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FANCC (Fanconi anaemia complementation group C)

Identity

Other namesFAC
FACC
FA3
HGNC (Hugo) FANCC
LocusID (NCBI) 2176
Location 9q22.32
Location_base_pair Starts at 97861336 and ends at 98079991 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Next to PTCH and XPAC !!
 
  Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

DNA/RNA

Description 14 exons; spans 80 kb.
Transcription mRNA of 2.3, 3.2, and 4.6 kb (alternative splicing in 5', variable 3' untranslated region, exon 13 skipping).

Protein

Description 558 amino acids; 63 kDa.
Expression Wide, in particular in the bones; high expression in proliferating cells, low in differentiated cells.
Localisation Cytoplasmic (mostly) and nuclear.
Function - FANCA and FANCG form a complex in the cytoplasm, through a N-term FANCA (involving the nuclear localization signal) - FANCG interaction; FANCC join the complex; phosphorylation of FANCA would induce its translocation into the nucleus. This FA complex translocates into the nucleus, where FANCE and FANCF are present; FANCE and FANCF join the complex. The FA complex subsequently interacts with FANCD2 by monoubiquitination of FANCD2 during S phase or following DNA damage. Activated (ubiquinated ) FANCD2, downstream in the FA pathway, will then interact with other proteins involved in DNA repair, possibly BRCA1; after DNA repair, FANCD2 return to the non-ubiquinated form.
- FANCC may have mutlifunctional roles, in addition to its involvement in the FA pathway. FANCC binds to cdc2 (mitotic cyclin-dependent kinase), STAT1, GRP94 (a chaperon protein), NADPH, and a number of other proteins; involved in DNA repair and in suppressing interferon gamma induced cellular apoptosis.
There are 15 FA genes that make up the FA pathway. Among these FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCM and FANCL form the core complex. During G1 phase of cell cycle these proteins are localized in the cytoplasm. During S phase or during DNA damage FANCA and FANCG at first form a complex in the cytoplasm followed by its interaction with FANCC. Then the complex translocates to the nucleus. In the nucleus other FA proteins like FANCE, F, B, M and L interact with the complex. They cooperatively bind to form the core complex. FANCL has E3 ubiquitin ligase activity. The core complex then activates FANCD2 and FANCI by monoubiquitination. The activated FANCD2-FANCI complex then interact with other FA genes like FANCP/SLX4, FANCD1/BRCA2, FANCJ/BRIP1 and FANCN/PALB2 for efficient DNA repair.
FANCC helps in accumulation of FANCE and it has role in foci formation of MRE11/RAD50/NBS1 complex in response to intrastrand crosslink inducers.
FANCC binds to cdc2 (mitotic cyclin-dependent kinase), it is necessary for DNA damage-induced G2/M checkpoint in vitro and in vivo.
In response to oxidative DNA damage, FANCC prevents premature senescence in hematopoietic stem cells. It interacts with cytochrome p-450 reductase and NADPH during increased production of reactive oxygen species (ROS).
In hematopoietic stem cells it regulates apoptosis, self renewal capacity and cell cycle control. It inhibits activity of dsRNA dependent protein kinase mediated death signaling pathway by interacting with Hsp70. FANCC and p53 cooperatively work in apoptosis. It has role in suppressing interferon gamma induced cellular apoptosis.
In normal oral epithelium, a gradual increase of FANCC protein expression from basal to parabasal layer to spinous layer suggesting its role in cellular proliferation and differentiation.
FANCC is important for proper functioning of monocytes/macrophages. It suppresses TNFα production in mononuclear phagocytes by suppressing TLR8 activity.
FANCC interacts with STAT1, GRP94 (a chaperon protein). It has role in telomere attrition and telomere recombination.
Homology No known homology.

Mutations

Germinal Most mutations are found in exon1, intron 4, and exon 14.

Implicated in

Entity Fanconi anaemia (FA)
Note FACC is implicated in the FA complementation group C; it represents about 15% of FA cases.
Disease Fanconi anaemia is a chromosome instability syndrome/cancer prone disease (at risk of leukaemia).
Prognosis - Fanconi anaemia's prognosis is poor; mean survival is 16 years: patients die of bone marrow failure (infections, haemorrhages), leukaemia, or androgen therapy related liver tumours.
- It has recently been shown that significant phenotypic differences were found between the various complementation groups. FA group C patients had less somatic abnormalities. However, there is a certain clinical heterogeneity.
Cytogenetics Spontaneous,chromatid/chromosome breaks; increased rate of breaks compared to control, when induced by breaking agent.
Hybrid/Mutated Gene Mutations in exon 4, 13 leading to deletion of exon 9 were reported in Brazilian Fanconi Anemia patients.
Oncogenesis Fanconi anemia patients are prone to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers.
Frequent deletion and promoter methylation are observed in FANCC gene in oral cancer, breast cancer, acute leukemia and pancreatic cancer.
  
