Identification of Flightless-I as a Substrate of the Cytokine-independent Survival Kinase CISK

Xu, Jun; Liao, Lan; Qin, Jun; Xu, Jianming; Liú, Dan; Songyang, Zhou

doi:10.1074/jbc.m807770200

Cited by 21 publications

(29 citation statements)

References 64 publications

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“…For bi-molecular fluorescence complementation (BiFC) assay, TAH1 was tagged at the C-terminus with the Cterminal fragment of YFP (YFPc, residues 156-239), whereas PML was Cterminally tagged with the N-terminal fragment of Venus YFP (YFPn, residues 1-155) . For RNAi, shRNA sequences were cloned into the pcl-mU6 retroviral vector between BamHI and HindIII sites (Xu et al, 2009). And siRNAs were reverse transfected into cells for 48 to 72 hours.…”

Section: Constructs Cell Lines and Antibodiesmentioning

confidence: 99%

The telomere-associated homeobox-containing protein TAH1 participates in telomere maintenance in ALT Cells

Feng

Luo

Jiang

et al. 2013

Journal of Cell Science

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SummaryThe majority of cancer cells rely on elevated telomerase expression and activity for rapid growth and proliferation. Telomerase-negative cancer cells, by contrast, often employ the alternative lengthening of telomeres (ALT) pathway to maintain telomeres. ALT cells are characterized by long and dynamic telomeres and the presence of ALT-associated promyelocytic leukemia (PML) bodies (APBs). Previous work has shown the importance of APBs to the ALT pathway, but their formation and precise role remain unclear. Here, we demonstrate that a homeobox-containing protein known as HMBOX1 can directly bind telomeric double-stranded DNA and associate with PML nuclear bodies. Hence, we renamed this protein TAH1 for telomere-associated homeobox-containing protein 1. TAH1 knockdown significantly reduced the number of APBs and led to an increase in DNA damage response signals at telomeres. Importantly, TAH1 inhibition also notably reduced the presence of telomere C-circles, indicating altered ALT activity. Our findings point to TAH1 as a novel link between pathways that regulate DNA damage responses, PML nuclear bodies, and telomere homeostasis in ALT cells, and provide insight into how ALT cells may achieve sustained growth and proliferation independent of the telomerase.

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Section: Constructs Cell Lines and Antibodiesmentioning

confidence: 99%

The telomere-associated homeobox-containing protein TAH1 participates in telomere maintenance in ALT Cells

Feng

Luo

Jiang

et al. 2013

Journal of Cell Science

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“…Cell index values were calculated using the RTCA Software (1.0.0.0805). All curves were normalised at the beginning of the treatment period applying the RTCA Software 23 24…”

Section: Methodsmentioning

confidence: 99%

Dual antitumour effect of 5-azacytidine by inducing a breakdown of resistance-mediating factors and epigenetic modulation

Venturelli

Berger

Weiland

et al. 2010

Gut

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BackgroundThe cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown promising anticancer activity in early clinical settings by selectively inducing apoptosis in different tumour types. However, some tumour entities such as hepatocellular carcinoma (HCC) display an inherent resistance to TRAIL. A huge effort has been made to unravel strategies for a clinically applicable sensitisation of resistant cancer cells to TRAIL. Reversible epigenetic alterations such as DNA methylation play a major role in development, maintenance and resistance phenomena of tumour cells. Currently, several clinical trials are exploiting the potential of epigenetic drugs, such as 5-azacytidine (5-aza-CR) or 5-aza-2 9 -deoxycytidine (5-aza-dC) to break primary or secondary resistance phenomena of cancer cells. Therefore, 5-aza-CR and 5-aza-dC were investigated in the context of TRAIL resistance. Methods Alterations in proliferation, apoptosis, regulatory proteins and toxicity were investigated in TRAIL-resistant hepatoma, and also in renal, colon and pancreatic cancer cells as well as non-transformed human-derived primary hepatocytes, tissue slices isolated from human liver and non-malignant colon cells, all of which had been exposed to demethylating drugs and/or TRAIL. Results Within hours, 5-aza-CR but not 5-aza-dC sensitised in vitro cultured tumour cells to TRAIL, first by activating caspases, followed by a subsequent induction of apoptosis. This surprisingly rapid sensitisation was confirmed in vivo employing a chorioallantoic membrane assay. As a major mechanism, a 5-aza-CR-induced inhibition of cellular protein synthesis was found which led to a breakdown of tumour-protecting factors such as the antiapoptotic factor FLICE inhibitory protein (FLIP). Importantly, TRAIL and 5-aza-CR did not induce relevant toxicity or apoptosis in primary hepatocytes, liver slices from different human donors and in normal colon cells. Conclusions Molecular evidence is provided for a novel 5-aza-CR-based translational approach enabling a twofold treatment of apoptosis-resistant tumour entities, not only by an epigenetic reversion of the malignancy-associated phenotype but also by an efficient resensitisation to apoptosis-inducing substances such as TRAIL.

