|
|
 Previous Article | Table of Contents | Next Article 
Blood, 1 September 2001, Vol. 98, No. 5, pp. 1392-1401
HEMATOPOIESIS
The Fanconi anemia complementation group C gene
product: structural evidence of multifunctionality
Qishen Pang,
Tracy A. Christianson,
Winifred Keeble,
Jane Diaz,
Gregory R. Faulkner,
Carol Reifsteck,
Susan Olson, and
Grover C. Bagby
From the Oregon Cancer Center, Department of Medicine
(Division of Hematology and Medical Oncology) and Department of
Molecular and Medical Genetics, Oregon Health Sciences University,
Portland, OR, and Molecular Hematopoiesis Laboratory, VA Medical
Center, Portland, OR.
The Fanconi anemia (FA) group C gene product (FANCC) functions to
protect cells from cytotoxic and genotoxic effects of cross-linking agents. 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. Because not all FANCC
mutations affect STAT1 activation, the hypothesis was considered that
cross-linker resistance function of FANCC depends on structural
elements that differ from those required for the cytokine signaling
functions of FANCC. Structure-function studies were designed to test
this notion. Six separate alanine-substituted mutations were generated in 3 highly conserved motifs of FANCC. All mutants complemented mitomycin C (MMC) hypersensitive phenotype of FA-C cells and corrected aberrant posttranslational activation of FANCD2 in FA-C mutant cells.
However, 2 of the mutants, S249A and E251A, failed to correct defective
STAT1 activation. FA-C lymphoblasts carrying these 2 mutants
demonstrated a defect in recruitment of STAT1 to the interferon  (IFN-) receptor and GST-fusion proteins bearing S249A and E251A mutations were less efficient binding partners for STAT1 in stimulated lymphoblasts. These same mutations failed to complement the
characteristic hypersensitive apoptotic responses of FA-C cells to
tumor necrosis factor- (TNF-) and IFN-. Cells bearing a
naturally occurring FANCC mutation (322delG) that preserves this
conserved region showed normal STAT1 activation but remained
hypersensitive to MMC. The conclusion is that a central highly
conserved domain of FANCC is required for functional interaction with
STAT1 and that structural elements required for STAT1-related functions differ from those required for genotoxic responses to cross-linking agents. 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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. Berwick, J. M. Satagopan, L. Ben-Porat, A. Carlson, K. Mah, R. Henry, R. Diotti, K. Milton, K. Pujara, T. Landers, et al.
Genetic Heterogeneity among Fanconi Anemia Heterozygotes and Risk of Cancer
Cancer Res.,
October 1, 2007;
67(19):
9591 - 9596.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. C. Bagby
The less-traveled Fanconi road
Blood,
June 1, 2006;
107(11):
4196 - 4197.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Shimamura
Inherited Bone Marrow Failure Syndromes: Molecular Features
Hematology,
January 1, 2006;
2006(1):
63 - 71.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Bijangi-Vishehsaraei, M. R. Saadatzadeh, A. Werne, K. A. W. McKenzie, R. Kapur, H. Ichijo, and L. S. Haneline
Enhanced TNF-{alpha}-induced apoptosis in Fanconi anemia type C-deficient cells is dependent on apoptosis signal-regulating kinase 1
Blood,
December 15, 2005;
106(13):
4124 - 4130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Chen, P. C. Van der Sluis, D. Boulware, L. A. Hazlehurst, and W. S. Dalton
The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells
Blood,
July 15, 2005;
106(2):
698 - 705.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Leveille, E. Blom, A. L. Medhurst, P. Bier, E. H. Laghmani, M. Johnson, M. A. Rooimans, A. Sobeck, Q. Waisfisz, F. Arwert, et al.
The Fanconi Anemia Gene Product FANCF Is a Flexible Adaptor Protein
J. Biol. Chem.,
September 17, 2004;
279(38):
39421 - 39430.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Saadatzadeh, K. Bijangi-Vishehsaraei, P. Hong, H. Bergmann, and L. S. Haneline
Oxidant Hypersensitivity of Fanconi Anemia Type C-deficient Cells Is Dependent on a Redox-regulated Apoptotic Pathway
J. Biol. Chem.,
April 16, 2004;
279(16):
16805 - 16812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Brodeur, I. Goulet, C. S. Tremblay, C. Charbonneau, M.-C. Delisle, C. Godin, C. Huard, E. W. Khandjian, M. Buchwald, G. Levesque, et al.
Regulation of the Fanconi Anemia Group C Protein through Proteolytic Modification
J. Biol. Chem.,
February 6, 2004;
279(6):
4713 - 4720.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. W. Lensch, M. Tischkowitz, T. A. Christianson, C. A. Reifsteck, S. A. Speckhart, P. M. Jakobs, M. E. O'Dwyer, S. B. Olson, M. M. Le Beau, S. V. Hodgson, et al.
Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia
Blood,
July 1, 2003;
102(1):
7 - 16.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Hadjur and F. R. Jirik
Increased sensitivity of Fancc-deficient hematopoietic cells to nitric oxide and evidence that this species mediates growth inhibition by cytokines
Blood,
May 15, 2003;
101(10):
3877 - 3884.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Adachi, T. Oda, H. Yagasaki, K. Nakasato, T. Taniguchi, A. D. D'Andrea, S. Asano, and T. Yamashita
Heterogeneous activation of the Fanconi anemia pathway by patient-derived FANCA mutants
Hum. Mol. Genet.,
December 1, 2002;
11(25):
3125 - 3134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Bogliolo, O. Cabre, E. Callen, V. Castillo, A. Creus, R. Marcos, and J. Surralles
The Fanconi anaemia genome stability and tumour suppressor network
Mutagenesis,
November 1, 2002;
17(6):
529 - 538.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Taniguchi and A. D. D'Andrea
The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of FANCC
Blood,
September 18, 2002;
100(7):
2457 - 2462.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Aube, M. Lafrance, C. Charbonneau, I. Goulet, and M. Carreau
Hematopoietic Stem Cells from Fancc-/- Mice Have Lower Growth and Differentiation Potential in Response to Growth Factors
Stem Cells,
September 1, 2002;
20(5):
438 - 447.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. R. Rutherford, N. E. Myatt, F. M. Gibson, A. A. Clarke ;, and G. C. Bagby Jr
The Fanconi anemia cell line HSC536N is not sensitive to interferon-gamma and does not cleave PARP in response to Fas-mediated cell killing
Blood,
April 1, 2002;
99(7):
2627 - 2630.
[Full Text]
[PDF]
|
|
|
| |
