fanconi anemia complementation group c protein

Summary

Summary: A Fanconi anemia complementation group protein that regulates the activities of CYTOCHROME P450 REDUCTASE and GLUTATHIONE S-TRANSFERASE. It is found predominately in the CYTOPLASM, but moves to the CELL NUCLEUS in response to FANCE PROTEIN.

Top Publications

  1. Couch F, Johnson M, Rabe K, Boardman L, McWilliams R, de Andrade M, et al. Germ line Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res. 2005;65:383-6 pubmed
    ..Taken together these data support the assertion that inherited mutations in FANCC can predispose to pancreatic cancer. ..
  2. Van Der Heijden M, Yeo C, Hruban R, Kern S. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res. 2003;63:2585-8 pubmed
    ..S. Sasaki, Nature (Lond.), 257: 501-503, 1975] suggests a therapeutic utility for a more complete characterization of the DNA repair defects and their causative genetic mutations in pancreatic cancer. ..
  3. Freie B, Li X, Ciccone S, Nawa K, Cooper S, Vogelweid C, et al. Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis. Blood. 2003;102:4146-52 pubmed
    ..Collectively, these data demonstrate that p53 and Fancc interact functionally to regulate apoptosis and tumorigenesis in Fancc-deficient cells. ..
  4. Van Der Heijden M, Brody J, Gallmeier E, Cunningham S, Dezentje D, Shen D, et al. Functional defects in the fanconi anemia pathway in pancreatic cancer cells. Am J Pathol. 2004;165:651-7 pubmed
    ..These results support the practical exploration of crosslinking agents for non-Fanconi anemia patients that have tumors defective in the Fanconi pathway. ..
  5. Niedzwiedz W, Mosedale G, Johnson M, Ong C, Pace P, Patel K. The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair. Mol Cell. 2004;15:607-20 pubmed
    ..These studies reveal that the FA proteins cooperate with key mutagenesis and repair processes that enable replication of damaged DNA. ..
  6. Fagerlie S, Koretsky T, Torok Storb B, Bagby G. Impaired type I IFN-induced Jak/STAT signaling in FA-C cells and abnormal CD4+ Th cell subsets in Fancc-/- mice. J Immunol. 2004;173:3863-70 pubmed
    ..We suggest that Fancc mutations result in a subtle immunological defect owing to the failure of FANCC to normally support Jak/STAT signaling. ..
  7. Garcia Higuera I, Taniguchi T, Ganesan S, Meyn M, Timmers C, Hejna J, et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. 2001;7:249-62 pubmed
    ..The FANCD2 protein, therefore, provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all FA subtypes. ..
  8. Nadler J, Braun R. Fanconi anemia complementation group C is required for proliferation of murine primordial germ cells. Genesis. 2000;27:117-23 pubmed
    ..This study demonstrates Fancc is required for mitotic proliferation of primordial germ cells. ..
  9. Pang Q, Fagerlie S, Christianson T, Keeble W, Faulkner G, Diaz J, et al. The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors. Mol Cell Biol. 2000;20:4724-35 pubmed

More Information

Publications62

  1. Kitao H, Yamamoto K, Matsushita N, Ohzeki M, Ishiai M, Takata M. Functional interplay between BRCA2/FancD1 and FancC in DNA repair. J Biol Chem. 2006;281:21312-20 pubmed
    ..These results provide insights into the functional interplay between the classical FA pathway and BRCA2. ..
  2. Van Der Heijden M, Brody J, Dezentje D, Gallmeier E, Cunningham S, Swartz M, et al. In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res. 2005;11:7508-15 pubmed
    ..MMC or other cross-linking agents as a clinical therapy for pancreatic cancer patients with tumors harboring defects in the Fanconi anemia/BRCA2 pathway should be specifically investigated. ..
  3. Whitney M, Royle G, Low M, Kelly M, Axthelm M, Reifsteck C, et al. Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconi anemia C gene. Blood. 1996;88:49-58 pubmed
    ..Progenitor cells from fac knock-out mice were hypersensitive to interferon gamma. This previously unrecognized phenotype may form the basis for BM failure in human FA. ..
  4. Gavish H, dos Santos C, Buchwald M. A Leu554-to-Pro substitution completely abolishes the functional complementing activity of the Fanconi anemia (FACC) protein. Hum Mol Genet. 1993;2:123-6 pubmed
    ..The physiological significance of this mutation is thus confirmed. ..
