Negative Feedback Regulation of Aurora-A via Phosphorylation of Fas-associated Factor-1

Jang, Moon‐Sun; Sul, Jee-Won; Choi, Byung-Jung; Suh, Jeehee; Kim, Nam-Soon; Kim, Woo Ho; Lim, Dae–Sik; Lee, Chang-Woo; Kim, Eun‐Hee

doi:10.1074/jbc.m804199200

Cited by 22 publications

(24 citation statements)

References 32 publications

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“…Expression of p27 results in protein interaction with pRb to suppress E2F1 activity, thereby establishing a negative feedback mechanism (Wang et al, 2005). Recently, we described a negative feedback mechanism between Aur-A (Aurora-A) and FAF1 (FAS-associated factor 1) (Jang et al, 2008). Here, we describe an additional negative feedback mechanism between an oncogene and a tumor suppressor (that is, Plk1 and FADD).…”

Section: Discussionmentioning

confidence: 93%

“…Phosphorylation dissociates TRADD (tumor necrosis factor receptor 1-associated death domain protein) from the TNFR1 (tumor necrosis factor receptor 1) signaling complex I and leads to the translocation of TRADD to complex II, thereby accelerating the signal transduction process (Jiang et al, 1999). In addition, phosphorylation appears to grant FAF1 the ability to induce mitotic arrest and cell death (Jang et al, 2008). Here, we add FADD to the list of death proteins, the function of which is regulated via phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…Samples were subjected to gel filtration chromatography at a flow rate of 0.5 ml/min on a Superose 6 column with the AKTA fast protein liquid chromatography system (GE Healthcare). The fast protein liquid chromatography analysis and size markers were described previously (Jang et al, 2008).…”

Section: Gel Filtration Chromatographymentioning

confidence: 99%

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Phosphorylation by polo-like kinase 1 induces the tumor-suppressing activity of FADD

et al. 2010

Oncogene

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Phosphorylation of the Fas-associated death domain (FADD) protein sensitizes cancer cells to various chemotherapeutics. However, the molecular mechanism underlying chemosensitization by phosphorylated FADD (P-FADD) is poorly understood. In this study, we describe the physical interactions and functional interplay between Polo-like kinase 1 (Plk1) and FADD. Plk1 phosphorylates FADD at Ser-194 in response to treatment with taxol. Overexpression of a phosphorylation-mimicking mutant, FADD S194D, caused degradation of Plk1 in an ubiquitin-independent manner, and delayed cytokinesis, consistent with the expected cellular phenotype of Plk1 deficiency. This demonstrates that Plk1 is regulated via a negative feedback loop by its substrate, FADD. Overexpression of FADD S194D sensitized HeLa cells to a low dose of taxol independently of caspase activation, whereas overexpression of FADD S194D resulted in caspase activation in response to a high dose of taxol. Therefore, we examined whether the death potential of P-FADD affected Plk1-mediated tumorigenesis. Transfection of FADD S194D inhibited colony formation by Plk1-overexpressing HeLa cells (HeLa-Plk1). Moreover, overexpression of FADD S194D suppressed tumorigenesis in nude mice xenografted with HeLa-Plk1. Therefore, this study reports the first in vivo validation of tumor-suppressing activity of P-FADD. Collectively, our data demonstrate that in response to taxol, Plk1 endows death-promoting and tumor-suppressor functions to its substrate, FADD.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Phosphorylation by polo-like kinase 1 induces the tumor-suppressing activity of FADD

et al. 2010

Oncogene

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“…FAF1 is reported to be an inhibitor of IjB kinase activation. 8 The phosphorylated FAF1 is reported to mediate the ubiquitin-independent, proteasome-dependent degradation of Aurora-A, 9 and most recently as a key component of the TNF-a/NF-jB signaling node that has been independently implicated in asbestos-induced oncogenesis through Arf inactivation. 10 In addition to being a member of the Fas deathinducing signaling complex, FAF1 reportedly interacts with a number of other proteins.…”