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“…FLI-I is the only member of the gelsolin superfamily that is essential for mouse development, as disruption of the mouse homologue fliih gene results in a rapid degeneration of the embryo (4). Knock-down of FLI-I increases apoptosis induced by cytokine withdrawal, suggesting that FLI-I is a survival factor (90). Recently, it was demonstrated the ability of FLI-I to bind and inhibit pro-inflammatory caspase 1 (51).…”

Section: Grx1 and S-glutathionylation In Pdreactive Species (Protein mentioning

confidence: 99%

Glutaredoxin 1 Protects Dopaminergic Cells by Increased Protein Glutathionylation in Experimental Parkinson's Disease

Rodríguez-Rocha

Garcia

Zavala-Flores

et al. 2012

Antioxidants & Redox Signaling

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Aims: Chronic exposure to environmental toxicants, such as paraquat, has been suggested as a risk factor for Parkinson's disease (PD). Although dopaminergic cell death in PD is associated with oxidative damage, the molecular mechanisms involved remain elusive. Glutaredoxins (GRXs) utilize the reducing power of glutathione to modulate redox-dependent signaling pathways by protein glutathionylation. We aimed to determine the role of GRX1 and protein glutathionylation in dopaminergic cell death. Results: In dopaminergic cells, toxicity induced by paraquat or 6-hydroxydopamine (6-OHDA) was inhibited by GRX1 overexpression, while its knockdown sensitized cells to paraquat-induced cell death. Dopaminergic cell death was paralleled by protein deglutathionylation, and this was reversed by GRX1. Mass spectrometry analysis of immunoprecipitated glutathionylated proteins identified the actin binding flightless-1 homolog protein (FLI-I) and the RalBP1-associated Eps domain-containing protein 2 (REPS2/POB1) as targets of glutathionylation in dopaminergic cells. Paraquat induced the degradation of FLI-I and REPS2 proteins, which corresponded with the activation of caspase 3 and cell death progression. GRX1 overexpression reduced both the degradation and deglutathionylation of FLI-I and REPS2, while stable overexpression of REPS2 reduced paraquat toxicity. A decrease in glutathionylated proteins and REPS2 levels was also observed in the substantia nigra of mice treated with paraquat. Innovation: We have identified novel protein targets of glutathionylation in dopaminergic cells and demonstrated the protective role of GRX1-mediated protein glutathionylation against paraquat-induced toxicity. Conclusions: These results demonstrate a protective role for GRX1 and increased protein glutathionylation in dopaminergic cell death induced by paraquat, and identify a novel protective role for REPS2.

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Identification of Flightless-I as a Substrate of the Cytokine-independent Survival Kinase CISK

Cited by 21 publications

References 64 publications

The telomere-associated homeobox-containing protein TAH1 participates in telomere maintenance in ALT Cells

The telomere-associated homeobox-containing protein TAH1 participates in telomere maintenance in ALT Cells

Dual antitumour effect of 5-azacytidine by inducing a breakdown of resistance-mediating factors and epigenetic modulation

Glutaredoxin 1 Protects Dopaminergic Cells by Increased Protein Glutathionylation in Experimental Parkinson's Disease

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