Entity Diabetes and obesity
Note FANCC prevents diabetes and obesity.
  

To be noted

Apart from its function in DNA damage repair, FANCC plays important role in apoptosis, cell cycle, differentiation and innate immunity.

External links

Nomenclature
HGNC (Hugo)FANCC   3584
Cards
AtlasFACC101
Entrez_Gene (NCBI)FANCC  2176  Fanconi anemia, complementation group C
GeneCards (Weizmann)FANCC
Ensembl (Hinxton)ENSG00000158169 [Gene_View]  chr9:97861336-98079991 [Contig_View]  FANCC [Vega]
AceView (NCBI)FANCC
Genatlas (Paris)FANCC
WikiGenes2176
SOURCE (Princeton)NM_000136 NM_001243743 NM_001243744
Genomic and cartography
GoldenPath (UCSC)FANCC  -  9q22.32   chr9:97861336-98079991 -  9q22.3   [Description]    (hg19-Feb_2009)
EnsemblFANCC - 9q22.3 [CytoView]
Mapping of homologs : NCBIFANCC [Mapview]
OMIM227645   227650   613899   
Gene and transcription
Genbank (Entrez)AI280997 AK222871 AK304887 AK310599 AK312548
RefSeq transcript (Entrez)NM_000136 NM_001243743 NM_001243744
RefSeq genomic (Entrez)AC_000141 NC_000009 NC_018920 NG_011707 NT_008470 NW_001839235 NW_004929366
Consensus coding sequences : CCDS (NCBI)FANCC
Cluster EST : UnigeneHs.494529 [ NCBI ]
CGAP (NCI)Hs.494529
Alternative Splicing : Fast-db (Paris)GSHG0030978
Alternative Splicing GalleryENSG00000158169
Gene ExpressionFANCC [ NCBI-GEO ]     FANCC [ SEEK ]   FANCC [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ00597 (Uniprot)
NextProtQ00597  [Medical]
With graphics : InterProQ00597
Splice isoforms : SwissVarQ00597 (Swissvar)
Domains : Interpro (EBI)Fanconi   
Related proteins : CluSTrQ00597
Domain families : Pfam (Sanger)Fanconi_C (PF02106)   
Domain families : Pfam (NCBI)pfam02106   
DMDM Disease mutations2176
Blocks (Seattle)Q00597
Human Protein AtlasENSG00000158169
Peptide AtlasQ00597
HPRD01967
IPIIPI00023608   IPI00745713   IPI00645428   
Protein Interaction databases
DIP (DOE-UCLA)Q00597
IntAct (EBI)Q00597
FunCoupENSG00000158169
BioGRIDFANCC
InParanoidQ00597
Interologous Interaction database Q00597
IntegromeDBFANCC
STRING (EMBL)FANCC
Ontologies - Pathways
Ontology : AmiGOmyeloid cell homeostasis  protein binding  nucleus  nucleoplasm  cytoplasm  cytosol  DNA repair  nucleotide-excision repair  protein complex assembly  germ cell development  removal of superoxide radicals  Fanconi anaemia nuclear complex  
Ontology : EGO-EBImyeloid cell homeostasis  protein binding  nucleus  nucleoplasm  cytoplasm  cytosol  DNA repair  nucleotide-excision repair  protein complex assembly  germ cell development  removal of superoxide radicals  Fanconi anaemia nuclear complex  
Pathways : BIOCARTARole of BRCA1, BRCA2 and ATR in Cancer Susceptibility [Genes]    BRCA1-dependent Ub-ligase activity [Genes]   
Pathways : KEGGFanconi anemia pathway   
REACTOMEFANCC
Protein Interaction DatabaseFANCC
Wikipedia pathwaysFANCC
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)FANCC
SNP (GeneSNP Utah)FANCC
SNP : HGBaseFANCC
Genetic variants : HAPMAPFANCC
1000_GenomesFANCC 
ICGC programENSG00000158169 
Cancer Gene: CensusFANCC 
Somatic Mutations in Cancer : COSMICFANCC 
CONAN: Copy Number AnalysisFANCC 
Mutations and Diseases : HGMDFANCC
OMIM227645    227650    613899   
GENETestsFANCC
Disease Genetic AssociationFANCC
Huge Navigator FANCC [HugePedia]  FANCC [HugeCancerGEM]
Genomic VariantsFANCC  FANCC [DGVbeta]
Exome VariantFANCC
dbVarFANCC
ClinVarFANCC
snp3D : Map Gene to Disease2176
General knowledge
Homologs : HomoloGeneFANCC
Homology/Alignments : Family Browser (UCSC)FANCC
Phylogenetic Trees/Animal Genes : TreeFamFANCC
Chemical/Protein Interactions : CTD2176
Chemical/Pharm GKB GenePA27997
Clinical trialFANCC
Cancer Resource (Charite)ENSG00000158169
Other databases
Probes
Litterature
PubMed116 Pubmed reference(s) in Entrez
CoreMineFANCC
iHOPFANCC

