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. 1997 Dec 1;100(11):2873–2880. doi: 10.1172/JCI119836

MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups.

Y Li 1, H Youssoufian 1
PMCID: PMC508494  PMID: 9389754

Abstract

Fanconi anemia (FA) consists of a group of at least five autosomal recessive disorders that share both clinical (e.g., birth defects and hematopoietic failure) and cellular (e.g., sensitivity to cross-linking agents and predisposition to apoptosis) features with each other. However, a common pathogenetic link among these groups has not been established. To identify genetic pathways that are altered in FA and characterize shared molecular defects, we used mRNA differential display to isolate genes that have altered expression patterns in FA cells. Here, we report that the expression of an interferon-inducible gene, MxA, is highly upregulated in cells of FA complementation groups A, B, C, and D, but it is suppressed in FA group C cells complemented with wild-type FAC cDNA as well as in non-FA cells. A posttranscriptional mechanism rather than transcriptional induction appears to account for MxA overexpression. Forced expression of MxA in Hep3B cells enhances their sensitivity to mitomycin C and induces apoptosis, similar to the FA phenotype. Thus, MxA is a downstream target of FAC and is the first genetic marker to be identified among multiple FA complementation groups. These data suggest that FA subtypes converge onto a final common pathway, which is intimately related to the interferon signaling mechanism. Constitutive activity of this pathway may explain a number of the phenotypic features of FA, particularly the pathogenesis of bone marrow failure.