  5. de Winter J, van Der Weel L, de Groot J, Stone S, Waisfisz Q, Arwert F, et al. The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG. Hum Mol Genet. 2000;9:2665-74 pubmed
    ..Our results, along with published data, culminate in a model in which a multi-protein FA complex serves a nuclear function to maintain genomic integrity. ..
  6. Medhurst A, Huber P, Waisfisz Q, de Winter J, Mathew C. Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway. Hum Mol Genet. 2001;10:423-9 pubmed
    ..These proteins may act either as a multimeric complex or by sequential recruitment of subsets of the proteins in a common pathway that protects the genomic integrity of mammalian cells. ..
  7. Gallmeier E, Calhoun E, Rago C, Brody J, Cunningham S, Hucl T, et al. Targeted disruption of FANCC and FANCG in human cancer provides a preclinical model for specific therapeutic options. Gastroenterology. 2006;130:2145-54 pubmed
    ..The impact of Fanconi gene defects on drug and irradiation sensitivity renders these genes promising targets for a specific, genotype-based therapy for individual cancer patients, providing a strong rationale for clinical trials. ..
  8. Sinha S, Singh R, Alam N, Roy A, Roychoudhury S, Panda C. Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: pathological significance in early- and late-onset breast carcinoma. Mol Cancer. 2008;7:84 pubmed publisher
  9. Hess C, Ameziane N, Schuurhuis G, Errami A, Denkers F, Kaspers G, et al. Hypermethylation of the FANCC and FANCL promoter regions in sporadic acute leukaemia. Cell Oncol. 2008;30:299-306 pubmed
    ..In addition, this is the first report to describe hypermethylation of FANCC and FANCL. This warrants the investigation of multiple FA-BRCA genes in other malignancies. ..
  10. Noll M, Battaile K, Bateman R, Lax T, Rathbun K, Reifsteck C, et al. Fanconi anemia group A and C double-mutant mice: functional evidence for a multi-protein Fanconi anemia complex. Exp Hematol. 2002;30:679-88 pubmed
    ..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. ..
  11. Anur P, Yates J, Garbati M, Vanderwerf S, Keeble W, Rathbun K, et al. p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes. Blood. 2012;119:1992-2002 pubmed publisher
  12. Pulliam A, Hobson M, Ciccone S, Li Y, Chen S, Srour E, et al. AMD3100 synergizes with G-CSF to mobilize repopulating stem cells in Fanconi anemia knockout mice. Exp Hematol. 2008;36:1084-90 pubmed publisher
  13. Seal S, Barfoot R, Jayatilake H, Smith P, Renwick A, Bascombe L, et al. Evaluation of Fanconi Anemia genes in familial breast cancer predisposition. Cancer Res. 2003;63:8596-9 pubmed
    ..The results indicate that FA gene mutations, other than in BRCA2, are unlikely to be a frequent cause of highly penetrant breast cancer predisposition. ..
  14. Dao K, Rotelli M, Petersen C, Kaech S, Nelson W, Yates J, et al. FANCL ubiquitinates ?-catenin and enhances its nuclear function. Blood. 2012;120:323-34 pubmed publisher
    ..Together, these results suggest that diminished Wnt/?-catenin signaling may be an underlying molecular defect in FANCL-deficient hematopoietic stem cells leading to their accelerated loss. ..
  15. Galimi F, Noll M, Kanazawa Y, Lax T, Chen C, Grompe M, et al. Gene therapy of Fanconi anemia: preclinical efficacy using lentiviral vectors. Blood. 2002;100:2732-6 pubmed
    ..This study strongly supports the use of lentiviral vectors for FA gene therapy in humans. ..
  16. Vanderwerf S, Svahn J, Olson S, Rathbun R, Harrington C, Yates J, et al. TLR8-dependent TNF-(alpha) overexpression in Fanconi anemia group C cells. Blood. 2009;114:5290-8 pubmed publisher
    ..In conclusion, FANCC suppresses TNF-alpha production in mononuclear phagocytes by suppressing TLR8 activity and this particular function of FANCC is independent of its function in protecting the genome from cross-linking agents. ..
  17. Bijangi Vishehsaraei K, Saadatzadeh M, Werne A, McKenzie K, Kapur R, Ichijo H, et al. Enhanced TNF-alpha-induced apoptosis in Fanconi anemia type C-deficient cells is dependent on apoptosis signal-regulating kinase 1. Blood. 2005;106:4124-30 pubmed
    ..Collectively, these data argue that the predisposition of Fancc-/- hematopoietic progenitors to apoptosis is mediated in part through altered redox regulation and Ask1 hyperactivation. ..
