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FANCC  -  Fanconi anemia, complementation group C

Homo sapiens

 
 
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Disease relevance of FANCC

 

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

 

Chemical compound and disease context of FANCC

 

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

References

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  2. Functional defects in the fanconi anemia pathway in pancreatic cancer cells. van der Heijden, M.S., Brody, J.R., Gallmeier, E., Cunningham, S.C., Dezentje, D.A., Shen, D., Hruban, R.H., Kern, S.E. Am. J. Pathol. (2004) [Pubmed]
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  4. Targeted disruption of FANCC and FANCG in human cancer provides a preclinical model for specific therapeutic options. Gallmeier, E., Calhoun, E.S., Rago, C., Brody, J.R., Cunningham, S.C., Hucl, T., Gorospe, M., Kohli, M., Lengauer, C., Kern, S.E. Gastroenterology (2006) [Pubmed]
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  7. The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex. Kupfer, G.M., Näf, D., Suliman, A., Pulsipher, M., D'Andrea, A.D. Nat. Genet. (1997) [Pubmed]
  8. Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. Lo Ten Foe, J.R., Rooimans, M.A., Bosnoyan-Collins, L., Alon, N., Wijker, M., Parker, L., Lightfoot, J., Carreau, M., Callen, D.F., Savoia, A., Cheng, N.C., van Berkel, C.G., Strunk, M.H., Gille, J.J., Pals, G., Kruyt, F.A., Pronk, J.C., Arwert, F., Buchwald, M., Joenje, H. Nat. Genet. (1996) [Pubmed]
  9. A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews. Whitney, M.A., Saito, H., Jakobs, P.M., Gibson, R.A., Moses, R.E., Grompe, M. Nat. Genet. (1993) [Pubmed]
  10. Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Cumming, R.C., Lightfoot, J., Beard, K., Youssoufian, H., O'Brien, P.J., Buchwald, M. Nat. Med. (2001) [Pubmed]
  11. Serial plasma carcinoembryonic antigen measurements during treatment of metastatic breast cancer. Mughal, A.W., Hortobagyi, G.N., Fritsche, H.A., Buzdar, A.U., Yap, H.Y., Blumenschein, G.R. JAMA (1983) [Pubmed]
  12. Thromboembolic complications after perioperative chemotherapy in women with early breast cancer: a European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group study. Clahsen, P.C., van de Velde, C.J., Julien, J.P., Floiras, J.L., Mignolet, F.Y. J. Clin. Oncol. (1994) [Pubmed]
  13. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. Jassem, J., Pieńkowski, T., Płuzańska, A., Jelic, S., Gorbunova, V., Mrsic-Krmpotic, Z., Berzins, J., Nagykalnai, T., Wigler, N., Renard, J., Munier, S., Weil, C. J. Clin. Oncol. (2001) [Pubmed]
  14. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. Swain, S.M., Whaley, F.S., Gerber, M.C., Ewer, M.S., Bianchine, J.R., Gams, R.A. J. Clin. Oncol. (1997) [Pubmed]
  15. Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Martin, M., Villar, A., Sole-Calvo, A., Gonzalez, R., Massuti, B., Lizon, J., Camps, C., Carrato, A., Casado, A., Candel, M.T., Albanell, J., Aranda, J., Munarriz, B., Campbell, J., Diaz-Rubio, E. Ann. Oncol. (2003) [Pubmed]
  16. FANCE: the link between Fanconi anaemia complex assembly and activity. Pace, P., Johnson, M., Tan, W.M., Mosedale, G., Sng, C., Hoatlin, M., de Winter, J., Joenje, H., Gergely, F., Patel, K.J. EMBO J. (2002) [Pubmed]
  17. The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality. Pang, Q., Christianson, T.A., Keeble, W., Diaz, J., Faulkner, G.R., Reifsteck, C., Olson, S., Bagby, G.C. Blood (2001) [Pubmed]
  18. Posttranscriptional cell cycle-dependent regulation of human FANCC expression. Heinrich, M.C., Silvey, K.V., Stone, S., Zigler, A.J., Griffith, D.J., Montalto, M., Chai, L., Zhi, Y., Hoatlin, M.E. Blood (2000) [Pubmed]
  19. A novel BTB/POZ transcriptional repressor protein interacts with the Fanconi anemia group C protein and PLZF. Hoatlin, M.E., Zhi, Y., Ball, H., Silvey, K., Melnick, A., Stone, S., Arai, S., Hawe, N., Owen, G., Zelent, A., Licht, J.D. Blood (1999) [Pubmed]