Bibliography

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Fanconi anemia proteins localize to chromatin and the nuclear matrix in a DNA damage- and cell cycle-regulated manner.
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Breaks at telomeres and TRF2-independent end fusions in Fanconi anemia.
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Hum Mol Genet. 2002 Feb 15;11(4):439-44.
PMID 11854176
 
The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC.
Pang Q, Christianson TA, Keeble W, Koretsky T, Bagby GC.
J Biol Chem. 2002 Dec 20;277(51):49638-43. Epub 2002 Oct 22.
PMID 12397061
 
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 Oct 1;11(21):2531-46.
PMID 12354779
 
Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis.
Freie B, Li X, Ciccone SL, Nawa K, Cooper S, Vogelweid C, Schantz L, Haneline LS, Orazi A, Broxmeyer HE, Lee SH, Clapp DW.
Blood. 2003 Dec 1;102(12):4146-52. Epub 2003 Jul 10.
PMID 12855557
 
Fanconi anaemia proteins: major roles in cell protection against oxidative damage.
Pagano G, Youssoufian H.
Bioessays. 2003 Jun;25(6):589-95. (REVIEW)
PMID 12766948
 
BRCA1-independent ubiquitination of FANCD2.
Vandenberg CJ, Gergely F, Ong CY, Pace P, Mallery DL, Hiom K, Patel KJ.
Mol Cell. 2003 Jul;12(1):247-54.
PMID 12887909
 
Regulation of the Fanconi anemia group C protein through proteolytic modification.
Brodeur I, Goulet I, Tremblay CS, Charbonneau C, Delisle MC, Godin C, Huard C, Khandjian EW, Buchwald M, Levesque G, Carreau M.
J Biol Chem. 2004 Feb 6;279(6):4713-20. Epub 2003 Nov 18.
PMID 14625294
 
A role for the Fanconi anemia C protein in maintaining the DNA damage-induced G2 checkpoint.
Freie BW, Ciccone SL, Li X, Plett PA, Orschell CM, Srour EF, Hanenberg H, Schindler D, Lee SH, Clapp DW.
J Biol Chem. 2004 Dec 3;279(49):50986-93. Epub 2004 Sep 17.
PMID 15377654
 
The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair.
Niedzwiedz W, Mosedale G, Johnson M, Ong CY, Pace P, Patel KJ.
Mol Cell. 2004 Aug 27;15(4):607-20.
PMID 15327776
 
Fanconi anemia C gene product regulates expression of genes involved in differentiation and inflammation.
Zanier R, Briot D, Dugas du Villard JA, Sarasin A, Rosselli F.
Oncogene. 2004 Jun 24;23(29):5004-13.
PMID 15077170
 
Germ line Fanconi anemia complementation group C mutations and pancreatic cancer.
Couch FJ, Johnson MR, Rabe K, Boardman L, McWilliams R, de Andrade M, Petersen G.
Cancer Res. 2005 Jan 15;65(2):383-6.
PMID 15695377
 
FANCC, FANCE, and FANCD2 form a ternary complex essential to the integrity of the Fanconi anemia DNA damage response pathway.
Gordon SM, Alon N, Buchwald M.
J Biol Chem. 2005 Oct 28;280(43):36118-25. Epub 2005 Aug 26.
PMID 16127171
 
Lack of self-renewal capacity in Fancc-/- stem cells after ex vivo expansion.
Habi O, Delisle MC, Messier N, Carreau M.
Stem Cells. 2005 Sep;23(8):1135-41. Epub 2005 Jul 14.
PMID 16020692
 
Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM.
Hirano S, Yamamoto K, Ishiai M, Yamazoe M, Seki M, Matsushita N, Ohzeki M, Yamashita YM, Arakawa H, Buerstedde JM, Enomoto T, Takeda S, Thompson LH, Takata M.
EMBO J. 2005 Jan 26;24(2):418-27. Epub 2004 Dec 23.
PMID 15616572
 
The nuclear accumulation of the Fanconi anemia protein FANCE depends on FANCC.
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DNA Repair (Amst). 2006 May 10;5(5):556-65. Epub 2006 Feb 28.
PMID 16513431
 
Evidence for subcomplexes in the Fanconi anemia pathway.
Medhurst AL, Laghmani el H, Steltenpool J, Ferrer M, Fontaine C, de Groot J, Rooimans MA, Scheper RJ, Meetei AR, Wang W, Joenje H, de Winter JP.
Blood. 2006 Sep 15;108(6):2072-80. Epub 2006 May 23.
PMID 16720839
 
Novel inactivating mutations of FANCC in Brazilian patients with Fanconi anemia.
Yates J, Keeble W, Pals G, Ameziane N, van Spaendonk R, Olson S, Akkari Y, Pasquini R, Bagby G.
Hum Mutat. 2006 Feb;27(2):214.
PMID 16429406
 
Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer.
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Cancer Res. 2007 Oct 1;67(19):9591-6.
PMID 17909071
 
Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated.
Kennedy RD, Chen CC, Stuckert P, Archila EM, De la Vega MA, Moreau LA, Shimamura A, d'Andrea AD.
J Clin Invest. 2007 May;117(5):1440-9. Epub 2007 Apr 12.
PMID 17431503
 
Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde.
Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, Buerstedde JM, Gillespie DA, Sale JE, Yamazoe M, Bishop DK, Takata M, Takeda S, Watanabe M, Swenberg JA, Nakamura J.
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PMID 18056434
 
Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence.
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J Cell Sci. 2007 May 1;120(Pt 9):1572-83. Epub 2007 Apr 3.
PMID 17405815
 
Hypermethylation of the FANCC and FANCL promoter regions in sporadic acute leukaemia.
Hess CJ, Ameziane N, Schuurhuis GJ, Errami A, Denkers F, Kaspers GJ, Cloos J, Joenje H, Reinhardt D, Ossenkoppele GJ, Zwaan CM, Waisfisz Q.
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PMID 18607065
 
Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: pathological significance in early- and late-onset breast carcinoma.
Sinha S, Singh RK, Alam N, Roy A, Roychoudhury S, Panda CK.
Mol Cancer. 2008 Nov 6;7:84.
PMID 18990233
 
The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features.
Barroso E, Pita G, Arias JI, Menendez P, Zamora P, Blanco M, Benitez J, Ribas G.
Breast Cancer Res Treat. 2009 Dec;118(3):655-60. Epub 2009 Jun 18.
PMID 19536649
 
TLR8-dependent TNF-(alpha) overexpression in Fanconi anemia group C cells.
Vanderwerf SM, Svahn J, Olson S, Rathbun RK, Harrington C, Yates J, Keeble W, Anderson DC, Anur P, Pereira NF, Pilonetto DV, Pasquini R, Bagby GC.
Blood. 2009 Dec 17;114(26):5290-8. Epub 2009 Oct 22.
PMID 19850743
 
Human FANCC is hypomorphic in murine Fancc-deficient cells.
Hays LE, Keeble WW, Yates JE, Rathbun RK, Koretsky T, Olson SB, Sun Z, Clapp DW, Bagby GC Jr.
Blood. 2010 Sep 23;116(12):2057-60. Epub 2010 Jun 16.
PMID 20554974
 
Genetic inactivation of the Fanconi anemia gene FANCC identified in the hepatocellular carcinoma cell line HuH-7 confers sensitivity towards DNA-interstrand crosslinking agents.
Palagyi A, Neveling K, Plinninger U, Ziesch A, Targosz BS, Denk GU, Ochs S, Rizzani A, Meier D, Thasler WE, Hanenberg H, De Toni EN, Bassermann F, Schafer C, Goke B, Schindler D, Gallmeier E.
Mol Cancer. 2010 May 28;9:127.
PMID 20509860
 
FANCC suppresses short telomere-initiated telomere sister chromatid exchange.
Rhee DB, Wang Y, Mizesko M, Zhou F, Haneline L, Liu Y.
Hum Mol Genet. 2010 Mar 1;19(5):879-87. Epub 2009 Dec 18.
PMID 20022886
 
