Relevant bibliographies by topics / Pathway FA

Academic literature on the topic 'Pathway FA'

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Published: 11 March 2023

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Journal articles on the topic "Pathway FA"

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Jenkins, Chelsea, Jenny Kan, and Maureen E. Hoatlin. "Targeting the Fanconi Anemia Pathway to Identify Tailored Anticancer Therapeutics." Anemia 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/481583.

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The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs). The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.
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Kennedy, R. D., P. Stuckert, E. Archila, M. De LaVega, C. Chen, L. Moreau, and A. D'Andrea. "Sensitivity of tumor cells deficient in the fanconi anemia pathway to inhibition of ataxia telangiectasia mutated (ATM)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 10509. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10509.

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10509 Loss of the fanconi anemia (FA) pathway function has been described in a number of sporadic tumor types including breast, ovarian, pancreatic, head and neck and hematological malignancies. Functionally, the FA pathway responds to stalled DNA replication following DNA damage. Given the importance of the FA pathway in the response to DNA damage, we hypothesized that cells deficient in this pathway may become hyper-dependent on alternative DNA damage response pathways in order to respond to endogenous genotoxic stress such as occurs during metabolism. Therefore, targeting these alternative pathways could offer therapeutic strategies in FA pathway deficient tumors. To identify new therapeutic targets we treated FA pathway competent and deficient cells with a DNA damage response siRNA library, that individually knocked out 230 genes. We identified a number of gene targets that were specifically toxic to FA pathway deficient cells, amongst which was the DNA damage response kinase Ataxia Telangiectasia Mutated (ATM). To test the requirement for ATM in FA pathway deficient cells, we interbred Fancg ± Atm± mice. Consistent with the siRNA screen result, Fancg-/- Atm-/- mice were non viable and Fancg± Atm-/- and Fancg-/- Atm ± progeny were less frequent that would have been expected. Several human cell lines with FA gene mutations were observed to have constitutive activation of ATM which was markedly reduced on correction with the appropriate wild-type FA gene. Interestingly, FA pathway deficient cells, including the FANCC mutant and FANCG mutant pancreatic cancer cell lines, were selectively sensitive to monotherapy with the ATM inhibitor KU55933, as measured by dose inhibition and colony count assays. FA pathway deficient cells also demonstrated an increased level of chromosomal breakage, cell cycle arrest and apoptosis following KU55933 treatment when compared to FA pathway corrected cells. We conclude that FA pathway deficient cells have an increased requirement for ATM activation in order to respond to sporadic DNA damage. This offers the possibility that monotherapy with ATM inhibitors could be a therapeutic strategy for tumors that are deficient for the FA pathway. No significant financial relationships to disclose.
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Li, Niu, Jian Wang, Susan S. Wallace, Jing Chen, Jia Zhou, and Alan D. D’Andrea. "Cooperation of the NEIL3 and Fanconi anemia/BRCA pathways in interstrand crosslink repair." Nucleic Acids Research 48, no. 6 (January 25, 2020): 3014–28. http://dx.doi.org/10.1093/nar/gkaa038.

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Abstract The NEIL3 DNA glycosylase is a base excision repair enzyme that excises bulky base lesions from DNA. Although NEIL3 has been shown to unhook interstrand crosslinks (ICL) in Xenopus extracts, how NEIL3 participants in ICL repair in human cells and its corporation with the canonical Fanconi anemia (FA)/BRCA pathway remain unclear. Here we show that the NEIL3 and the FA/BRCA pathways are non-epistatic in psoralen-ICL repair. The NEIL3 pathway is the major pathway for repairing psoralen-ICL, and the FA/BRCA pathway is only activated when NEIL3 is not present. Mechanistically, NEIL3 is recruited to psoralen-ICL in a rapid, PARP-dependent manner. Importantly, the NEIL3 pathway repairs psoralen-ICLs without generating double-strand breaks (DSBs), unlike the FA/BRCA pathway. In addition, we found that the RUVBL1/2 complex physically interact with NEIL3 and function within the NEIL3 pathway in psoralen-ICL repair. Moreover, TRAIP is important for the recruitment of NEIL3 but not FANCD2, and knockdown of TRAIP promotes FA/BRCA pathway activation. Interestingly, TRAIP is non-epistatic with both NEIL3 and FA pathways in psoralen-ICL repair, suggesting that TRAIP may function upstream of the two pathways. Taken together, the NEIL3 pathway is the major pathway to repair psoralen-ICL through a unique DSB-free mechanism in human cells.
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Hays, Laura E. "Multifunctionality of the FA pathway." Blood 121, no. 1 (January 3, 2013): 3–4. http://dx.doi.org/10.1182/blood-2012-11-464636.