  18. Kamimae Lanning A, Goloviznina N, Kurre P. Fetal origins of hematopoietic failure in a murine model of Fanconi anemia. Blood. 2013;121:2008-12 pubmed publisher
    ..Our studies suggest that compromised hematopoiesis in Fancc(-/-) animals is developmentally programmed and does not arise de novo in bone marrow. ..
  19. Taniguchi T, D Andrea A. The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of FANCC. Blood. 2002;100:2457-62 pubmed
    ..Our data indicate that FANCE is a component of the nuclear FA complex in vivo and is required for the monoubiquitination of FANCD2 and the downstream events in the FA pathway. ..
  20. Otsuki T, Young D, Sasaki D, Pando M, Li J, Manning A, et al. Fanconi anemia protein complex is a novel target of the IKK signalsome. J Cell Biochem. 2002;86:613-23 pubmed
    ..When exposed to mitomycin C, cells expressing IKK2 K > M develop a cell cycle abnormality characteristic of FA. Thus, FANCA may function to recruit IKK2, thus providing the cell a means of rapidly responding to stress. ..
  21. Gibson R, Morgan N, Goldstein L, Pearson I, Kesterton I, Foot N, et al. Novel mutations and polymorphisms in the Fanconi anemia group C gene. Hum Mutat. 1996;8:140-8 pubmed
    ..This study indicates that the proportion of FA patients from complementation group C is generally likely to be less than 10%. Guidelines for the selection of FA patients for FAC mutation screening are proposed. ..
  22. Hadjur S, Ung K, Wadsworth L, Dimmick J, Rajcan Separovic E, Scott R, et al. Defective hematopoiesis and hepatic steatosis in mice with combined deficiencies of the genes encoding Fancc and Cu/Zn superoxide dismutase. Blood. 2001;98:1003-11 pubmed
    ..These results suggested that the altered redox state likely present in Fancc(-/-) Sod1(-/-) hematopoietic progenitors was responsible for an impairment of cell proliferation or survival. (Blood. 2001;98:1003-1011) ..
  23. Ghosh A, Maiti G, Bandopadhyay M, Chakraborty J, Biswas J, Roychoudhury S, et al. Inactivation of 9q22.3 tumor suppressor genes predict outcome for patients with head and neck squamous cell carcinoma. Anticancer Res. 2013;33:1215-20 pubmed
    ..FANCC and PTCH1 alterations might be used as molecular markers for prognosis and to develop strategies for effective treatment planning. ..
  24. Garavelli L, Piemontese M, Cavazza A, Rosato S, Wischmeijer A, Gelmini C, et al. Multiple tumor types including leiomyoma and Wilms tumor in a patient with Gorlin syndrome due to 9q22.3 microdeletion encompassing the PTCH1 and FANC-C loci. Am J Med Genet A. 2013;161A:2894-901 pubmed publisher
    ..We propose including leiomyomas among minor criteria of the NBCCS. ..
  25. Haneline L, Broxmeyer H, Cooper S, Hangoc G, Carreau M, Buchwald M, et al. Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac-/- mice. Blood. 1998;91:4092-8 pubmed
    ..Together these data suggest a role of Fac in affecting the signaling of multiple cytokine pathways and support cytokine-mediated apoptosis as a major mechanism responsible for BM failure observed in FA patients. ..
  26. Rio P, Navarro S, Guenechea G, Sánchez Domínguez R, Lamana M, Yañez R, et al. Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34+ cells from Fanconi anemia patients. Blood. 2017;130:1535-1542 pubmed publisher
  27. Ceccaldi R, Parmar K, Mouly E, Delord M, Kim J, Regairaz M, et al. Bone marrow failure in Fanconi anemia is triggered by an exacerbated p53/p21 DNA damage response that impairs hematopoietic stem and progenitor cells. Cell Stem Cell. 2012;11:36-49 pubmed publisher
  28. Salles D, Cabral R, Pizzatti L, Bisch P, Paixão J, de Almeida C, et al. Changes in protein expression due to deleterious mutations in the FA/BRCA pathway. Biochem Biophys Res Commun. 2007;364:755-60 pubmed
    ..We found six differentially expressed proteins; among them, the checkpoint mediator protein MDC1 whose expression was disrupted in FANCC-/- cells. The potential role of differentially expressed proteins in FA phenotype is discussed. ..