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confidence: 99%

Structure and interaction of ubiquitin‐associated domain of human Fas‐associated factor 1

et al. 2009

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Fas-associated factor (FAF)-1 is a multidomain protein that was first identified as a member of the Fas death-inducing signaling complex, but later found to be involved in various biological processes. Although the exact mechanisms are not clear, FAF1 seems to play an important role in cancer, asbestos-induced mesotheliomas, and Parkinson's disease. It interacts with polyubiquitinated proteins, Hsp70, and p97/VCP (valosin-containing protein), in addition to the proteins of the Fas-signaling pathway. We have determined the crystal structure of the ubiquitinassociated domain of human FAF1 (hFAF1-UBA) and examined its interaction with ubiquitin and ubiquitin-like proteins using nuclear magnetic resonance. hFAF1-UBA revealed a canonical threehelical bundle that selectively binds to mono-and di-ubiquitin (Lys48-linked), but not to SUMO-1 (small ubiquitin-related modifier 1) or NEDD8 (neural precursor cell expressed, developmentally down-regulated 8). The interaction between hFAF1-UBA and di-ubiquitin involves hydrophobic interaction accompanied by a transition in the di-ubiquitin conformation. These results provide structural insight into the mechanism of polyubiquitin recognition by hFAF1-UBA.Additional Supporting Information may be found in the online version of this article The first two authors contributed equally to this work.Abbreviations: hFAF1, human Fas-associated factor 1; Ub, Ubiquitin; di-Ub, Lys48-linked di-ubiquitin; RMSD, root mean square deviation; CSP, chemical shift perturbation.

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“…[21][22][23] In addition, FAF1 arrests the cell cycle by negatively regulating Aurora-A. 24 FAF1 also interacts with polyubiquitinated proteins and valosin-containing protein (VCP), inhibiting ubiquitin-dependent protein degradation. 25 Consistently with its cell death-promoting roles, FAF1 downregulation has been observed in gastric and uterine cervix carcinomas.…”

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FAF1 mediates regulated necrosis through PARP1 activation upon oxidative stress leading to dopaminergic neurodegeneration

Kim

2016

Cell Death Differ

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Cumulative damage caused by oxidative stress results in diverse pathological conditions. Therefore, elucidating the molecular mechanisms underlying cell death following oxidative stress is important. Here, we describe a novel role for Fas-associated factor 1 (FAF1) as a crucial regulator of necrotic cell death elicited by hydrogen peroxide. Upon oxidative insult, FAF1 translocated from the cytoplasm to the nucleus and promoted the catalytic activation of poly(ADP-ribose) polymerase 1 (PARP1) through physical interaction. Moreover, FAF1 depletion prevented PARP1-linked downstream events involved in the triggering of cell death, including energetic collapse, mitochondrial depolarization and nuclear translocation of apoptosis-inducing factor (AIF), implying that FAF1 has a key role in PARP1-dependent necrosis in response to oxidative stress. We further investigated whether FAF1 might contribute to the pathogenesis of Parkinson's disease through excessive PARP1 activation. Indeed, the overexpression of FAF1 using a recombinant adeno-associated virus system in the mouse ventral midbrain promoted PARP1 activation and dopaminergic neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Collectively, our data demonstrate the presence of an FAF1-PARP1 axis that is involved in oxidative stress-induced necrosis and in the pathology of Parkinson's disease.

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Negative Feedback Regulation of Aurora-A via Phosphorylation of Fas-associated Factor-1

Cited by 22 publications

References 32 publications

Phosphorylation by polo-like kinase 1 induces the tumor-suppressing activity of FADD

Phosphorylation by polo-like kinase 1 induces the tumor-suppressing activity of FADD

Structure and interaction of ubiquitin‐associated domain of human Fas‐associated factor 1

FAF1 mediates regulated necrosis through PARP1 activation upon oxidative stress leading to dopaminergic neurodegeneration

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