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Zhang, Haojian, David Kozono, Kevin O'Connor, Sofia Vidal-Cardenas, Abigail Hamilton, Emily Gaudiano, Joel S. Greenberger, Markus Grompe, Kalindi Parmar, and Alan D. D'Andrea. "Bone Marrow Failure in Fanconi Anemia from Hyperactive TGF-β Signaling." Blood 124, no. 21 (December 6, 2014): 356. http://dx.doi.org/10.1182/blood.v124.21.356.356.

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Abstract Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients develop bone marrow failure during the first decade of life due to attrition of hematopoietic stem and progenitor cells (HSPCs). FA patients also develop other hematologic manifestations, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) due to clonal evolution. FA is caused by biallelic mutants in one of sixteen FANC genes, the products of which cooperate in the FA/BRCA DNA repair pathway and regulate cellular resistance to DNA cross-linking agents. Bone marrow failure in FA may result, directly or indirectly, from hyperactivation of cell autonomous or microenvironmental growth suppressive pathways induced due to genotoxic stress. Recent studies suggest that one suppressive pathway may be the hyperactive p53 response observed in HSPCs from FA patients. In order to further identify suppressive mechanisms accounting for bone marrow failure in FA, we performed a whole genome-wide shRNA screen in FA cells. Specifically, we screened for candidate genes whose knockdown would rescue cellular growth inhibition and genotoxic stress induced by a DNA cross-linking agent mitomycin C (MMC). We transduced a FA-deficient human fibroblast line with pools of shRNAs and screened for rescue of MMC-inhibited growth. Selected shRNA inserts were identified by next generation sequencing. The top hits in the screen were shRNAs directed against multiple components of the TGF-β signaling pathway. Consistent with this, disruption of the TGF-β signaling pathway by shRNA/sgRNA-mediated knockdown of SMAD3 or TGFR1 (downstream components of the TGF- β pathway) rescued growth of multiple cell lines from several FA complementation groups in presence of genotoxic agents (e.g. MMC or acetaldehyde). Pharmacologic inhibition of the TGF- β pathway using small molecule inhibitors resulted in improved survival of FA-deficient lymphoblast cells in presence of MMC or acetaldehyde, suggesting that a hyperactive, TGF-β-mediated, suppression pathway may account, at least in part, for reduced FA cell growth. Interestingly, genes encoding TGF-β pathway signaling components were highly expressed in the bone marrow from FA patients and FA mice. Moreover, disruption of the TGF- β pathway by shRNA-mediated knockdown of SMAD3 rescued the growth defects of primary HSPCs from FA-deficient murine bone marrow. To further implicate the TGF-β pathway, we established primary stromal cell lines from the bone marrow of FA-deficient mice as well as human FA patients. We confirmed that TGF-β signaling was hyperactive in these stroma cells resulting in growth suppression and elevated phospho-ERK levels due to non-canonical signaling of the pathway. Inhibitors of TGF-β signaling partially rescued the growth defects and reduced phospho-ERK levels in these FA stroma cells. The deficiency of FA DNA repair pathway leads to cellular defects in homologous recombination (HR) repair and hyperactivation of toxic non-homologous end joining (NHEJ)-mediated repair. We therefore tested whether inhibition of the TGF-β pathway in FA cells could rescue HR defects and account for the improvement of FA cellular growth. Interestingly, disruption of the TGF-β signaling pathway caused a decrease in NHEJ activity. Disruption of the TGF-β pathway also resulted in reduced MMC-mediated DNA damage and increased HR. Taken together, our results demonstrate that primary FA hematopoietic and bone marrow stromal cells exhibit hyperactive TGF-β signaling accounting at least in part for the bone marrow failure in FA. Inhibitors of the TGF-β signaling pathway may therefore be useful in the clinical treatment of patients with bone marrow failure and Fanconi anemia. Disclosures No relevant conflicts of interest to declare.
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Niraj, Joshi, Anniina Färkkilä, and Alan D. D'Andrea. "The Fanconi Anemia Pathway in Cancer." Annual Review of Cancer Biology 3, no. 1 (March 4, 2019): 457–78. http://dx.doi.org/10.1146/annurev-cancerbio-030617-050422.

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Fanconi anemia (FA) is a complex genetic disorder characterized by bone marrow failure (BMF), congenital defects, inability to repair DNA interstrand cross-links (ICLs), and cancer predisposition. FA presents two seemingly opposite characteristics: ( a) massive cell death of the hematopoietic stem and progenitor cell (HSPC) compartment due to extensive genomic instability, leading to BMF, and ( b) uncontrolled cell proliferation leading to FA-associated malignancies. The canonical function of the FA proteins is to collaborate with several other DNA repair proteins to eliminate clastogenic (chromosome-breaking) effects of DNA ICLs. Recent discoveries reveal that the FA pathway functions in a critical tumor-suppressor network to preserve genomic integrity by stabilizing replication forks, mitigating replication stress, and regulating cytokinesis. Homozygous germline mutations (biallelic) in 22 FANC genes cause FA, whereas heterozygous germline mutations in some of the FANC genes (monoallelic), such as BRCA1 and BRCA2, do not cause FA but significantly increase cancer susceptibility sporadically in the general population. In this review, we discuss our current understanding of the functions of the FA pathway in the maintenance of genomic stability, and we present an overview of the prevalence and clinical relevance of somatic mutations in FA genes.
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Seton-Rogers, Sarah. "Stress management by the FA pathway." Nature Reviews Cancer 15, no. 12 (November 13, 2015): 699. http://dx.doi.org/10.1038/nrc4047.

