dihydro-lipoamide dehydrogenase (E3; EC 1.8.1.4), and an additional protein known as the E3-binding protein (E3BP). Rapid post-translational regulation of the complex is mediated in large part by reversible phosphorylation of the ␣ subunit of E1 that is catalyzed by isoforms of PDH kinase and PDH phosphatase.The E1 enzyme (EC 1.2.4.1) is a heterotetrameric (␣ 2 ␤ 2 ) ␣-ketoacid decarboxylase that irreversibly oxidizes pyruvate to acetyl-CoA in the presence of thiamine pyrophosphate (TPP) and also catalyzes the subsequent reductive acetylation of the lipoyl moiety of E2. Most reported mutations of the PDH complex are located in the X-linked gene for the ␣ subunit of the E1 component (MIM 312170). Only a small number of patients have been described with mutations in the E2, E3, E3BP, or PDH phosphatase g...

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Section: Resultsmentioning

confidence: 99%

Pyruvate Dehydrogenase Complex Deficiency Caused by Ubiquitination and Proteasome-mediated Degradation of the E1β Subunit

Han¹,

Zhong²,

Srivastava

et al. 2008

Journal of Biological Chemistry

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“…1). BCA2 has been shown to be overexpressed in 56% of 945 invasive breast tumors (10) and knockdown of BCA2 in the T47D breast cancer cell line significantly decreased cell proliferation (10). However, the mechanism by which BCA2 promotes breast cell proliferation is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…RNF126 and BCA2 E3 ligases share similar protein structures, which contain a RING finger at the C-terminus and a Zn finger near the Nterminus (9). The expression of BCA2 has been shown to correlate with pathologic outcome in invasive breast cancer (10). p21 Waf1/Cip1 is an inhibitor of cyclin-dependent kinases and is required for proper cell-cycle progression.…”

Section: Introductionmentioning

confidence: 99%

E3 Ubiquitin Ligase RNF126 Promotes Cancer Cell Proliferation by Targeting the Tumor Suppressor p21 for Ubiquitin-Mediated Degradation

et al. 2013

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To identify novel oncogenic E3 ubiquitin ligases as anticancer targets, we screened an E3 ubiquitin ligase siRNA library containing siRNA pools against 555 individual E3s using the sulphorhodamine B assay in the MDA-MB-231 breast cancer cell line and the PC3 prostate cancer cell line. RNF126 was identified and validated as a candidate from this screening. Knockdown of RNF126 dramatically decreased cell viability in these cancer cell lines. Consistently, RNF126 knockdown delayed cell-cycle G 1 -S progression and decreased cell proliferation. Using protein array analysis we found that RNF126 silencing increased cell-cycle dependent kinase inhibitor p21 cip protein levels in both MDA-MB-231 and PC3. Knockdown of RNF126 stabilized the p21 protein rather than increased p21 mRNA levels. We showed that RNF126 interacts with p21 and RNF126 overexpression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner. RNF126 knockdown induced loss of cell viability in MDA-MB-231 and PC-3 can be partially rescued by depletion of p21. RNF126 stable knockdown in PC3 inhibited tumor growth in SCID mice. Finally, we found that RNF126 is highly expressed in a subset of breast cancer cell lines and negatively correlated with p21 expression levels. These findings suggest that RNF126 promotes cancer cell proliferation by targeting p21 for ubiquitin-mediated degradation. RNF126 could be a novel therapeutic target in breast and prostate cancers. Cancer Res; 73(1); 385-94. Ó2012 AACR.

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“…1A). Rabring7 has previously been shown to have RINGfinger-dependent auto-ubiquitylation activity (Amemiya et al, 2008;Burger et al, 2005;Sakane et al, 2007). To determine whether RNF126 exhibits RING-finger-dependent E3 ligase activity, we used in vitro auto-ubiquitylation assays with the E2 enzyme UbcH5b.…”

Section: Introductionmentioning

confidence: 99%

The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the Epidermal Growth Factor Receptor

Smith¹,

Berry²,

McGlade³

2013

Journal of Cell Science

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SummaryActivation of the epidermal growth factor receptor (EGFR) results in internalization and ubiquitin-dependent endosomal sorting, leading to lysosomal degradation. Here we describe the role of the RING-finger-domain-containing protein RNF126 and the related protein, Rabring7 in EGFR endosomal sorting. We demonstrate that RNF126 specifies K48-linked chains with UbcH5b and also functions with Ubc13/Uev1a to form K63-linked chains in vitro. RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In the absence of c-Cbl or in cells expressing Cbl-70Z, the binding of RNF126 and Rabring7 to the EGFR is reduced, suggesting that RNF126 and Rabring7 function downstream of c-Cbl. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded. In addition, depletion of RNF126 or Rabring7 destabilizes ESCRT-II and reduces the number of multivesicular bodies formed after EGF stimulation. We also show that the depletion of Rabring7 attenuates the degradation of MET and that both RNF126 and Rabring7 regulate the sorting of CXCR4 from an early endocytic compartment. Together these data suggest that RNF126 and Rabring7 play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors.

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A Novel RING-Type Ubiquitin Ligase Breast Cancer-Associated Gene 2 Correlates with Outcome in Invasive Breast Cancer

Cited by 90 publications

References 26 publications

Pyruvate Dehydrogenase Complex Deficiency Caused by Ubiquitination and Proteasome-mediated Degradation of the E1β Subunit

Pyruvate Dehydrogenase Complex Deficiency Caused by Ubiquitination and Proteasome-mediated Degradation of the E1β Subunit

E3 Ubiquitin Ligase RNF126 Promotes Cancer Cell Proliferation by Targeting the Tumor Suppressor p21 for Ubiquitin-Mediated Degradation

The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the Epidermal Growth Factor Receptor

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