Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells.

Segal, Gerald M.; Magenis, R. Ellen; Brown, Matthew A.; Keeble, Winifred; Smith, T. D.; Heinrich, Michael C.; Bagby, Grover C.

doi:10.1172/jci117405

Cited by 43 publications

(11 citation statements)

References 36 publications

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“…In keeping with this, a specific role for FANCC in the survival and/or proliferation of hematopoietic progenitor cells (HPCs) has been suggested. 12 Interestingly, Fancc Ϫ/Ϫ HPCs were shown to be hypersensitive to the growth-inhibiting effects of 3 unrelated cytokines: interferon ␥ (IFN␥), tumor necrosis factor ␣ (TNF␣), and macrophage inflammatory protein 1␣ (MIP-1␣). [13][14][15] In keeping with these results, obtained in Fancc Ϫ/Ϫ murine cells, HPCs from FANCC-deficient individuals were shown to up-regulate fas and interferon response factor 1 (IRF-1) expression at significantly lower doses of IFN␥ than those required for control cells.…”

Section: Introductionmentioning

confidence: 99%

Increased sensitivity of Fancc-deficient hematopoietic cells to nitric oxide and evidence that this species mediates growth inhibition by cytokines

Hadjur

Jirik

2003

Blood

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Section: Introductionmentioning

confidence: 99%

Increased sensitivity of Fancc-deficient hematopoietic cells to nitric oxide and evidence that this species mediates growth inhibition by cytokines

Hadjur

Jirik

2003

Blood

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“…This notion derives from reports that suppression of FANCC gene expression represses clonal growth of normal erythroid and granulocyte-macrophage progenitor cells and that disruption of the FANCC gene, in mice, rendered hematopoietic progenitor cells hypersensitive to the apoptotic effects of interferon ␥ (IFN-␥) and tumor necrosis factor-␣ (TNF-␣). 3,14,27,28 Conversely, overexpression of FANCC suppresses apoptosis in human hematopoietic factor-dependent progenitor cell lines, 29 in CD34 ϩ cells from FA-C patients, 14,30 and in hematopoietic progenitor cells from fancc knock-out mice. 31 One function of FANCC that may account for its importance in hematopoietic control is its role in governing proper activation of STAT molecules.…”

Section: Introductionmentioning

confidence: 99%

“…This notion derives from reports that suppression of FANCC gene expression represses clonal growth of normal erythroid and granulocyte-macrophage progenitor cells and that disruption of the FANCC gene, in mice, rendered hematopoietic progenitor cells hypersensitive to the apoptotic effects of interferon ␥ (IFN-␥) and tumor necrosis factor-␣ (TNF-␣). 3,14,27,28 Conversely, overexpression of FANCC suppresses apoptosis in human hematopoietic factor-dependent progenitor cell lines, 29 in CD34 ϩ cells from FA-C patients, 14,30 One function of FANCC that may account for its importance in hematopoietic control is its role in governing proper activation of STAT molecules. Recently, we reported that lymphoblasts from FA-C patients were defective in STAT1 activation in response to stimulation with 26 We also noted that in FA-C cells STAT1 failed to dock at the IFN-␥ receptor ␣-chain (IFN-␥R␣) and activated STAT1 dimers failed to translocate to the nucleus but that expression of a normal FANCC protein corrected these defects.…”

mentioning

confidence: 99%

The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality

Pang

Christianson

Keeble

et al. 2001

Blood

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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 GSTfusion 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. IntroductionFanconi anemia (FA) is an autosomal recessive disease characterized by bone marrow failure, variable congenital anomalies, and a predisposition to leukemia. [1][2][3] Cells from patients with FA exhibit hypersensitivity to alkylating agents such as mitomycin C (MMC) and diepoxybutane (DEB). Indeed, the hypersensitivity to cytotoxic effects of DNA cross-linking agents is currently used as the basis for the diagnostic tests for FA. 4,5 It is known that FA is genetically heterogeneous, with at least 7 complementation groups (A-G) identified thus far. 6,7 The genes encoding the groups A (FANCA), 8 C (FANCC), 9 D2 (FANCD2), 10 G (FANCG), 11 and F (FANCF) 12 have been cloned. The group C locus, FANCC, encodes a 63-kd protein of unknown function. 9 Expression of the normal FANCC complementary DNA (cDNA) in FA-C cells prevents MMC-induced chromosomal aberrations, prevents G 2 arrest in cell cycle, and prevents growth inhibition and apoptosis. 13,14 FANCC forms complexes with at least 3 other FA proteins, ...

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“…In this regard, it is interesting to speculate on the contribution of one of the FAZF specific interacting partners, FANCC. FANCC mRNA is expressed in CD34 ϩ cells (33,34) and is evidently necessary for survival (10). Experiments with CD34 ϩ cells from FA patients as well as evidence from FanccϪ/Ϫ mouse models reinforces the idea that FANCC is critical for early hematopoietic cell development (7,(35)(36)(37)(38).…”

Section: Fig 4 Fazf Is Expressed During Erythroid and Myeloid Diffementioning

confidence: 68%

“…Cells from FA patients are hypersensitive to DNA cross-linking agents such as mitomycin C. In addition, FA cells have an abnormal cell cycle profile, and this abnormality is exacerbated by treatment with mitomycin C (7). CD34 ϩ cells isolated from FA-C patients fail to thrive in vitro (8,9), and treating normal CD34 ϩ cells with antisense oligodinucleotides directed against the FANCC gene recapitulates the defective phenotype (10). These results suggest that FA genes are involved in ensuring the proper growth and differentiation of primitive hematopoietic cells.…”

Section: Fazfmentioning

confidence: 94%

The Effects of the Fanconi Anemia Zinc Finger (FAZF) on Cell Cycle, Apoptosis, and Proliferation Are Differentiation Stage-specific

Dai¹,

Chevallier²,

Stone³

et al. 2002

Journal of Biological Chemistry

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FAZF, a member of the BTB/POZ family of transcriptional repressor proteins, has been shown to bind to FANCC, the protein defective in patients with the bone marrow failure syndrome Fanconi anemia complementation group C. Because bone marrow failure in Fanconi anemia has been attributed to a failure of the hematopoietic stem cell population to produce sufficient progeny, we documented the expression of FAZF in human CD34؉ hematopoietic progenitor cells. FAZF was expressed at high levels in early stages of differentiation but declined during subsequent differentiation into erythroid and myeloid lineages. Consistent with its presumed role as a transcriptional repressor, FAZF was found in the nuclear compartment, where it resides in distinct nuclear speckles at or near sites of DNA replication. Using a FAZF-inducible myeloid cell line, we found that enforced expression of FAZF was accompanied by accumulation in the G 1 phase of the cell cycle followed later by apoptosis. These results suggest an essential role for FAZF during the proliferative stages of primitive hematopoietic progenitors, possibly acting in concert with (a subset of) the Fanconi anemia proteins.

show abstract

Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells.

Cited by 43 publications

References 36 publications

Increased sensitivity of Fancc-deficient hematopoietic cells to nitric oxide and evidence that this species mediates growth inhibition by cytokines

Increased sensitivity of Fancc-deficient hematopoietic cells to nitric oxide and evidence that this species mediates growth inhibition by cytokines

The Fanconi anemia complementation group C gene product: structural evidence of multifunctionality

The Effects of the Fanconi Anemia Zinc Finger (FAZF) on Cell Cycle, Apoptosis, and Proliferation Are Differentiation Stage-specific

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