ライフサイエンスコーパス: FANCC

1 FANCC and FANCE act as substrate receptors and restrict

2 FANCC and FANCG disruption abrogated FANCD2 monoubiquiti

3 FANCC and FANCG disruption also resulted in increased cl

4 FANCC is also required for optimal activation of STAT1 i

5 FANCC is found in both the cytoplasmic and the nuclear c

6 FANCC is one of the most commonly mutated FA genes in FA

7 FANCC mutations are often the cause of FA in patients of

8 FANCC(-/-) cells were hypersensitive to both dsRNA and t

9 FANCC-deficient macrophages are also hypersensitive to T

10 FANCC-deficient THP-1 cells and macrophages from Fancc(-

11 n occurred despite deletion of the 5' and 3' FANCC untranslated regions, indicating that information

12 ns in all 27 families: FANCA (7), FANCB (3), FANCC (3), FANCD1 (1), FANCD2 (3), FANCF (2), FANCG (2),

13 t with DNA interstrand-cross-linking agents, FANCC and FANCG disruption caused increased clastogenic

14 Because not all FANCC mutations affect STAT1 activation, the hypothesis

15 We found that although FANCC mRNA levels are constant throughout the cell cycle

16 beta-catenin and FANCC nuclear entry is defective in FA mutant cells and

17 Moreover, cytoplasmic FANCA and FANCC formed a cytoplasmic complex and interacted with N

18 Finally, depletion of FANCA and FANCC in NPMc-positive leukemic cells significantly incr

19 so suggest cytoplasmic function of FANCA and FANCC in NPMc-related leukemogenesis.

20 ilized the endogenous forms of the FANCA and FANCC proteins in the FA-G cells.

21 e previously demonstrated that the FANCA and FANCC proteins interact and form a nuclear complex in no

22 a complex in the nucleus with the FANCA and FANCC proteins.

23 ein is required for binding of the FANCA and FANCC proteins.

24 tivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines.

25 nuclear protein complex containing FANCA and FANCC.

26 rmined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overproduction of bo

27 mmatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to

28 Because FANCE and FANCC interact in vitro and FANCE is required for FANCD2

29 educed MMC sensitivity but FANCF, FANCG, and FANCC did not.

30 anemia complementation group G- (FANCG-) and FANCC-deficient pancreatic tumor lines were more sensiti

31 genetic mapping we have excluded ZNF169 and FANCC as well as PTCH (PATCHED) and TGFBR1 (transforming

32 Disease-associated FANCC mutants do not bind to FANCE, cannot accumulate in

33 ANCC, the first cancer cell line found to be FANCC-null.

34 Because FANCC protects hematopoietic cells from apoptotic cues i

35 depended upon a physical interaction between FANCC and Hsp70 but not on interactions of FANCC with ot

36 FANCA protein is required for FANCG binding, FANCC binding, nuclear localization, and functional acti

37 s part of this nuclear complex, binding both FANCC and FANCD2.

38 Disruption of both FANCC and Ku70 suppresses sensitivity to cross-linking a

39 Mutations in BRCA2, FANCC and NBN decreased nuclear localization of BRCA1 in

40 uncertain significance or with known BRCA2, FANCC or NBN mutations were tested.

41 ivating mutations of Fanconi anemia group C (FANCC) are excessively apoptotic and demonstrate hyperse

42 ing mutations of FA complementation group C (FANCC) are genetically unstable and hypersensitive to ap

43 fifteen FA proteins, Fanconi anemia group C (FANCC) is one of eight FA core complex components of the

44 Fanconi anemia complementation group C (FANCC) protein interacts with Parkin, is required in vit

45 aploid cells for FA complementation group C (FANCC), a gene encoding a component of the FA core compl

46 Fanconi anemia, complementation group C (FANCC)-deficient hematopoietic stem and progenitor cells

47 Because certain FANCC mutations interdict its anti-apoptotic function wi

48 In conclusion, FANCC suppresses TNF-alpha production in mononuclear pha

49 vels are constant throughout the cell cycle, FANCC is expressed in a cell cycle-dependent manner, wit

50 Using a patient-derived FANCC mutant and a nuclearized FANCC, we demonstrated th

51 We endogenously disrupted FANCC and FANCG in a human adenocarcinoma cell line and

52 not contain motifs that bind to SH3 domains, FANCC and FANCF, did not interact with the SH3 domain of

53 Ectopically expressed FANCC point mutants were capable of fully complementing

54 FANCA, FANCC, FANCG, and FANCF proteins form a multisubunit nuc

55 genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as BRCA1

56 r pathway including at least 6 genes (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG).