  29. Liebetrau W, Budde A, Savoia A, Grummt F, Hoehn H. p53 activates Fanconi anemia group C gene expression. Hum Mol Genet. 1997;6:277-83 pubmed
    ..We suggest that the p53 binding site contributes to, but may not be an absolute prerequisite for p53-directed transcriptional activation. We conclude that the FAC gene can be added to the list of genes that interact with p53. ..
  30. Hu L, Huang W, Hjort E, Eklund E. Increased Fanconi C expression contributes to the emergency granulopoiesis response. J Clin Invest. 2013;123:3952-66 pubmed publisher
    ..These studies have implications for understanding the pathogenesis of bone marrow failure in Fanconi anemia and suggest possible therapeutic approaches. ..
  31. Youssoufian H, Kruyt F, Li X. Protein replacement by receptor-mediated endocytosis corrects the sensitivity of Fanconi anemia group C cells to mitomycin C. Blood. 1999;93:363-9 pubmed
    ..We suggest that receptor-mediated endocytosis of cytokine-fusion proteins may be of general use to deliver macromolecules into hematopoietic progenitor cells. ..
  32. Hays L, Keeble W, Yates J, Rathbun R, Koretsky T, Olson S, et al. Human FANCC is hypomorphic in murine Fancc-deficient cells. Blood. 2010;116:2057-60 pubmed publisher
  33. Ueda F, Sumi K, Tago K, Kasahara T, Funakoshi Tago M. Critical role of FANCC in JAK2 V617F mutant-induced resistance to DNA cross-linking drugs. Cell Signal. 2013;25:2115-24 pubmed publisher
    ..Taken together, FANCC is most likely to be critical for resistance to DNA cross-linking drug-induced DNA damage in cells transformed by JAK2 V617F mutant. ..
  34. Li J, Sipple J, Maynard S, Mehta P, Rose S, Davies S, et al. Fanconi anemia links reactive oxygen species to insulin resistance and obesity. Antioxid Redox Signal. 2012;17:1083-98 pubmed publisher
    ..These findings establish a pathogenic and mechanistic link between ROS and insulin resistance in a unique human disease setting. ROS accumulation contributes to the insulin resistance in FA deficiency by targeting both PTP-? and PKR. ..
  35. Pang Q, Christianson T, Keeble W, Diaz J, Faulkner G, Reifsteck C, et al. The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality. Blood. 2001;98:1392-401 pubmed
    ..Preservation of signaling capacity of cells bearing the del322G mutation may account for the reduced severity and later onset of bone marrow failure associated with this mutation. ..
  36. Li Z, Zou Y, Deng Y. [Progress of research on protein composition and gene therapy of Fanconi anaemia - review]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2004;12:231-5 pubmed
    ..In this review the clinical manifestations and gene composition of FA, and the functions of encoded FA proteins were summarized. The hematopoietic stem cell transplantation and gene therapy for FA patients were discussed. ..
  37. Chandrasekharappa S, Lach F, Kimble D, Kamat A, Teer J, Donovan F, et al. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood. 2013;121:e138-48 pubmed publisher
    ..FANCC mutations are often the cause of FA in patients of Ashkenazi Jewish (AJ) ancestry, and we identified 2 novel FANCC mutations in 2 patients of AJ ancestry. We describe here a strategy for efficient molecular diagnosis of FA. ..
  38. Zhang X, Li J, Sejas D, Rathbun K, Bagby G, Pang Q. The Fanconi anemia proteins functionally interact with the protein kinase regulated by RNA (PKR). J Biol Chem. 2004;279:43910-9 pubmed
    ..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. ..
  39. Sejas D, Rani R, Qiu Y, Zhang X, Fagerlie S, Nakano H, et al. Inflammatory reactive oxygen species-mediated hemopoietic suppression in Fancc-deficient mice. J Immunol. 2007;178:5277-87 pubmed
    ..Our data implicate a role of inflammation in pathogenesis of FA and BM failure diseases in general. ..
  40. Freie B, Ciccone S, Li X, Plett P, Orschell C, Srour E, et al. A role for the Fanconi anemia C protein in maintaining the DNA damage-induced G2 checkpoint. J Biol Chem. 2004;279:50986-93 pubmed
    ..Here we show that the Fanconi anemia complementation group C protein (Fancc) is necessary for proper function of the DNA damage-induced G2/M checkpoint in vitro ..
  41. Segal G, Magenis R, Brown M, Keeble W, Smith T, Heinrich M, et al. Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells. J Clin Invest. 1994;94:846-52 pubmed
    ..We conclude that, while the FACC gene product plays a role in defining cellular tolerance to cross-linking agents, it also functions to regulate growth, differentiation, and/or survival of normal hematopoietic progenitor cells. ..
