Disease relevance of FANCC

• We found that spontaneous SCE levels were elevated approximately 2-fold in chicken DT40 cells deficient in Fanconi anemia (FA) gene FANCC [1].
• Recently, several sequence changes in FANCC and FANCG were reported in pancreatic cancer [2].
• Studies using FANCA and FANCC knockout mice suggest that bone marrow precursors express interferon-gamma hypersensitivity and show progressive apoptosis [3].
• Finally, FANCC and FANCG disruption increased spontaneous chromosomal breakage, supporting the role of these genes in genome maintenance and likely explaining why they are mutated in sporadic cancer [4].
• METHODS: We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and determined the impact of these genes on drug sensitivity, irradiation sensitivity, and genome maintenance [4].

Psychiatry related information on FANCC

• A total of 149 chemotherapy-naive, female outpatients, under 50 years of age and with no history of alcohol consumption, scheduled to receive their first cycle of FAC chemotherapy, were included [5].
• These second tumors developed after a median latency period of 17.5 months for the FAC-treated group and 13 months for the controls [6].

High impact information on FANCC

• The two cloned FA genes, FAA and FAC, encode proteins that are unrelated to each other or to other proteins in GenBank [7].
• A cDNA for the group C gene (FAC) was reported and localized to chromosome 9q22.3 (ref.8) [8].
• In order to determine the fraction of Fanconi anaemia caused by FACC mutations, we used reverse transcription PCR and chemical mismatch cleavage (CMC) to examine the FACC cDNA in 17 FA cell lines [9].
• Here we show that glutathione S-transferase P1-1 (GSTP1) interacts with FANCC, and that overexpression of both proteins in a myeloid progenitor cell line prevents apoptosis following factor deprivation [10].
• FANCC increases GSTP1 activity after the induction of apoptosis [10].

Chemical compound and disease context of FANCC

• Serial plasma carcinoembryonic antigen (CEA) levels were measured in 167 patients with metastatic breast cancer treated with fluorouracil, doxorubicin hydrochloride, and cyclophosphamide (FAC) [11].
• PURPOSE AND METHODS: Data from a randomized phase III trial in early breast cancer, comparing surgery followed by one short intensive course of perioperative fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus surgery alone, were analyzed for the occurrence of thromboembolic complications within 6 weeks after surgery [12].
• PATIENTS AND METHODS: A total of 267 women with metastatic breast cancer were randomized to receive either AT (doxorubicin 50 mg/m(2) followed 24 hours later by paclitaxel 220 mg/m(2)) or FAC (5-fluorouracil 500 mg/m(2), doxorubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2)), each administered every 3 weeks for up to eight cycles [13].
• PURPOSE: To assess whether dexrazoxane (DZR) given after a cumulative doxorubicin dose of 300 mg/m2 confers cardioprotection in patients with advanced breast cancer treated with fluorouracil, doxorubicin, and cyclophosphamide (FAC) [14].
• BACKGROUND: The purpose of this study was to determine the relative efficacy of doxorubicin versus methotrexate in combination with intravenous cyclophosphamide and 5-fluorouracil (FAC versus CMF) as adjuvant chemotherapy for operable breast cancer [15].

Biological context of FANCC

• Disease-associated FANCC mutants do not bind to FANCE, cannot accumulate in the nucleus and are unable to prevent chromosome breakage [16].
• FANCC is also required for optimal activation of STAT1 in response to cytokine and growth factors and for suppressing cytokine-induced apoptosis by modulating the activity of double-stranded RNA-dependent protein kinase [17].
• We found that although FANCC mRNA levels are constant throughout the cell cycle, FANCC is expressed in a cell cycle-dependent manner, with the lowest levels seen in cells synchronized at the G1/S boundary and the highest levels in the M-phase [18].
• These results suggest that the function of FANCC may be linked to a transcriptional repression pathway involved in chromatin remodeling [19].
• We therefore sought to define the specific role of FANCC protein in signal transduction through receptors that activate STAT1 [20].