  20. The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors. Pang, Q., Fagerlie, S., Christianson, T.A., Keeble, W., Faulkner, G., Diaz, J., Rathbun, R.K., Bagby, G.C. Mol. Cell. Biol. (2000) [Pubmed]
  21. FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity. Pang, Q., Keeble, W., Christianson, T.A., Faulkner, G.R., Bagby, G.C. EMBO J. (2001) [Pubmed]
  22. Carboxy terminal region of the Fanconi anemia protein, FANCG/XRCC9, is required for functional activity. Kuang, Y., Garcia-Higuera, I., Moran, A., Mondoux, M., Digweed, M., D'Andrea, A.D. Blood (2000) [Pubmed]
  23. Functional correction of FA-C cells with FANCC suppresses the expression of interferon gamma-inducible genes. Fagerlie, S.R., Diaz, J., Christianson, T.A., McCartan, K., Keeble, W., Faulkner, G.R., Bagby, G.C. Blood (2001) [Pubmed]
  24. Fanconi anemia group A and C double-mutant mice: functional evidence for a multi-protein Fanconi anemia complex. Noll, M., Battaile, K.P., Bateman, R., Lax, T.P., Rathbun, K., Reifsteck, C., Bagby, G., Finegold, M., Olson, S., Grompe, M. Exp. Hematol. (2002) [Pubmed]
  25. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. Verlinsky, Y., Rechitsky, S., Schoolcraft, W., Strom, C., Kuliev, A. JAMA (2001) [Pubmed]
  26. Cisplatin triggers apoptotic or nonapoptotic cell death in Fanconi anemia lymphoblasts in a concentration-dependent manner. Ferrer, M., Izeboud, T., Ferreira, C.G., Span, S.W., Giaccone, G., Kruyt, F.A. Exp. Cell Res. (2003) [Pubmed]
  27. Mitomycin C and diepoxybutane action mechanisms and FANCC protein functions: further insights into the role for oxidative stress in Fanconi's anaemia phenotype. Pagano, G. Carcinogenesis (2000) [Pubmed]
  28. In vivo administration of interferon gamma does not cause marrow aplasia in mice with a targeted disruption of FANCC. Kurre, P., Anandakumar, P., Grompe, M., Kiem, H.P. Exp. Hematol. (2002) [Pubmed]
  29. Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems. Gordon, S.M., Buchwald, M. Blood (2003) [Pubmed]
  30. Regulation of the Fanconi anemia group C protein through proteolytic modification. Brodeur, I., Goulet, I., Tremblay, C.S., Charbonneau, C., Delisle, M.C., Godin, C., Huard, C., Khandjian, E.W., Buchwald, M., Lévesque, G., Carreau, M. J. Biol. Chem. (2004) [Pubmed]
  31. Fanconi anemia C gene product regulates expression of genes involved in differentiation and inflammation. Zanier, R., Briot, D., Dugas du Villard, J.A., Sarasin, A., Rosselli, F. Oncogene (2004) [Pubmed]
  32. An oxidative mechanism of interferon induced priming of the Fas pathway in Fanconi anemia cells. Pearl-Yafe, M., Halperin, D., Halevy, A., Kalir, H., Bielorai, B., Fabian, I. Biochem. Pharmacol. (2003) [Pubmed]
  33. Strong FANCA/FANCG but weak FANCA/FANCC interaction in the yeast 2-hybrid system. Reuter, T., Herterich, S., Bernhard, O., Hoehn, H., Gross, H.J. Blood (2000) [Pubmed]
  34. Functional interplay between BRCA2/FancD1 and FancC in DNA repair. Kitao, H., Yamamoto, K., Matsushita, N., Ohzeki, M., Ishiai, M., Takata, M. J. Biol. Chem. (2006) [Pubmed]
  35. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Kutler, D.I., Singh, B., Satagopan, J., Batish, S.D., Berwick, M., Giampietro, P.F., Hanenberg, H., Auerbach, A.D. Blood (2003) [Pubmed]
  36. The genetics of FANCC and FANCG in familial pancreatic cancer. Rogers, C.D., van der Heijden, M.S., Brune, K., Yeo, C.J., Hruban, R.H., Kern, S.E., Goggins, M. Cancer Biol. Ther. (2004) [Pubmed]
  37. DNA cross-link-dependent RAD50/MRE11/NBS1 subnuclear assembly requires the Fanconi anemia C protein. Pichierri, P., Averbeck, D., Rosselli, F. Hum. Mol. Genet. (2002) [Pubmed]
  38. Preclinical protocol for in vivo selection of hematopoietic stem cells corrected by gene therapy in Fanconi anemia group C. Noll, M., Bateman, R.L., D'Andrea, A.D., Grompe, M. Mol. Ther. (2001) [Pubmed]
  39. In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. van der Heijden, M.S., Brody, J.R., Dezentje, D.A., Gallmeier, E., Cunningham, S.C., Swartz, M.J., DeMarzo, A.M., Offerhaus, G.J., Isacoff, W.H., Hruban, R.H., Kern, S.E. Clin. Cancer Res. (2005) [Pubmed]
 
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