  42. Li X, Plett P, Yang Y, Hong P, Freie B, Srour E, et al. Fanconi anemia type C-deficient hematopoietic stem/progenitor cells exhibit aberrant cell cycle control. Blood. 2003;102:2081-4 pubmed
    ..Collectively, these data provide a previously unrecognized phenotype in Fancc-/- hematopoietic stem/progenitor cells, which may contribute to the progressive bone marrow failure in Fanconi anemia. ..
  43. Kuang Y, Garcia Higuera I, Moran A, Mondoux M, Digweed M, D Andrea A. Carboxy terminal region of the Fanconi anemia protein, FANCG/XRCC9, is required for functional activity. Blood. 2000;96:1625-32 pubmed
    ..Additional amino acid sequences at the carboxy terminus of FANCG are required for the binding of FANCC in the complex. (Blood. 2000;96:1625-1632) ..
  44. Youssoufian H. Localization of Fanconi anemia C protein to the cytoplasm of mammalian cells. Proc Natl Acad Sci U S A. 1994;91:7975-9 pubmed
    ..These observations suggest an indirect role for FACC in regulating DNA repair in this group of Fanconi anemia. ..
  45. Li J, Sejas D, Burma S, Chen D, Pang Q. Nucleophosmin suppresses oncogene-induced apoptosis and senescence and enhances oncogenic cooperation in cells with genomic instability. Carcinogenesis. 2007;28:1163-70 pubmed
    ..Our study demonstrates a novel mechanism of NPM tumorigenesis by establishing NPM as a crucial inhibitor of oncogene-induced apoptosis and senescence. ..
  46. Léveillé F, Ferrer M, Medhurst A, Laghmani E, Rooimans M, Bier P, et al. The nuclear accumulation of the Fanconi anemia protein FANCE depends on FANCC. DNA Repair (Amst). 2006;5:556-65 pubmed
    ..This strengthens the idea that FANCE recruits FANCD2 to the core complex, without interfering with the binding of FANCC. ..
  47. Levran O, Attwooll C, Henry R, Milton K, Neveling K, Rio P, et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet. 2005;37:931-3 pubmed
    ..Using genetic mapping, mutation identification and western-blot data, we identify the defective protein in FA-J cells as BRIP1 (also called BACH1), a DNA helicase that is a binding partner of the breast cancer tumor suppressor BRCA1. ..
  48. Hirano S, Yamamoto K, Ishiai M, Yamazoe M, Seki M, Matsushita N, et al. Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM. EMBO J. 2005;24:418-27 pubmed
    ..Our cell survival data suggest that the FA proteins serve to facilitate HR, but not global TLS, during crosslink repair. ..
  49. Kurre P, Anandakumar P, Grompe M, Kiem H. In vivo administration of interferon gamma does not cause marrow aplasia in mice with a targeted disruption of FANCC. Exp Hematol. 2002;30:1257-62 pubmed
    ..Additional selective pressure may be necessary to achieve targeted ablation of uncorrected, FA-phenotype, marrow cells. ..
  50. Cumming R, Lightfoot J, Beard K, Youssoufian H, O Brien P, Buchwald M. Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Nat Med. 2001;7:814-20 pubmed
    ..The prevention of protein oxidation by FANCC reveals a novel mechanism of enzyme regulation during apoptosis and has implications for the treatment of degenerative diseases with thiol reducing agents. ..
  51. Heinrich M, Silvey K, Stone S, Zigler A, Griffith D, Montalto M, et al. Posttranscriptional cell cycle-dependent regulation of human FANCC expression. Blood. 2000;95:3970-7 pubmed
    ..Our observation of dynamic control of FANCC expression by the proteasome has important implications for understanding the molecular regulation of the multiprotein complex. (Blood. 2000;95:3970-3977) ..
  52. Kruyt F, Hoshino T, Liu J, Joseph P, Jaiswal A, Youssoufian H. Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase. Blood. 1998;92:3050-6 pubmed
    ..We propose that FAC plays a fundamental role in vivo by attenuating the activity of RED, thereby regulating a major detoxification pathway in mammalian cells. ..
  53. Li Y, Youssoufian H. MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups. J Clin Invest. 1997;100:2873-80 pubmed
    ..Constitutive activity of this pathway may explain a number of the phenotypic features of FA, particularly the pathogenesis of bone marrow failure. ..