The E3 ubiquitin ligase complex component COP1 regulates PEA3 group member stability and transcriptional activity

Baert, Jean-Luc; Monté, Didier; Verreman, Kathye; Degerny, Cindy; Coutte, Laurent; Launoit, Yvan de

doi:10.1038/onc.2009.471

Cited by 39 publications

(39 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result indicates that c-Jun may not be the only Cop1 targets that positively contribute to cancer formation. Recent biochemical evidence indicates that Cop1 targets the three PEA3 group members (61). This group consists of the three highly conserved Ets transcription factors, ERM, ETV1, and PEA3, which are often overexpressed in different types of cancers and have been shown to promote tumorigenesis and metastasis (62,63).…”

Section: Discussionmentioning

confidence: 99%

Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice

Migliorini¹,

Bogaerts²,

Defever³

et al. 2011

J. Clin. Invest.

113

135

View full text Add to dashboard Cite

Biochemical studies have suggested conflicting roles for the E3 ubiquitin ligase constitutive photomorphogenesis protein 1 (Cop1; also known as Rfwd2) in tumorigenesis, providing evidence for both the oncoprotein c-Jun and the tumor suppressor p53 as its targets. Here we present what we believe to be the first in vivo investigation of the role of Cop1 in cancer etiology. Using an innovative genetic approach to generate an allelic series of Cop1, we found that Cop1 hypomorphic mice spontaneously developed malignancy at a high frequency in the first year of life and were highly susceptible to radiation-induced lymphomagenesis. Further analysis revealed that c-Jun was a key physiological target for Cop1 and that Cop1 constitutively kept c-Jun at low levels in vivo and thereby modulated c-Jun/AP-1 transcriptional activity. Importantly, Cop1 deficiency stimulated cell proliferation in a c-Jun-dependent manner. Focal deletions of COP1 were observed at significant frequency across several cancer types, and COP1 loss was determined to be one of the mechanisms leading to c-Jun upregulation in human cancer. We therefore conclude that Cop1 is a tumor suppressor that functions, at least in part, by antagonizing c-Jun oncogenic activity. In the absence of evidence for a genetic interaction between Cop1 and p53, our data strongly argue against the use of Cop1-inhibitory drugs for cancer therapy. IntroductionThe turnover and the activity of several key oncoproteins and tumor suppressors are controlled by the ubiquitin proteasome system (UPS). The UPS comprises two discrete steps: the covalent attachment of multiple ubiquitin molecules to the protein substrate and degradation of the polyubiquitylated protein by the 26S proteasome complex. The first step is mediated by at least three enzymes: the ubiquitin-activating enzyme E1, the ubiquitin-conjugating enzyme E2, and the ubiquitin ligase E3. Few reports have linked E1 and E2 to cancer development; in contrast, cumulative evidence indicates alterations in the activity of some E3 ligases in the etiology of human malignancies (1). Because E3 ligases are the specific recognition element of the system and are themselves potentially "drugable'" enzymes, they can serve as potential cancer targets as well as cancer biomarkers.A direct molecular link between deregulation of E3 ligase activity and cancer is illustrated by the well-described oncogenic activity of the RING finger-containing protein Mdm2. In physiological conditions, Mdm2 directly binds the p53 tumor suppressor protein and via its RING finger domain acts as an E3 ligase to promote p53 ubiquitylation and proteasomal degradation (2). In tumors, p53 function is altered either by inactivating mutations of the TP53 gene itself or as the result of aberrant expression and/or func-

show abstract

Section: Discussionmentioning

confidence: 99%

Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice

Migliorini¹,

Bogaerts²,

Defever³

et al. 2011

J. Clin. Invest.

113

135

View full text Add to dashboard Cite

show abstract

“…Photomorphogenesis is a critical fate decision in plants; cop/det/fus genes couple light signals with transcriptionally regulated photomorphogenesis by regulating the protein stability of key transcription factors (32,33). Mammalian COP1 and DET1 have been previously identified as regulators of protein degradation of Pea3 and other ETS factors at baseline (22,24,34). However, their roles in MAPK signaling-dependent regulation are not fully appreciated.…”

