Ubiquitin-Conjugating Enzyme UBE2D2 Is Responsible for FBXW2 (F-Box and WD Repeat Domain Containing 2)-Mediated Human GCM1 (Glial Cell Missing Homolog 1) Ubiquitination and Degradation1

Chiang, Meng-Hsiu; Chen, Liangfu; Chen, Hung−Wen

doi:10.1095/biolreprod.108.071407

Cited by 20 publications

(14 citation statements)

References 30 publications

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“…Here we showed that SKP2 is a novel substrate of FBXW2 with following lines of supporting evidence: (1) FBXW2 binds to SKP2 under physiological conditions; (2) FBXW2-SKP2 binding is dependent on an evolutionarily conserved FBXW2 putative consensus binding motif ( TS ELL S ) on SKP2; (3) FBXW2 overexpression reduces SKP2 levels by shortening its protein half-life; (4) FBXW2 depletion increases SKP2 levels by extending its protein half-life; (5) FBXW2, but not its FBXW2ΔF mutant, promotes ubiquitylation and subsequent degradation of SKP2; (6) FBXW2 mediated negative regulation of SKP2 is independent of CDH1. At the present time, the only known substrate of FBXW2 is GCM1 (Glial cell missing homolog 1)6768, a transcription factor that regulate placental development6970 without any known implication in cancer. Identification of SKP2 as a novel substrate of FBXW2 extended the list of FBXW2 substrates and revealed its biological function in human cancer.…”

Section: Discussionmentioning

confidence: 99%

The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

Zhou

Yang

et al. 2017

Nat Commun

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β-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of β-TrCP1 and an E3 ligase for SKP2. While β-TrCP1 promotes FBXW2 ubiquitylation and shortens its half-life, FBXW2 does the same to SKP2. FBXW2 has tumour suppressor activity against lung cancer cells and blocks oncogenic function of both β-TrCP1 and SKP2. The levels of β-TrCP1-FBXW2-SKP2 are inversely correlated during cell cycle with FBXW2 and β-TrCP/SKP2 being high or low, respectively, in arrested cells, whereas the opposite is true in proliferating cells. Consistently, FBXW2 predicts a better patient survival, whereas β-TrCP1 and SKP2 predict a worse survival. Finally, the gain- and loss-of-function mutations of FBXW2 are found in various human cancers. Collectively, our data show that the β-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation.

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Section: Discussionmentioning

confidence: 99%

The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

Zhou

Yang

et al. 2017

Nat Commun

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“…27 As a syncytialization-promoting molecule, GCM1 is required for the differentiation of the human trophoblast. 28 Previously, an interesting study by Chen and coworkers 29 found that GCM1 is a direct target for CUL1, and the CUL1–SCF complex mediates ubiquitination and degradation of human GCM1. In this study, GCM1 mRNA was upregulated after CUL1 siRNA transfection in primary cultured term CTB cells, suggesting a non-ubiquitination-related role of CUL1 on GCM1, which requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

CUL1 promotes trophoblast cell invasion at the maternal–fetal interface

Zhang

Chen

et al. 2013

Cell Death Dis

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Human trophoblast progenitor cells differentiate via two distinct pathways, to become the highly invasive extravillous cytotrophoblast (CTB) cells (EVT) or fuse to form syncytiotrophoblast. Inadequate trophoblast differentiation results in poor placenta perfusion, or even complications such as pre-eclampsia (PE). Cullin1 (CUL1), a scaffold protein in cullin-based ubiquitin ligases, plays an important role in early embryonic development. However, the role of CUL1 in trophoblast differentiation during placenta development has not been examined. Here we show that CUL1 was expressed in CTB cells and EVT in the first trimester human placentas by immunohistochemistry. CUL1 siRNA significantly inhibited outgrowth of extravillous explants in vitro, as well as invasion and migration of HTR8/SVneo cells of EVT origin. This inhibition was accompanied by decreased gelatinolytic activities of matrix metalloproteinase (MMP)-9 and increased expression of tissue inhibitors of MMPs (TIMP-1 and -2). Consistently, exogenous CUL1 promoted invasion and migration of HTR8/SVneo cells. Notably, CUL1 was gradually decreased during trophoblast syncytialization and CUL1 siRNA significantly enhanced forskolin-induced fusion of choriocarcinoma BeWo cells. CUL1 protein levels in human pre-eclamptic placental villi were significantly lower as compared to their matched control placentas. Taken together, our results suggest that CUL1 promotes human trophoblast cell invasion and dysregulation of CUL1 expression may be associated with PE.