Upregulation of Fanconi anemia DNA repair genes in melanoma compared with non-melanoma skin cancer.
Kao WH, Riker AI, Kushwaha DS, Ng K, Enkemann SA, Jove R, Buettner R, Zinn PO, Sanchez NP, Villa JL, d'Andrea AD, Sanchez JL, Kennedy RD, Chen CC, Matta JL.
J Invest Dermatol. 2011 Oct;131(10):2139-42. doi: 10.1038/jid.2011.181. Epub 2011 Jun 23.
PMID 21697891
 
FANCD1/BRCA2 plays predominant role in the repair of DNA damage induced by ACNU or TMZ.
Kondo N, Takahashi A, Mori E, Noda T, Zdzienicka MZ, Thompson LH, Helleday T, Suzuki M, Kinashi Y, Masunaga S, Ono K, Hasegawa M, Ohnishi T.
PLoS One. 2011 May 9;6(5):e19659.
PMID 21573016
 
Oxidative stress in Fanconi anaemia: from cells and molecules toward prospects in clinical management.
Pagano G, Aiello Talamanca A, Castello G, Pallardo FV, Zatterale A, Degan P.
Biol Chem. 2011 Nov 7. [Epub ahead of print]
PMID 22059913
 
p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes.
Anur P, Yates J, Garbati MR, Vanderwerf S, Keeble W, Rathbun K, Hays LE, Tyner JW, Svahn J, Cappelli E, Dufour C, Bagby GC.
Blood. 2012 Mar 1;119(9):1992-2002. Epub 2012 Jan 10.
PMID 22234699
 
Association of FANCC and PTCH1 with the development of early dysplastic lesions of the head and neck.
Ghosh A, Ghosh S, Maiti GP, Mukherjee S, Mukherjee N, Chakraborty J, Roy A, Roychoudhury S, Panda CK.
Ann Surg Oncol. 2012 Jul;19 Suppl 3:S528-38. Epub 2011 Aug 23.
PMID 21861228
 
Towards a molecular understanding of the fanconi anemia core complex.
Hodson C, Walden H.
Anemia. 2012;2012:926787. Epub 2012 May 22.
PMID 22675617
 
Association of FANCC polymorphisms with FEV1 decline in aspirin exacerbated respiratory disease.
Kim JH, Park BL, Pasaje CF, Bae JS, Park JS, Park SW, Uh ST, Choi JS, Kim YH, Kim MK, Choi IS, Cho SH, Choi BW, Park CS, Shin HD.
Mol Biol Rep. 2012 Mar;39(3):2385-94. Epub 2011 Jun 14.
PMID 21670957
 
Fanconi anemia links reactive oxygen species to insulin resistance and obesity.
Li J, Sipple J, Maynard S, Mehta PA, Rose SR, Davies SM, Pang Q.
Antioxid Redox Signal. 2012 Oct 15;17(8):1083-98. Epub 2012 Jun 25.
PMID 22482891
 
Impaired function of Fanconi anemia type C-deficient macrophages.
Liu Y, Ballman K, Li D, Khan S, Derr-Yellin E, Shou W, Haneline LS.
J Leukoc Biol. 2012 Feb;91(2):333-40. Epub 2011 Nov 21.
PMID 22106009
 
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Contributor(s)

Written02-1998Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated06-2002Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated07-2012Hemantika Dasgupta, Chinmay Kumar Panda
Chittaranjan National Cancer Institute, 37, S P Mukherjee Road, Kolkata 700026, India

Citation

This paper should be referenced as such :
Huret JL . FANCC (Fanconi anaemia complementation group C). Atlas Genet Cytogenet Oncol Haematol. February 1998 .
Huret JL . FANCC (Fanconi anaemia complementation group C). Atlas Genet Cytogenet Oncol Haematol. June 2002 .
Dasgupta H, Panda CK . FANCC (Fanconi anaemia complementation group C). Atlas Genet Cytogenet Oncol Haematol. July 2012 .
URL : http://AtlasGeneticsOncology.org/Genes/FACC101.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/handle/2042/32097/02-1998-FACC101.pdf   [ Bibliographic record ]
http://documents.irevues.inist.fr/bitstream/2042/37892/1/06-2002-FACC101.pdf   [ Bibliographic record ]

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indexed on : Fri Apr 18 17:23:13 CEST 2014

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