title: FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth.
abstract: Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. One characteristic of FA is an extremely high incidence of cancer, indicating the importance of the FA pathway in tumor suppression. However, the role of this pathway in the development and progression of human cancers in individuals who do not have FA has not been clearly determined. Here, we report that elevated expression of what we believe to be a novel splice variant of FA complementation group L (FANCL), which we identified and named FAVL, can impair the FA pathway in non-FA human tumor cells and act as a tumor promoting factor. FAVL expression was elevated in half of the human carcinoma cell lines and carcinoma tissue samples tested. Expression of FAVL resulted in decreased FANCL expression by sequestering FANCL to the cytoplasm and enhancing its degradation. Importantly, this impairment of the FA pathway by FAVL elevation provided human cancer cells with a growth advantage, caused chromosomal instability in vitro, and promoted tumor development in a xenograft mouse model. These data indicate that FAVL impairment of the FA pathway likely contributes to the development of non-FA human cancers and therefore add a challenging layer of complexity to the pathogenesis of human cancer. We further believe that these data will prove useful for developing additional tools for fighting human cancer.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Deping
authors.initials: D
authors.lastname: Zhao
authors.forename: Hwan Ki
authors.initials: HK
authors.lastname: Park
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Roy B
authors.initials: RB
authors.lastname: Dyer
authors.forename: Wanguo
authors.initials: W
authors.lastname: Liu
authors.forename: George G
authors.initials: GG
authors.lastname: Klee
authors.forename: Mark A
authors.initials: MA
authors.lastname: McNiven
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.forename: Peiwen
authors.initials: P
authors.lastname: Fei
mesh_terms: D000818:Animals; D001483:Base Sequence; D002277:Carcinoma / Q000196:embryology*; D002869:Chromosome Aberrations; D018450:Disease Progression; D005199:Fanconi Anemia / Q000378:metabolism*; D052240:Fanconi Anemia Complementation Group L Protein / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction
chemical_list: C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein
references.citation: Curr Opin Hematol. 2003 Jan;10(1):68-76
references.pmid: 12483114
references.citation: Nature. 2008 Mar 13;452(7184):230-3
references.pmid: 18337823
references.citation: Nat Genet. 2003 Oct;35(2):165-70
references.pmid: 12973351
references.citation: Nat Genet. 2007 Feb;39(2):162-4
references.pmid: 17200671
references.citation: Mol Cell. 2007 Feb 9;25(3):331-43
references.pmid: 17289582
references.citation: Science. 2002 Jul 26;297(5581):606-9
references.pmid: 12065746
references.citation: Nature. 1971 Apr 9;230(5293):370-3
references.pmid: 4927726
references.citation: Cancer Res. 2002 Dec 15;62(24):7316-27
references.pmid: 12499275
references.citation: Cell Cycle. 2005 Jan;4(1):80-6
references.pmid: 15611632
references.citation: Nat Rev Cancer. 2003 Jan;3(1):23-34
references.pmid: 12509764
references.citation: Nat Genet. 2005 Sep;37(9):958-63
references.pmid: 16116422
references.citation: Genes Dev. 2003 Aug 15;17(16):1933-6
references.pmid: 12893780
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14519-24
references.pmid: 16971483
references.citation: J Biol Chem. 2006 Apr 21;281(16):10896-905
references.pmid: 16474167
references.citation: Semin Hematol. 2006 Jul;43(3):147-56
references.pmid: 16822457
references.citation: Nat Med. 2003 May;9(5):568-74
references.pmid: 12692539
references.citation: Cancer Biol Ther. 2006 Dec;5(12):1632-6
references.pmid: 17106252
references.citation: Blood. 2003 Mar 1;101(5):2072
references.pmid: 12584146
references.citation: Blood. 2006 Jun 1;107(11):4223-33
references.pmid: 16493006
references.citation: Cancer Cell. 2005 Sep;8(3):255-65
references.pmid: 16153896
references.citation: Mech Ageing Dev. 2005 Jan;126(1):79-86
references.pmid: 15610765
references.citation: Cancer Cell. 2004 Dec;6(6):597-609
references.pmid: 15607964
references.citation: Nat Rev Genet. 2007 Oct;8(10):735-48
references.pmid: 17768402
references.citation: Nat Med. 2004 Aug;10(8):789-99
references.pmid: 15286780
references.citation: Cell Cycle. 2006 Jan;5(2):164-7
references.pmid: 16357529
references.citation: Dev Cell. 2007 May;12(5):661-2
references.pmid: 17488615
references.citation: Cell Cycle. 2004 Oct;3(10):1331-9
references.pmid: 15467456
references.citation: Nat Rev Mol Cell Biol. 2007 May;8(5):394-404
references.pmid: 17450177
references.citation: Nat Genet. 2007 Feb;39(2):165-7
references.pmid: 17200668
references.citation: Genes Dev. 2005 Dec 15;19(24):2925-40
references.pmid: 16357213
references.citation: Cancer Cell. 2002 Jul;2(1):9-15
references.pmid: 12150820
references.citation: Cancer Cell. 2005 Feb;7(2):114-5
references.pmid: 15710323
references.citation: Nature. 2000 Nov 16;408(6810):307-10
references.pmid: 11099028
references.citation: Science. 2003 Oct 24;302(5645):643-6
references.pmid: 14576434
references.citation: J Natl Cancer Inst. 1991 Dec 4;83(23):1743-8
references.pmid: 1663169
references.citation: Cell. 2002 May 17;109(4):459-72
references.pmid: 12086603
references.citation: EMBO J. 2007 Apr 18;26(8):2104-14
references.pmid: 17396147
references.citation: Exp Gerontol. 1992 Jul-Aug;27(4):447-53
references.pmid: 1459221
references.citation: Nat Genet. 2005 Sep;37(9):934-5
references.pmid: 16116423
references.citation: Cancer. 2005 Dec 15;104(12):2807-16
references.pmid: 16284991
references.citation: Cell. 2007 Apr 20;129(2):289-301
references.pmid: 17412408