FBG1 is a promiscuous ubiquitin ligase that sequesters APC2 and causes S-phase arrest

Wen, Hsiang; Kim, Namhun; Fuentes, Ernesto J.; Mallinger, Adam; Gonzalez‐Alegre, Pedro; Glenn, Kevin A.

doi:10.4161/cc.9.22.13743

Cited by 8 publications

(6 citation statements)

References 57 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies indeed report a functional role of our identified GFAP-regulated gene set in the regulation of proliferation, mitosis, and tumour growth. While the high-malignant gene SPC24 positively regulates cell proliferation [ 40 , 49 ], the low-malignant gene FBXO2 induces growth arrest [ 50 , 51 ]. NOS2 and VAV3 stimulate glioma-initiating cell proliferation and tumour growth in xenograft models [ 34 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

GFAPδ/GFAPα ratio directs astrocytoma gene expression towards a more malignant profile

et al. 2017

View full text Add to dashboard Cite

Astrocytomas are the most common malignant brain tumours and are to date incurable. It is unclear how astrocytomas progress into higher malignant grades. The intermediate filament cytoskeleton is emerging as an important regulator of malignancy in several tumours. The majority of the astrocytomas express the intermediate filament protein Glial Fibrillary Acidic Protein (GFAP). Several GFAP splice variants have been identified and the main variants expressed in human astrocytoma are the GFAPα and GFAPδ isoforms. Here we show a significant downregulation of GFAPα in grade IV astrocytoma compared to grade II and III, resulting in an increased GFAPδ/α ratio. Mimicking this increase in GFAPδ/α ratio in astrocytoma cell lines and comparing the subsequent transcriptomic changes with the changes in the patient tumours, we have identified a set of GFAPδ/α ratio-regulated high-malignant and low-malignant genes. These genes are involved in cell proliferation and protein phosphorylation, and their expression correlated with patient survival. We additionally show that changing the ratio of GFAPδ/α, by targeting GFAP expression, affected expression of high-malignant genes. Our data imply that regulating GFAP expression and splicing are novel therapeutic targets that need to be considered as a treatment for astrocytoma.

show abstract

Section: Discussionmentioning

confidence: 99%

GFAPδ/GFAPα ratio directs astrocytoma gene expression towards a more malignant profile

et al. 2017

View full text Add to dashboard Cite

show abstract

“…APC2 was significantly increased when inhibited Talin-1’s expression. Wen H et al found that when free APC2 was decreased the proliferation of cell was inhibited [ 39 ]. Our in vitro study found that the VSMCs proliferation was promoted when Talin-1 was decreased and APC2 might play an important role in this process.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Talin-1 expression associates with increased proliferation and migration of vascular smooth muscle cells in aortic dissection

Wei

Sun

et al. 2017

BMC Cardiovasc Disord

View full text Add to dashboard Cite

BackgroundThis study aimed to assessed whether Talin-1 is involved in the pathogenesis of aortic dissection via regulating vascular smooth muscle cell (VSMC) biological function.MethodsHuman aortic samples were obtained from organ donors who died from nonvascular diseases as normal controls and from patients undergoing surgical repair of thoracic aortic dissection. The expression level and distribution of Talin-1 were detected using westernblot analysis and immunohistochemistry in each sample. We inhibited the expression of Talin-1 via RNA interference in VSMCs. VSMC proliferation was detected by Cell-counting Kit-8 analyses. Scratch test and flow cytometry were used to identify the migration and apoptosis ability. Antibody microarray analysis and qRT-PCR were used to detect some protein and mRNA changes which were induced by Talin-1 downregulation.ResultsTalin-1 was significantly downregulated in the media of aortic dissection samples compared with controls (P < 0.05). Talin-1 knockdown significantly induced VSMC proliferation and migration in vitro. Proteins which involved in cell cycle can be regulated by downregulating Talin-1. Down regulation of Talin-1 can significanly increased the expression of anaphase-promoting complex subunit 2 (APC2) and decreased p19 alternative reading frame (p19ARF), Cullin-3, and beta actin’s expression.ConclusionsTalin-1 induces VSMCs proliferation and migration. It downregulated in aortic dissection, which might play a potential role in the development of aortic dissection.

show abstract

“…Furthermore, FBG1 forms heterodimers with SKP1 reducing glycoprotein aggregation (Yoshida et al, 2007). A recent report highlighted promiscuous interactions of FBG1 with different adaptor proteins through its N-terminal domain that potentially modulate substrate selection (Wen et al, 2010). We observed an effect of FBG1 when lacking its N-terminal domain (both the F-box and PEST domains) on torsinA levels which further suggests the presence of SCF-independent and CHIP-independent mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…TorsinA(wt) and (ΔE) (Gonzalez-Alegre and Paulson, 2004) and HA-FBG1 inducible PC6.3 cells (Wen et al, 2010) were induced with doxycycline at 1.5 μg/ml as described (Gordon et al, 2011). Cos7 and HEK293 cells were grown and maintained in DMEM (Gibco) with 10% FBS as described (Gordon and Gonzalez-Alegre, 2008).…”

Section: Methodsmentioning

confidence: 99%

The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin–proteasome pathway and macroautophagy

et al. 2012

View full text Add to dashboard Cite

DYT1 dystonia is a dominantly inherited, disabling neurological disorder with low penetrance that is caused by the deletion of a glutamic acid (ΔE) in the protein torsinA. We previously showed that torsinA(wt) is degraded through macroautophagy while torsinA(ΔE) is targeted to the ubiquitin proteasome pathway (UPP). The different catabolism of torsinA(wt) and (ΔE) potentially modulates torsinA(wt):torsinA(ΔE) stoichiometry. Therefore, gaining a mechanistic understanding on how the protein quality control machinery clears torsinA(ΔE) in neurons may uncover important regulatory steps in disease pathogenesis. Here, we asked whether FBG1, a ubiquitin ligase known to degrade neuronal glycoproteins, is implicated in the degradation of torsinA(ΔE) by the UPP. In a first set of studies completed in cultured cells, we show that FBG1 interacts with and influences the steady-state levels of torsinA(wt) and (ΔE). Interestingly, FBG1 achieves this effect promoting the degradation of torsinA not only through the UPP, but also by macroautophagy. To determine the potential clinical significance of these findings, we asked if eliminating expression of Fbg1 triggers a motor phenotype in torsinA(ΔE) knock in mice, a model of non-manifesting DYT1 mutation carriers. We detected differences in spontaneous locomotion between aged torsinA(ΔE) knock in-Fbg1 knock out and control mice. Furthermore, neuronal levels of torsinA were unaltered in Fbg1 null mice, indicating that redundant systems likely compensate in vivo for the absence of this ubiquitin ligase. In summary, our studies support a non-essential role for FBG1 on the degradation of torsinA and uncover a novel link of FBG1 to the autophagy pathway.

show abstract

FBG1 is a promiscuous ubiquitin ligase that sequesters APC2 and causes S-phase arrest

Cited by 8 publications

References 57 publications

GFAPδ/GFAPα ratio directs astrocytoma gene expression towards a more malignant profile

GFAPδ/GFAPα ratio directs astrocytoma gene expression towards a more malignant profile

Downregulation of Talin-1 expression associates with increased proliferation and migration of vascular smooth muscle cells in aortic dissection

The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin–proteasome pathway and macroautophagy

Contact Info

Product

Resources

About