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Taylor, Sarah J., Mark J. Arends, and Simon P. Langdon. "Inhibitors of the Fanconi anaemia pathway as potential antitumour agents for ovarian cancer." Exploration of Targeted Anti-tumor Therapy 1, no. 1 (February 29, 2020): 26–52. http://dx.doi.org/10.37349/etat.2020.00003.

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The Fanconi anaemia (FA) pathway is an important mechanism for cellular DNA damage repair, which functions to remove toxic DNA interstrand crosslinks. This is particularly relevant in the context of ovarian and other cancers which rely extensively on interstrand cross-link generating platinum chemotherapy as standard of care treatment. These cancers often respond well to initial treatment, but reoccur with resistant disease and upregulation of DNA damage repair pathways. The FA pathway is therefore of great interest as a target for therapies that aim to improve the efficacy of platinum chemotherapies, and reverse tumour resistance to these. In this review, we discuss recent advances in understanding the mechanism of interstrand cross-link repair by the FA pathway, and the potential of the component parts as targets for therapeutic agents. We then focus on the current state of play of inhibitor development, covering both the characterisation of broad spectrum inhibitors and high throughput screening approaches to identify novel small molecule inhibitors. We also consider synthetic lethality between the FA pathway and other DNA damage repair pathways as a therapeutic approach.
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O'Connor, Kevin, Sofia Vidal-Cardenas, Haojian Zhang, Alfredo Rodriguez, Lisa Moreau, Chunyu Yang, Michael W. Epperly, et al. "Hyperactive Non-Canonical TGF-β Pathway Signaling in Fanconi Anemia Bone Marrow Stromal Cells Contributes to Growth Suppression." Blood 128, no. 22 (December 2, 2016): 1039. http://dx.doi.org/10.1182/blood.v128.22.1039.1039.

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Abstract Introduction: Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients develop bone marrow failure during the first decade of life due to attrition of hematopoietic stem cells (HSCs). FA is caused by autosomal recessive or X-linked mutations in one of nineteen FANC genes, the products of which cooperate in the FA/BRCA DNA repair pathway and regulate cellular resistance to genotoxic DNA cross-linking agents. Although its mechanism is unknown, bone marrow failure in FA may be the result, directly or indirectly, of hyperactivation of cell-autonomous or microenvironmental growth-suppressive pathways induced, in part, due to genotoxic stress. We have recently identified canonical transforming growth factor-β (TGF-β) pathway-mediated growth suppression of HSCs as a cause of bone marrow failure in FA (Zhang H et al, Cell Stem Cell, 2016). We have shown that TGF-β pathway inhibition rescues genotoxic stress, proliferation defects and engraftment defects of FA-deficient HSCs, and ameliorates bone marrow failure in FA mice. Previous studies have suggested that bone marrow stromal fibroblasts from human FA patients and FA pathway-deficient mouse models, like HSCs, are hypersensitive to genotoxic stress and have impaired growth. Here, we therefore investigated the possible suppressive function of the TGF-β pathway in bone marrow stromal cells derived from FA mice and patients with FA. Methods: We established primary stromal cell lines from bone marrow of FA-deficient mice (Fancd2-/- mice) or wild-type sibling control mice. Primary bone marrow stromal cultures were also established from FA patients or normal healthy donors. The stromal cells were characterized and evaluated for growth kinetics, mitomycin C (MMC) sensitivity, chromosome breakage, inflammatory signals and response to the TGF-β inhibitors. CRISPR/Cas-9 technology was used to knockdown specific genes in stromal cells. Results: As expected,the primary bone marrow stromal cells from Fancd2-/- mice exhibited classical FA phenotypes, including hypersensitivity to a DNA cross-linking agent, MMC, and increased MMC-induced chromosomal radials. Fancd2-/- stromal cells also demonstrated a growth defect characterized by an enrichment of cells in G1 and elevated p21 expression. Interestingly, the FA stromal cells derived from FA patients or from Fancd2-/- mice expressed constitutively elevated levels of phosphorylated (activated) ERK1/2 (pERK) compared to control cells. In order to determine whether the factor responsible for inducing ERK1/2 phosphorylation in the murine FA stromal cells was cell-intrinsic or cell-extrinsic, we examined the conditioned media from the stromal cells. Indeed the FA stromal cells secreted a high level of TGF-β cytokine responsible for increased pERK levels, and expressed a high level of secreted TGF-β mRNA. The high level of pERK indicated that the TGF-β non-canonical pathway was hyperactive in the FA stromal cells. Interestingly, CRISPR/Cas9-mediated knockdown of Tgfbr1 or inhibition of the TGF-β pathway by a treatment with a small molecule inhibitor of TGFβR1 or a neutralizing antibody against TGF-β in these cells reduced pERK levels, promoted DNA repair and rescued MMC sensitivity. In addition, a MEK inhibitor also significantly improved the clonogenic growth of Fancd2-/- stromal cells. However, CRISPR/Cas9-mediated knockdown of Smad3, a downstream target of the canonical TGF-β pathway, did not rescue the growth inhibition of FA stromal cells in MMC, further indicating that hyperactivation of the canonical pathway is less relevant to their growth defect. Collectively, these results demonstrated that the hyperactive TGF-β pathway increases phosphorylation of ERK1/2 in FA stromal cells through the non-canonical signaling pathway and impairs their growth after genotoxic stress. Conclusions: The primary FA bone marrow stromal cells exhibit hyperactive non-canonical TGF-β pathway signaling and blocking this pathway improves their growth under genotoxic stress. The TGF-β signaling pathway-mediated growth suppression in bone marrow stromal cells may account, at least in part, for defective microenvironment, impaired HSC function and bone marrow failure in FA. This work suggests that the TGF-β signaling pathway may be a potential therapeutic target for the treatment of bone marrow failure in FA. Disclosures Shimamura: TransCellular Therapeutics: Other: Husband is founder. No revenue to date.; Novartis: Other: In discussion regarding possible clinical trial for aplastic anemia; Glaxo Smith Kline: Honoraria.
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Milletti, Giacomo, Luisa Strocchio, Daria Pagliara, Katia Girardi, Roberto Carta, Angela Mastronuzzi, Franco Locatelli, and Francesca Nazio. "Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition." Cancers 12, no. 9 (September 20, 2020): 2684. http://dx.doi.org/10.3390/cancers12092684.

