FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity

Pang, Qishen; Keeble, Winifred; Christianson, Tracy A.; Faulkner, Gregory R.; Bagby, Grover C.

doi:10.1093/emboj/20.16.4478

Cited by 122 publications

(120 citation statements)

References 60 publications

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“…Interestingly, FANCC seems to be involved both in the protection of cells against oxidative damage and in the control of TNF-α activity (45). Cytoplasmic FANCC interacts with heat shock protein 70 to protect cells from IFN-γ/TNF-α-induced apoptosis (46). Such activation may involve transforming growth factor β1, which induces concomitant activation of a caspase signaling cascade, in response to oxidative damage, followed by PARP cleavage and p53-independent apoptosis (47).…”

Section: Discussionmentioning

confidence: 99%

Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells

Lyakhovich

Surrallés

2010

Molecular Cancer Research

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Fanconi anemia (FA) is a rare syndrome characterized by developmental abnormalities, progressive bone marrow failure, and cancer predisposition. Cells from FA patients exhibit hypersensitivity to DNA cross-linking agents and oxidative stress that may trigger apoptosis. Damage-induced activation of caspases and poly ADP ribose polymerase (PARP) enzymes have been described for some of the FA complementation groups. Here, we show the constitutive activation of caspase-3 and PARP cleavage in the FA cells without exposure to exogenous DNA-damaging factors. These effects can be reversed in the presence of reactive oxygen species scavenger Nacetylcystein. We also show the accumulation of oxidized proteins in FA cells, which is accompanied by the tumor necrosis factor (TNF)-α oversecretion and the upregulation of early stress response kinases pERK1/2 and p-P38. Suppression of TNF-α secretion by the extracellular signal-regulated kinase inhibitor PD98059 results in reduction of caspase-3 cleavage, suggesting a possible mechanism of caspases-3 activation in FA cells. Thus, the current study is the first evidence demonstrating the damage-independent activation of caspase-3 and PARP in FA cells, which seems to occur through mitogen-activated protein kinase activation and TNF-α oversecretion.

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Section: Discussionmentioning

confidence: 99%

Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells

Lyakhovich

Surrallés

2010

Molecular Cancer Research

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“…27) was constructed by site-directed mutagenesis by using SF␤91-PKR as the template and primers (sense, 5Ј-GGAAAGACTTACGTT-ATTAGACGTGTTAAATATAATAAC-3Ј; antisense, 5Ј-GTTATTATA-TTTAACACGTCTAATAACGTAAGTCTTTCC-3Ј). The FA-C patientderived mutant FANCC L554P cDNA (28) was removed from pLXSN-L554P (24) and subcloned into the NotI site of SF␤91 as described above. The SF␤91 plasmids (10 g each) were used to produce retroviral supernatant.…”

Section: Construction Of Retroviral Expression Vectors and Transduction-mentioning

confidence: 99%

“…Immunoprecipitation and Immunoblotting-Whole cell extracts (WCE), prepared in Nonidet P-40 lysis buffer (24), were precleared with 50 l of 50% protein A-Sepharose suspension (Amersham Biosciences) for 1 h at 4°C. After separation of the protein A-Sepharose, the extract was incubated with the indicated primary antibodies.…”

Section: Construction Of Retroviral Expression Vectors and Transduction-mentioning

confidence: 99%

“…3) suggests that FANCC binds to PKR and then recruits other components to the complex, resulting in the displacement of FANCC and control of PKR activity. The release of FANCC from the complex may depend upon a functional interaction between FANCC and the other two FA proteins (12,18) or the association of FANCC with Hsp70 (23,24). Disruption of these interactions would be expected to lead to the kind of abnormal PKR activation in FA cells (Fig.…”

Section: Fig 3 the Activity Of Pkr Kinase In Normal And Fa Bone Marmentioning

confidence: 99%

“…We thus sought to investigate the mechanism by which FANCC modulates PKR activity. We found that suppression of the PKR kinase in FA cells required a coordinated action of FANCC and the molecular chaperone Hsp70, a cytoprotective factor we have previously shown to act in concert with FANCC to protect hematopoietic cells from cytotoxicity induced by mitogenic inhibitors interferon ␥ (IFN-␥) and tumor necrosis factor ␣ (TNF-␣) (24). In this report, we demonstrate that three FA proteins, FANCA, FANCC, and FANCG, functionally interact with the PKR kinase.…”

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confidence: 99%

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The Fanconi Anemia Proteins Functionally Interact with the Protein Kinase Regulated by RNA (PKR)

Zhang

Sejas

et al. 2004

Journal of Biological Chemistry

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Protein kinase regulated by RNA (PKR) plays critical roles in cell growth and apoptosis and is implicated as a potential pathogenic factor of Alzheimer's, Parkinson's, and Huntington's diseases. Here we report that this proapoptotic kinase is also involved in Fanconi anemia (FA), a disease characterized by bone marrow (BM) failure and leukemia. We have used a BM extract to show that three FA proteins, FANCA, FANCC, and FANCG, functionally interact with the PKR kinase, which in turn regulates translational control. By using a combined immunoprecipitation and reconstituted kinase assay, in which an active PKR kinase complex was captured from a normal cell extract, we demonstrated functional interactions between the FA proteins and the PKR kinase. In primary human BM cells, mutations in the FANCA, FANCC, and FANCG genes markedly increase the amount of PKR bound to FANCC, and this PKR accumulation is correlated with elevated PKR activation and hypersensitivity of BM progenitor cells to growth repression mediated by the inhibitory cytokines interferon-␥ and tumor necrosis factor-␣. Specific inhibition of PKR by 2-aminopurine in these FA BM cells attenuates PKR activation and apoptosis induction. In lymphoblasts derived from an FA-C patient, overexpression of a dominant negative mutant PKR (PKR K296R ) suppressed PKR activation and apoptosis induced by interferon-␥ and tumor necrosis factor-␣. Furthermore, by using genetically matched wild-type and PKR-null cells, we demonstrated that forced expression of a patient-derived FA-C mutant (FANCC L554P ) augmented double-stranded RNA-induced PKR activation and cell death. Thus, inappropriate activation of PKR as a consequence of certain FA mutations might play a role in bone marrow failure that frequently occurred in FA.

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Inherited Bone Marrow Failure Syndromes

Dror¹

2006

Pediatric Hematology

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FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity

Cited by 122 publications

References 60 publications

Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells

Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells

The Fanconi Anemia Proteins Functionally Interact with the Protein Kinase Regulated by RNA (PKR)

Inherited Bone Marrow Failure Syndromes

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