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Selected References

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  1. Aebi M., Fäh J., Hurt N., Samuel C. E., Thomis D., Bazzigher L., Pavlovic J., Haller O., Staeheli P. cDNA structures and regulation of two interferon-induced human Mx proteins. Mol Cell Biol. 1989 Nov;9(11):5062–5072. doi: 10.1128/mcb.9.11.5062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arnheiter H., Haller O. Antiviral state against influenza virus neutralized by microinjection of antibodies to interferon-induced Mx proteins. EMBO J. 1988 May;7(5):1315–1320. doi: 10.1002/j.1460-2075.1988.tb02946.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chang K. C., Hansen E., Foroni L., Lida J., Goldspink G. Molecular and functional analysis of the virus- and interferon-inducible human MxA promoter. Arch Virol. 1991;117(1-2):1–15. doi: 10.1007/BF01310488. [DOI] [PubMed] [Google Scholar]
  4. Chen M., Tomkins D. J., Auerbach W., McKerlie C., Youssoufian H., Liu L., Gan O., Carreau M., Auerbach A., Groves T. Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia. Nat Genet. 1996 Apr;12(4):448–451. doi: 10.1038/ng0496-448. [DOI] [PubMed] [Google Scholar]
  5. Cumming R. C., Liu J. M., Youssoufian H., Buchwald M. Suppression of apoptosis in hematopoietic factor-dependent progenitor cell lines by expression of the FAC gene. Blood. 1996 Dec 15;88(12):4558–4567. [PubMed] [Google Scholar]
  6. Dreiding P., Staeheli P., Haller O. Interferon-induced protein Mx accumulates in nuclei of mouse cells expressing resistance to influenza viruses. Virology. 1985 Jan 15;140(1):192–196. doi: 10.1016/0042-6822(85)90460-x. [DOI] [PubMed] [Google Scholar]
  7. Duckworth-Rysiecki G., Cornish K., Clarke C. A., Buchwald M. Identification of two complementation groups in Fanconi anemia. Somat Cell Mol Genet. 1985 Jan;11(1):35–41. doi: 10.1007/BF01534732. [DOI] [PubMed] [Google Scholar]
  8. Fanconi G. Familial constitutional panmyelocytopathy, Fanconi's anemia (F.A.). I. Clinical aspects. Semin Hematol. 1967 Jul;4(3):233–240. [PubMed] [Google Scholar]
  9. Fu X. Y., Schindler C., Improta T., Aebersold R., Darnell J. E., Jr The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7840–7843. doi: 10.1073/pnas.89.16.7840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gabriel S. E., Brigman K. N., Koller B. H., Boucher R. C., Stutts M. J. Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science. 1994 Oct 7;266(5182):107–109. doi: 10.1126/science.7524148. [DOI] [PubMed] [Google Scholar]
  11. Horisberger M. A. Interferon-induced human protein MxA is a GTPase which binds transiently to cellular proteins. J Virol. 1992 Aug;66(8):4705–4709. doi: 10.1128/jvi.66.8.4705-4709.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Horisberger M. A., McMaster G. K., Zeller H., Wathelet M. G., Dellis J., Content J. Cloning and sequence analyses of cDNAs for interferon- and virus-induced human Mx proteins reveal that they contain putative guanine nucleotide-binding sites: functional study of the corresponding gene promoter. J Virol. 1990 Mar;64(3):1171–1181. doi: 10.1128/jvi.64.3.1171-1181.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Horisberger M. A., Staeheli P., Haller O. Interferon induces a unique protein in mouse cells bearing a gene for resistance to influenza virus. Proc Natl Acad Sci U S A. 1983 Apr;80(7):1910–1914. doi: 10.1073/pnas.80.7.1910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Joenje H., Lo ten Foe J. R., Oostra A. B., van Berkel C. G., Rooimans M. A., Schroeder-Kurth T., Wegner R. D., Gille J. J., Buchwald M., Arwert F. Classification of Fanconi anemia patients by complementation analysis: evidence for a fifth genetic subtype. Blood. 1995 Sep 15;86(6):2156–2160. [PubMed] [Google Scholar]
  15. Krug R. M., Shaw M., Broni B., Shapiro G., Haller O. Inhibition of influenza viral mRNA synthesis in cells expressing the interferon-induced Mx gene product. J Virol. 1985 Oct;56(1):201–206. doi: 10.1128/jvi.56.1.201-206.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kruyt F. A., Dijkmans L. M., van den Berg T. K., Joenje H. Fanconi anemia genes act to suppress a cross-linker-inducible p53-independent apoptosis pathway in lymphoblastoid cell lines. Blood. 1996 Feb 1;87(3):938–948. [PubMed] [Google Scholar]
  17. Liang P., Pardee A. B. Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science. 1992 Aug 14;257(5072):967–971. doi: 10.1126/science.1354393. [DOI] [PubMed] [Google Scholar]
  18. Liu J. M., Buchwald M., Walsh C. E., Young N. S. Fanconi anemia and novel strategies for therapy. Blood. 1994 Dec 15;84(12):3995–4007. [PubMed] [Google Scholar]
  19. 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. Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. Nat Genet. 1996 Nov;14(3):320–323. doi: 10.1038/ng1196-320. [DOI] [PubMed] [Google Scholar]
  20. Marathi U. K., Howell S. R., Ashmun R. A., Brent T. P. The Fanconi anemia complementation group C protein corrects DNA interstrand cross-link-specific apoptosis in HSC536N cells. Blood. 1996 Sep 15;88(6):2298–2305. [PubMed] [Google Scholar]
  21. Meier E., Fäh J., Grob M. S., End R., Staeheli P., Haller O. A family of interferon-induced Mx-related mRNAs encodes cytoplasmic and nuclear proteins in rat cells. J Virol. 1988 Jul;62(7):2386–2393. doi: 10.1128/jvi.62.7.2386-2393.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Miller L. H. Malaria. Protective selective pressure. Nature. 1996 Oct 10;383(6600):480–481. doi: 10.1038/383480a0. [DOI] [PubMed] [Google Scholar]