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“…8, 9 Furthermore, in vitro studies support a mechanistic relevance of post-translational GCM1 modifications for syncytiotrophoblast formation. 26, 27 However, physiological regulators of post-translational GCM1 modifications and their relevance in human placental diseases remain largely unknown. We demonstrate that expression of p45 NF-E2, which regulates both GCM1 acetylation and sumoylation, is closely related to the post-translational modification of GCM1 in human placentae without or with IUGR.…”

Section: Discussionmentioning

confidence: 99%

p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction

et al. 2017

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Placental insufficiency jeopardizes prenatal development, potentially leading to intrauterine growth restriction (IUGR) and stillbirth. Surviving fetuses are at an increased risk for chronic diseases later in life. IUGR is closely linked with altered trophoblast and placental differentiation. However, due to a paucity of mechanistic insights, suitable biomarkers and specific therapies for IUGR are lacking. The transcription factor p45 NF-E2 (nuclear factor erythroid derived 2) has been recently found to regulate trophoblast differentiation in mice. The absence of p45 NF-E2 in trophoblast cells causes IUGR and placental insufficiency in mice, but mechanistic insights are incomplete and the relevance of p45 NF-E2 for human syncytiotrophoblast differentiation remains unknown. Here we show that p45 NF-E2 negatively regulates human syncytiotrophoblast differentiation and is associated with IUGR in humans. Expression of p45 NF-E2 is reduced in human placentae complicated with IUGR compared with healthy controls. Reduced p45 NF-E2 expression is associated with increased syncytiotrophoblast differentiation, enhanced glial cells missing-1 (GCM1) acetylation and GCM1 desumoylation in IUGR placentae. Induction of syncytiotrophoblast differentiation in BeWo and primary villous trophoblast cells with 8-bromo-adenosine 3′,5′-cyclic monophosphate (8-Br-cAMP) reduces p45 NF-E2 expression. Of note, p45 NF-E2 knockdown is sufficient to increase syncytiotrophoblast differentiation and GCM1 expression. Loss of p45 NF-E2 using either approach resulted in CBP-mediated GCM1 acetylation and SENP-mediated GCM1 desumoylation, demonstrating that p45 NF-E2 regulates post-translational modifications of GCM1. Functionally, reduced p45 NF-E2 expression is associated with increased cell death and caspase-3 activation in vitro and in placental tissues samples. Overexpression of p45 NF-E2 is sufficient to repress GCM1 expression, acetylation and desumoylation, even in 8-Br-cAMP exposed BeWo cells. These results suggest that p45 NF-E2 negatively regulates differentiation and apoptosis activation of human syncytiotrophoblast by modulating GCM1 acetylation and sumoylation. These studies identify a new pathomechanism related to IUGR in humans and thus provide new impetus for future studies aiming to identify new biomarkers and/or therapies of IUGR.

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Ubiquitin-Conjugating Enzyme UBE2D2 Is Responsible for FBXW2 (F-Box and WD Repeat Domain Containing 2)-Mediated Human GCM1 (Glial Cell Missing Homolog 1) Ubiquitination and Degradation1

Cited by 20 publications

References 30 publications

The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

CUL1 promotes trophoblast cell invasion at the maternal–fetal interface

p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction

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