Anatomical context of FANCC

• We identified the molecular chaperone Hsp70 as an interacting partner of FANCC in lymphoblasts and HeLa cells using 'pull-down' and co-immunoprecipitation experiments [21].
• Interestingly, a truncated mutant form of the FANCG protein, lacking the carboxy terminus, binds in a complex with FANCA and translocates to the nucleus; however, this mutant protein fails to bind to FANCC and fails to correct the mitomycin C sensitivity of an FA-G cell line [22].
• High constitutive expression of the IFNgamma-inducible genes, IFN-stimulated gene factor 3 gamma subunit (ISGF3gamma), IFN regulatory factor-1 (IRF-1), and the cyclin-dependent kinase inhibitor p21(WAF1) was found in FANCC mutant B lymphoblasts, low-density bone marrow cells, and murine embryonic fibroblasts [23].
• CONCLUSIONS: These results support a model where both FANCA and FANCC are part of a multi-protein nuclear FA complex with identical function in cellular responses to DNA damage and germ cell survival [24].
• SETTING: In vitro fertilization programs at large medical centers in Chicago, Ill, and Denver, Colo. PARTICIPANTS: A couple, both carriers of the IVS 4 + 4 A-->T mutation in the FANCC gene with an affected child requiring an HLA-compatible donor for cord blood transplantation [25].

Associations of FANCC with chemical compounds

• Six separate alanine-substituted mutations were generated in 3 highly conserved motifs of FANCC [17].
• DESIGN: DNA analysis for the IVS 4 + 4 A-->T (adenine to thymine) mutation in the FA complement C (FANCC) gene in single blastomeres, obtained by biopsy of embryos, to identify genetic status and HLA markers of each embryo before intrauterine transfer [25].
• DNA fragmentation was clearly visible under high cisplatin conditions and to some extent at a low concentration in FA-A cells, but not in the FA-C cell line regardless of the presence of functional FANCC, suggesting an unknown deficiency in these cells [26].
• Mitomycin C and diepoxybutane action mechanisms and FANCC protein functions: further insights into the role for oxidative stress in Fanconi's anaemia phenotype [27].
• RESULTS: Serial weekly intraperitoneal administrations of escalating doses of rmIFN-gamma did not affect peripheral blood counts in FANCC(-/-) mice, even after subsequent antibody-mediated fas ligation [28].

Physical interactions of FANCC

• Additional amino acid sequences at the carboxy terminus of FANCG are required for the binding of FANCC in the complex [22].
• A Leu554Pro mutant of FANCC failed to interact with FANCE [29].
• FANCC is found in both the cytoplasmic and the nuclear compartments and interacts with certain other FA complementation group proteins as well as with non-FA proteins [18].
• FANCC has been shown to interact with several cytoplasmic and nuclear proteins and to delay the onset of apoptosis through redox regulation of GSTP1 [30].
• Because apoptotic responses of mutant FA-C cells involve activation of interferon-inducible, dsRNA-dependent protein kinase PKR, we sought to identify FANCC-binding cofactors that may modulate PKR activation [21].

Regulatory relationships of FANCC

• The observed specific changes in gene expression suggest that FANCC regulates specifically myeloid differentiation and unmasks a previously unsuspected anti-inflammatory role for the FA proteins [31].
• Enhanced ROS accumulation and decreased intracellular glutathione levels were observed in FA-C B-cell lines primed with IFN-gamma and treated with agonistic anti-Fas antibody than in isogenic control cells corrected with FANCC [32].

Other interactions of FANCC

• Here we show that the recently identified FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2 [16].
• Neither FANCA nor FANCC was found to interact with itself [33].
• However, in coimmunoprecipitation experiments STAT1 did not dock at the IFN-gammaR of FA-C cells, an abnormality corrected by transduction of the FANCC gene [20].
• A novel BTB/POZ transcriptional repressor protein interacts with the Fanconi anemia group C protein and PLZF [19].
• The fancc/brca2DeltaCTD double mutant revealed an epistatic relationship between FANCC and BRCA2 CTD in terms of x-ray sensitivity [34].

Analytical, diagnostic and therapeutic context of FANCC

• Multivariate analysis of overall survival time shows that FANCC mutations (P =.007) and hematopoietic stem cell transplantation (P = <.0001) define a poor-risk subgroup [35].
• Sequence analysis of 38 individuals with familial pancreatic cancer enrolled in the National Familial Pancreatic Tumor Registry (NFPTR) revealed previously identified polymorphisms within two exons and one intron of FANCC, and in three introns of FANCG [36].
• Analysis by pulsed-field gel electrophoresis and single-cell gel electrophoresis of MMC-treated cells showed that FA cells from complementation group C (FA-C cells, defective in the FANCC gene) form double-strand breaks and unhook MMC-induced ICL similarly to FANCC wild-type cells [37].
• Furthermore, this nontoxic regimen also selected FANCC-mutant HSC corrected by ex vivo retroviral gene therapy [38].
• Hypersensitivity to cross-linking agents was confirmed in vivo; FANCC-deficient xenografts of PL11 and BRCA2-deficient xenografts of CAPAN1 regressed on treatment with two different regimens of MMC whereas Fanconi anemia-proficient xenografts did not [39].

References