57 ported FA-binding proteins, including FANCA, FANCC, FANCG, cdc2, and GRP94, thus validating the appro

58 the physical interaction of at least FANCA, FANCC, and FANCG, and possibly of other FA and non-FA pr

59 Fluorescent-tagged versions of FANCA, FANCC, and FANCG colocalize in cytoplasm and nucleus, ch

60 6 known Fanconi anemia gene products (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG proteins) interac

61 plex with the Fanconi anemia proteins FANCA, FANCC, and FANCG.

62 The FA proteins FANCA, FANCC, FANCE, FANCF, FANCG, and FANCL participate in a c

63 tract to show that three FA proteins, FANCA, FANCC, and FANCG, functionally interact with the PKR kin

64 d at least 3 of the encoded proteins, FANCA, FANCC, and FANCG/XRCC9, interact in a multisubunit prote

65 least three of the encoded proteins, FANCA, FANCC, and FANCG/XRCC9, interact in a nuclear complex, r

66 Given that FANCA, FANCC, and FANCG complementation groups account for more

67 n BRCA2 or its effector RAD51 and the FANCA, FANCC and FANCG proteins.

68 mary human BM cells, mutations in the FANCA, FANCC, and FANCG genes markedly increase the amount of P

69 interstrand cross-links and that the FANCA, FANCC, and FANCG proteins are bound to this damaged DNA

70 , which is minimally dependent on the FANCA, FANCC, and FANCG proteins, does not require FANCD2.

71 that a nuclear complex containing the FANCA, FANCC, FANCF, and FANCG proteins is required for the act

72 -hybrid analysis to determine whether FANCA, FANCC, FANCF, and FANCG directly interact with ERCC1 and

73 NCE protein coimmunoprecipitates with FANCA, FANCC, and FANCG but not with FANCD2.

74 , we demonstrated that the cytoplasmic FANCA-FANCC complex was essential for NPMc stability.

75 nuclear accumulation of FANCC protein, FANCA-FANCC complex formation, monoubiquitination and nuclear

76 s to all nine cloned FA genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL),

77 ast 13 complementation groups (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ

78 ni anemia-associated proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) form a nuclear Fan

79 molecular mass of cytoplasmic FANCA, FANCG, FANCC, and nuclear FANCD2 were normal.

80 Our data suggest that the FAZF/FANCC interaction maps to a region of FANCC deleted in F

81 Finally, FANCC and FANCG disruption increased spontaneous chromos

82 integrity of the FA pathway is required for FANCC nuclear activity.

83 Consequently, loss of a functional FANCC results in decreased activation of STAT1 following

84 n, murine and human cells lacking functional FANCC did not maintain the G2 checkpoint as compared wit

85 ger gene ZNF169 and the Fanconi anaemia gene FANCC.

86 nd a genetic interaction between the FA gene FANCC and the nonhomologous end joining (NHEJ) factor Ku

87 mia (FA) Group C complementation group gene (FANCC) encodes a protein, FANCC, with a predicted M(r) o

88 rally selected mutations in DNA repair genes FANCC, FANCG and BRCA2 respectively, were less sensitive

89 Hsp70, FANCC, and PKR form a ternary complex in lymphoblasts an

90 In whole cells, Hsp70-FANCC binding and protection from IFN-gamma/TNF-alpha-in

91 ned to ectopically express instructive human FANCC (hFANCC) mutants in murine Fancc-deficient hematop

92 ining a disruption of the homologue of human FANCC (Fancc) results in a time-dependent increase in ap

93 yviral vector construct expressing the human FANCC cDNA to efficiently transduce murine FA stem cells

94 nt protein kinase PKR, we sought to identify FANCC-binding cofactors that may modulate PKR activation

95 IRF-1, were not differentially activated in FANCC(-/-) cells, but enforced expression of a nonphosph

96 ts induced a higher fraction of apoptosis in FANCC(-/-) cells than in normal cells.

97 ally abrogated the PKR-mediated apoptosis in FANCC(-/-) cells.

98 Recently, several sequence changes in FANCC and FANCG were reported in pancreatic cancer.

99 Human cells deficient in FANCC and FANCG are also hypersensitive to plasma levels

100 tification of a large homozygous deletion in FANCC, the first cancer cell line found to be FANCC-null

101 affinity for double-stranded RNA (dsRNA) in FANCC(-/-) cells.

102 dent kinase inhibitor p21(WAF1) was found in FANCC mutant B lymphoblasts, low-density bone marrow cel

103 n, and that a FA disease-causing mutation in FANCC abrogates this function.