  23. Pavlovic J., Arzet H. A., Hefti H. P., Frese M., Rost D., Ernst B., Kolb E., Staeheli P., Haller O. Enhanced virus resistance of transgenic mice expressing the human MxA protein. J Virol. 1995 Jul;69(7):4506–4510. doi: 10.1128/jvi.69.7.4506-4510.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pavlovic J., Zürcher T., Haller O., Staeheli P. Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol. 1990 Jul;64(7):3370–3375. doi: 10.1128/jvi.64.7.3370-3375.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pestka S., Langer J. A., Zoon K. C., Samuel C. E. Interferons and their actions. Annu Rev Biochem. 1987;56:727–777. doi: 10.1146/annurev.bi.56.070187.003455. [DOI] [PubMed] [Google Scholar]
  26. Pronk J. C., Gibson R. A., Savoia A., Wijker M., Morgan N. V., Melchionda S., Ford D., Temtamy S., Ortega J. J., Jansen S. Localisation of the Fanconi anaemia complementation group A gene to chromosome 16q24.3. Nat Genet. 1995 Nov;11(3):338–340. doi: 10.1038/ng1195-338. [DOI] [PubMed] [Google Scholar]
  27. Raefsky E. L., Platanias L. C., Zoumbos N. C., Young N. S. Studies of interferon as a regulator of hematopoietic cell proliferation. J Immunol. 1985 Oct;135(4):2507–2512. [PubMed] [Google Scholar]
  28. Rathbun R. K., Faulkner G. R., Ostroski M. H., Christianson T. A., Hughes G., Jones G., Cahn R., Maziarz R., Royle G., Keeble W. Inactivation of the Fanconi anemia group C gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells. Blood. 1997 Aug 1;90(3):974–985. [PubMed] [Google Scholar]
  29. Ronni T., Melén K., Malygin A., Julkunen I. Control of IFN-inducible MxA gene expression in human cells. J Immunol. 1993 Mar 1;150(5):1715–1726. [PubMed] [Google Scholar]
  30. Rothman J. H., Raymond C. K., Gilbert T., O'Hara P. J., Stevens T. H. A putative GTP binding protein homologous to interferon-inducible Mx proteins performs an essential function in yeast protein sorting. Cell. 1990 Jun 15;61(6):1063–1074. doi: 10.1016/0092-8674(90)90070-u. [DOI] [PubMed] [Google Scholar]
  31. Schroeder S. A., Gaughan D. M., Swift M. Protection against bronchial asthma by CFTR delta F508 mutation: a heterozygote advantage in cystic fibrosis. Nat Med. 1995 Jul;1(7):703–705. doi: 10.1038/nm0795-703. [DOI] [PubMed] [Google Scholar]
  32. Staeheli P., Haller O., Boll W., Lindenmann J., Weissmann C. Mx protein: constitutive expression in 3T3 cells transformed with cloned Mx cDNA confers selective resistance to influenza virus. Cell. 1986 Jan 17;44(1):147–158. doi: 10.1016/0092-8674(86)90493-9. [DOI] [PubMed] [Google Scholar]
  33. Staeheli P., Haller O. Interferon-induced Mx protein: a mediator of cellular resistance to influenza virus. Interferon. 1987;8:1–23. [PubMed] [Google Scholar]
  34. Staeheli P., Sutcliffe J. G. Identification of a second interferon-regulated murine Mx gene. Mol Cell Biol. 1988 Oct;8(10):4524–4528. doi: 10.1128/mcb.8.10.4524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Staeheli P., Yu Y. X., Grob R., Haller O. A double-stranded RNA-inducible fish gene homologous to the murine influenza virus resistance gene Mx. Mol Cell Biol. 1989 Jul;9(7):3117–3121. doi: 10.1128/mcb.9.7.3117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Strathdee C. A., Duncan A. M., Buchwald M. Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9. Nat Genet. 1992 Jun;1(3):196–198. doi: 10.1038/ng0692-196. [DOI] [PubMed] [Google Scholar]
  37. Strathdee C. A., Gavish H., Shannon W. R., Buchwald M. Cloning of cDNAs for Fanconi's anaemia by functional complementation. Nature. 1992 Apr 30;356(6372):763–767. doi: 10.1038/356763a0. [DOI] [PubMed] [Google Scholar]
  38. Wang C. Q., Udupa K. B., Lipschitz D. A. Interferon-gamma exerts its negative regulatory effect primarily on the earliest stages of murine erythroid progenitor cell development. J Cell Physiol. 1995 Jan;162(1):134–138. doi: 10.1002/jcp.1041620116. [DOI] [PubMed] [Google Scholar]
  39. Weatherall D. J. Host genetics and infectious disease. Parasitology. 1996;112 (Suppl):S23–S29. [PubMed] [Google Scholar]
  40. Whitney M. A., Royle G., Low M. J., Kelly M. A., Axthelm M. K., Reifsteck C., Olson S., Braun R. E., Heinrich M. C., Rathbun R. K. Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the Fanconi anemia C gene. Blood. 1996 Jul 1;88(1):49–58. [PubMed] [Google Scholar]
  41. Whitney M., Thayer M., Reifsteck C., Olson S., Smith L., Jakobs P. M., Leach R., Naylor S., Joenje H., Grompe M. Microcell mediated chromosome transfer maps the Fanconi anaemia group D gene to chromosome 3p. Nat Genet. 1995 Nov;11(3):341–343. doi: 10.1038/ng1195-341. [DOI] [PubMed] [Google Scholar]
  42. Yamashita T., Barber D. L., Zhu Y., Wu N., D'Andrea A. D. The Fanconi anemia polypeptide FACC is localized to the cytoplasm. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6712–6716. doi: 10.1073/pnas.91.14.6712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Youssoufian H., Auerbach A. D., Verlander P. C., Steimle V., Mach B. Identification of cytosolic proteins that bind to the Fanconi anemia complementation group C polypeptide in vitro. Evidence for a multimeric complex. J Biol Chem. 1995 Apr 28;270(17):9876–9882. doi: 10.1074/jbc.270.17.9876. [DOI] [PubMed] [Google Scholar]
  44. Youssoufian H. Cytoplasmic localization of FAC is essential for the correction of a prerepair defect in Fanconi anemia group C cells. J Clin Invest. 1996 May 1;97(9):2003–2010. doi: 10.1172/JCI118635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Youssoufian H. Localization of Fanconi anemia C protein to the cytoplasm of mammalian cells. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):7975–7979. doi: 10.1073/pnas.91.17.7975. [DOI] [PMC free article] [PubMed] [Google Scholar]

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