Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1

Cumming, Robert; Lightfoot, Jeff; Beard, Kristin; Youssoufian, Hagop; O’Brien, Peter J.; Buchwald, Manuel

doi:10.1038/89937

Cited by 234 publications

(159 citation statements)

References 42 publications

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“…Elevated levels of GST are associated with increased resistance to apoptosis initiated by a variety of stimuli (Kodym et al, 1999;Voehringer et al, 2000;Cumming et al, 2001). These data are consistent with GSTs acting as inhibitors of the MAP kinase pathway.…”

Section: Resistancesupporting

confidence: 72%

The role of glutathione-S-transferase in anti-cancer drug resistance

2003

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Section: Resistancesupporting

confidence: 72%

The role of glutathione-S-transferase in anti-cancer drug resistance

2003

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“…However, no defined biochemical mechanism for this hypersensitivity has been elucidated, although studies have implicated cytokine dysregulation, excessive, oxidative damage, defects in DNA repair, and lack of cell cycle control (23)(24)(25)(26)(27). Patient and cellular phenotypes across all the complementation groups are similar, suggesting an inter-relatedness or cooperativity between the FA proteins.…”

mentioning

confidence: 86%

Phosphorylation of Fanconi Anemia (FA) Complementation Group G Protein, FANCG, at Serine 7 Is Important for Function of the FA Pathway

Qiao¹,

Mi²,

Wilson

et al. 2004

Journal of Biological Chemistry

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Fanconi anemia (FA) 1 is a genetic disease of cancer susceptibility marked by congenital defects, bone marrow failure, and myeloid leukemia (1-4). To date at least 11 complementation groups have been defined (5-7). Eight genes have been cloned (8 -17). However, the gene products resemble no known proteins and have few identifiable functional protein motifs. One exception is the recently cloned FANCL gene, which contains the ubiquitin ligase motif. In addition, the FANCD1 gene has been identified as BRCA2, one of the familial breast cancer genes.Cells derived from patients with the FA exhibit characteristic hypersensitivity caused by DNA cross-linking agents and generalized decreased survival (18 -22). However, no defined biochemical mechanism for this hypersensitivity has been elucidated, although studies have implicated cytokine dysregulation, excessive, oxidative damage, defects in DNA repair, and lack of cell cycle control (23-27). Patient and cellular phenotypes across all the complementation groups are similar, suggesting an inter-relatedness or cooperativity between the FA proteins.This cooperativity has been borne out by work we have done in showing binding of FANCA and FANCC in a protein complex in both nucleus and cytoplasm (28 -30). Recent work has found the FANCE, FANCF, FANCG, and FANCL proteins in the complex as well (31-34). A large complex is suggested by our recent work (35), and binding does not occur in any of the complementation groups except the FA-D1, D2, I, and J groups (7).One clue to FA function lies in the study of the FANCA protein, which contains a classic bipartite nuclear localization signal and is phosphorylated. Generally, FANCA nuclear localization, phosphorylation, and binding to FANCC are abolished in all complementation groups except the FA-D1 and D2 groups (28 -30, 33). This suggests that a nuclear event is critical to the normal function of the FA proteins, and the aberrant proteins in the FA-D groups may have a role downstream of the FA complex in the nucleus. However, some have found FANCA point mutants that are expressed, translocated to the nucleus, and are phosphorylated to some extent. Some of these mutants are of intermediate MMC sensitivity (36).Over the years, little information has been found that addresses the regulation of the FA proteins. mRNA or protein levels change little in response to DNA damage or the cell cycle. Our recent work has revealed that at least a subset of the FA proteins resides in the nucleus bound to chromatin, where increased protein binding occurs in response to DNA damage (37). One of the non-core complex FA proteins, FANCD2, becomes monoubiquitinated in response to DNA damage (38).In addition, we have shown during the cell cycle that the FA proteins detach from chromatin during mitosis, and FANCG becomes phosphorylated while remaining part of the complex (37). One group has demonstrated that FANCG has a isoform seen in asynchronous cells that is phosphatase sensitive (39).In this paper we report the identification of a phosphopeptide from ...

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“…A line of molecular evidence has related at least two FA gene-encoded proteins with redox pathways. The protein encoded by the Fanconi gene C (FANCC) has been shown to associate with redox-related activities, namely, NADPH cytochrome P450 reductase (Kruyt et al 1998) and glutathione S-transferase (Cumming et al 2001). A recent study has provided evidence that the FANCG protein interacts with cytochrome P450 2E1 protein, an activity also known to be involved in redox biotransformation of xenobiotics (Futaki et al 2002).…”

Section: Prooxidant State In Fa Phenotypementioning

confidence: 99%