104 rt the assertion that inherited mutations in FANCC can predispose to pancreatic cancer.

105 Compared with Fancc(-)(/)(-) mice lacking FANCC, a component of the FA core complex, Helq(gt/gt) m

106 genes encoding normal FANCC but not a mutant FANCC bearing an inactivating point mutation (L554P) bou

107 clear foci, whereas a patient-derived mutant FANCC that is compromised for nuclear localization canno

108 e S-transferase fusion genes encoding normal FANCC but not a mutant FANCC bearing an inactivating poi

109 ormality corrected by transduction of normal FANCC cDNA.

110 A certain number of these proteins, notably FANCC, also function independently to modulate apoptotic

111 ish (AJ) ancestry, and we identified 2 novel FANCC mutations in 2 patients of AJ ancestry.

112 tient-derived FANCC mutant and a nuclearized FANCC, we demonstrated that the cytoplasmic FANCA-FANCC

113 Cells bearing a naturally occurring FANCC mutation (322delG) that preserves this conserved r

114 is required for the nuclear accumulation of FANCC and provides a critical bridge between the FA comp

115 CE cDNA restores the nuclear accumulation of FANCC protein, FANCA-FANCC complex formation, monoubiqui

116 inding assays showed that the association of FANCC and Hsp70 involves the ATPase domain of Hsp70 and

117 nus of FANCG are required for the binding of FANCC in the complex.

118 studies revealed that the initial binding of FANCC was to nonphosphorylated STAT1 but that subsequent

119 ion without interfering with the capacity of FANCC to participate functionally in the FA multimeric c

120 the grandmothers, those who were carriers of FANCC mutations were found to be at highest risk (SIR, 2

121 Our observation of dynamic control of FANCC expression by the proteasome has important implica

122 clude that Hsp70 requires the cooperation of FANCC to suppress PKR activity and support survival of h

123 is that a central highly conserved domain of FANCC is required for functional interaction with STAT1

124 motif within the Hsp70-interacting domain of FANCC.

125 Expression of FANCC cDNA in Fancc-/- stem cells protected them from TN

126 immunological defect owing to the failure of FANCC to normally support Jak/STAT signaling.

127 e direct interaction of FANCF with FANCG, of FANCC with FANCE and a weaker interaction of FANCE with

128 red that cross-linker resistance function of FANCC depends on structural elements that differ from th

129 , at least in part, because this function of FANCC is abrogated.

130 The mitophagy function of FANCC is genetically distinct from its role in genomic D

131 LR8 activity and this particular function of FANCC is independent of its function in protecting the g

132 was concluded that an essential function of FANCC is to suppress, indirectly, the activity of PKR an

133 These results suggest that the function of FANCC may be linked to a transcriptional repression path

134 gh a mechanism distinct from the function of FANCC.

135 ired for the cytokine signaling functions of FANCC.

136 ning a disruption of the murine homologue of FANCC (FancC) to evaluate short- and long-term multiline

137 educed the IFN and dsRNA hypersensitivity of FANCC(-/-) cells.

138 The recent identification of FANCC and FANCG mutations in resected pancreatic tumors

139 n FANCC and Hsp70 but not on interactions of FANCC with other Fanconi proteins.

140 A characteristic matching of FANCC-null, FANCG-null, BRCA2/FANCD1-null, and PALB2/FAN

141 re generated in 3 highly conserved motifs of FANCC.

142 we report inherited and somatic mutations of FANCC and FANCG present in young-onset pancreatic cancer

143 chaperone Hsp70 as an interacting partner of FANCC in lymphoblasts and HeLa cells using 'pull-down' a

144 e FAZF/FANCC interaction maps to a region of FANCC deleted in FA patients with a severe disease pheno

145 we have studied the molecular regulation of FANCC expression.

146 Previously, we showed that regulation of FANCC involved proteolytic processing during apoptosis.

147 To further assess the relevance of FANCC and FANCG mutations to pancreatic cancer we conduc

148 ain of Hsp70 and the central 320 residues of FANCC, and that both Hsp40 and ATP/ADP are required.

149 refore sought to define the specific role of FANCC protein in signal transduction through receptors t

150 tensive investigation, the biologic roles of FANCC and of the other cloned FA gene products (FANCA an

151 plemented by retroviral-mediated transfer of FANCC.

152 croarray and proteomic methods to studies on FANCC-deficient cells we found that genes encoding prote

153 Knockdown of FANCA or FANCC in leukemic OCI/AML3 cells induced rapid degradati

154 BS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity.

155 nd FANCG, whereas overexpression of FANCG or FANCC did not restore FANCA levels.