Section: Pea3-ets Factors Are Mapk Nuclear Effectors Of Mapk Signalinmentioning

confidence: 99%

“…To study the clinical relevance of the Pea3-ETS protein staTo corroborate that Pea3-ETS stability downstream of COP1 or DET1 loss mediates MAPK inhibitor resistance, we generated A375 cells with exogenous expression of WT (ETV1 WT ) and a mutant ETV1 (ETV1 AAD ) that had diminished binding to COP1 (22,24) and was therefore resistant to COP1-mediated protein degradation in response to MAPK pathway inhibition by vemurafenib or trametinib (Figure 7, A-C, and Supplemental Figure 9). ETV1…”

Section: Decoupling Of Mapk Signaling and The Pea3-ets Transcriptionamentioning

confidence: 99%

“…This implicates the dynamic regulation of ETV1 protein stability as a critical mechanism to couple ERK activity to a downstream nuclear transcriptional response in GISTs and melanoma. Previously, COP1 has been shown to be an E3 ligase that mediates the degradation of Pea3 transcription factors, and in prostate cancer, COP1 loss is an alternative mechanism for overexpressing ETS factors in genomic translocation (22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors

Xie¹,

Cao²,

Wong³

et al. 2018

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…5B). ETV5 is targeted for proteasomal degradation by CRL4 COP1/DET1 (29). Therefore, we hypothesized that Ras signaling stabilized Etv5 by inactivating CRL4 COP1/DET1 .…”

Section: Etv5 Is Required For Lung Tumor Initiation By Oncogenic Krasmentioning

confidence: 99%

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

Zhang¹,

Newton²,

Kummerfeld³

et al. 2017

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

112

View full text Add to dashboard Cite

Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation-specific (ETS) family transcription factor Etv5 is essential to maintain AT2 cell identity. Deletion of Etv5 from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells. Consistent with a defect in the AT2 stem cell population, Etv5 deficiency markedly reduced recovery following bleomycin-induced lung injury. Lung tumorigenesis driven by mutant KrasG12D was also compromised by Etv5 deficiency. ERK activation downstream of Ras was found to stabilize Etv5 through inactivation of the cullin-RING ubiquitin ligase CRL4 COP1/DET1 that targets Etv5 for proteasomal degradation. These findings identify Etv5 as a critical output of Ras signaling in AT2 cells, contributing to both lung homeostasis and tumor initiation.A lveolar type II (AT2) cells are a stem cell population that self renews and differentiates into alveolar type I (AT1) cells during lung homeostasis or in response to injury (1, 2). They also give rise to lung adenocarcinoma induced by oncogenic Kras (1, 3-5). AT2 cells are derived from bipotent progenitor cells at the sacculation stage (1). In the adult lung, mature AT2 cells also secrete surfactant phospholipids to maintain normal alveolar function. Sustained Kras activity stimulates the self-renewal of AT2 cells, which eventually leads to abnormal tissue growth (1). An AT2 gene-expression signature has been reported (6, 7), but it is unclear how the identity of AT2 cells is specified and maintained.Given that Ras/MAPK signaling is essential for the self-renewal of AT2 cells and for the initiation of lung adenocarcinoma, identification of the transcription factors that are activated by Ras in AT2 cells is a step toward defining the transcriptional programs underlying AT2 stemness. The PEA3 subgroup of the ETS family of transcription factors, comprised of ETS transcription variants 1, 4, and 5 (Etv1, Etv4, and Etv5) (8), is known to be engaged by Ras/MAPK signaling. Etv4 and Etv5 are expressed in distal lung epithelium during development and are involved in branching morphogenesis and epithelial cell differentiation (9-11). Alveolar epithelial cells in the adult lung also express Etv5 (7, 12), but a critical role for Etv5 in this setting remains elusive.PEA3 transcription factors are also implicated in tumorigenesis. Overexpression of ETV1 or ETV4 has been linked to prostate cancer (13,14), and stabilization of ETV1 by mutant, active tyrosine kinase receptor KIT is thought to drive an oncogenic program in gastrointestinal stromal tumors (GIST) (15). ETV1, ETV4, and ETV5 are labile proteins because of their regulation by the ubiquitin-proteasome system. In GIST, ETV1 protein is stabilized by activation of the Ras/MAPK pathway through an unkno...

show abstract

The E3 ubiquitin ligase complex component COP1 regulates PEA3 group member stability and transcriptional activity

Cited by 39 publications

References 20 publications

Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice

Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice

COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors

Transcription factor Etv5 is essential for the maintenance of alveolar type II cells

Contact Info

Product

Resources

About