156 Because no evidence was found of a PKR/FANCC complex in normal cells, it was concluded that an

157 he Fanconi anemia (FA) group C gene product (FANCC) functions to protect cells from cytotoxic and gen

158 a (FA) complementation group C gene product (FANCC) functions to protect hematopoietic cells from cyt

159 tner for the Fanconi anemia group C protein (FANCC) by yeast two-hybrid screening.

160 previously found that the Fanconi C protein (FANCC) interacts with the C-terminal-binding protein-1 (

161 ce and human Fanconi anemia group C protein (FANCC) patients have increased apoptosis in response to

162 tation group gene (FANCC) encodes a protein, FANCC, with a predicted M(r) of 63,000 daltons.

163 The Fanconi anemia (FA) group C protein, FANCC, interacts with STAT1 following stimulation with I

164 at least one of the Fanconi anemia proteins, FANCC, exhibits functions in hematopoietic cells in addi

165 Unlike other FA core complex proteins, FANCC is mainly localized in the cytoplasm, where it is

166 olecular interacting partners of proteolytic FANCC fragments.

167 econstituted mice expressing the recombinant FANCC transgene was comparable with wild-type controls.

168 Overexpression of wild-type PKR-sensitized FANCC(-/-) cells to apoptosis induced by IFN-gamma and d

169 small molecules using TLR agonist-stimulated FANCC- and Fanconi anemia, complementation group A (FANC

170 loss of the BLM helicase complex suppresses FANCC phenotypes and we confirm this interaction in cell

171 ort survival of hematopoietic cells and that FANCC does not require the multimeric FA complex to exer

172 ss, indirectly, the activity of PKR and that FANCC inactivation results in IFN hypersensitivity, at l

173 We therefore conclude that FANCC acts in concert with Hsp70 to prevent apoptosis in

174 We conclude that FANCC expression is controlled by posttranscriptional me

175 atives, although there is some evidence that FANCC mutations are possibly breast cancer susceptibilit

176 We also report that FANCC with CtBP1 acts as a negative regulator of Dickkop

177 Here we report that FANCC with CtBP1 forms a complex with beta-catenin, and

178 organism with no FA orthologs, we show that FANCC inhibited the kinase activity of PKR both in vivo

179 analysis of overall survival time shows that FANCC mutations (P =.007) and hematopoietic stem cell tr

180 works within the cytoplasm, we suggest that FANCC and the FANCA-FANCG complexes suppress MMC cytotox

181 the FA multimeric complex, we suspected that FANCC enhances cell survival independent of its particip

182 only mutated FA genes in FA patients and the FANCC subtype tends to have a relatively early onset of

183 Because the FANCC protein deficient in FA group C works within the c

184 Consequently, because the FANCC protein is involved in the activation of STAT1 thr

185 regions, indicating that information in the FANCC coding sequence is sufficient to mediate cell cycl

186 notypic correction following transfer of the FANCC complementary DNA (cDNA) into bone marrow cells.

187 Mice with a targeted disruption of the FANCC gene (fancc -/- nullizygous mice) exhibit many of

188 abnormality corrected by transduction of the FANCC gene.

189 NCC gene, suggesting a potential role of the FANCC protein in innate immunity.

190 s and one direct or indirect function of the FANCC protein is to suppress apoptotic responses to IFN-

191 Thus, the FANCC protein functions to modulate expression of a fami

192 owever, this mutant protein fails to bind to FANCC and fails to correct the mitomycin C sensitivity o

193 epressor proteins, has been shown to bind to FANCC, the protein defective in patients with the bone m

194 c2, which was previously reported to bind to FANCC, we showed that cdc2 chiefly phosphorylated a 14-k

195 markedly increase the amount of PKR bound to FANCC, and this PKR accumulation is correlated with elev

196 en synthase kinase 3beta inhibition leads to FANCC nuclear accumulation and FA pathway activation, as

197 to have a G2 checkpoint phenotype similar to FANCC-deficient cells, indicating that FANCD2, which is

198 Two truncating FANCC mutations but no truncating FANCG mutations were i

199 We also show that FAZF and wild-type FANCC can colocalize in nuclear foci, whereas a patient-

200 orrected by the re-expression of a wild-type FANCC gene, suggesting a potential role of the FANCC pro

201 As an approach to understanding FANCC function, we have studied the molecular regulation

202 g protein-1 (CtBP1) interacted directly with FANCC and other FA core complex proteins.