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Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches.
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Dissertations / Theses on the topic "Pathway FA"

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Friemann, Verena [Verfasser], and Helmut [Akademischer Betreuer] Hanenberg. "Retrovirale Komplementation durch RAD51C - ein Kandidatengen aus dem FA/BRCA-Pathway / Verena Friemann. Gutachter: Helmut Hanenberg." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2014. http://d-nb.info/1051734649/34.

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Yarde, Danielle N. "The Fanconi Anemia (FA)/BRCA DNA Damage Repair Pathway is Regulated by NF-κB and Mediates Drug Resistance in Multiple Myeloma." Scholar Commons, 2010. https://scholarcommons.usf.edu/etd/1818.

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The Fanconi Anemia (FA)/BRCA DNA damage repair pathway plays a critical role in the cellular response to stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA DNA damage repair pathway genes are overexpressed and causative for resistance in multiple myeloma (MM) cell lines selected for resistance to melphalan. We hypothesized that the FA/BRCA DNA damage repair pathway mediates response and resistance to chemotherapeutic agents used to treat multiple myeloma and other cancers, and targeting this pathway is vital to overcoming drug resistance. In this dissertation, we show that FA/BRCA pathway genes are collectively overexpressed in MM, prostate, and ovarian cancer cell lines selected for resistance to melphalan and cisplatin, respectively. Interestingly, cells selected for resistance to topoisomerase II inhibitors selectively overexpress only FANCF. We also show that FA/BRCA pathway expression can be inhibited by the proteasome inhibitor bortezomib. FA/BRCA pathway mRNA expression was inhibited by bortezomib in myeloma cell lines and patient samples. FANCD2 gene and protein expression are downregulated by bortezomib, and remain attenuated in the face of melphalan treatment. Melphalan-induced FANCD2 foci formation was also inhibited by bortezomib, and this drug enhanced melphalan-induced DNA damage, likely via inhibition of FA-mediated DNA damage repair. Next, we analyzed regulation of the FA/BRCA pathway. We demonstrate that NF-kappaB, specifically the Re1B/p50 subunits, transcriptionally regulates members of the FA/BRCA pathway, and inhibition of these subunits by siRNA, BMS-345541, and bortezomib reduces FA/BRCA pathway expression. Furthermore, knocking down Re1B and p50 simultaneously attenuates FANCD2 protein expression and results in diminished DNA repair and enhanced sensitivity to melphalan. Importantly, melphalan resistance was restored when FANCD2 was re-expressed in these cells. We also show that bortezomib regulates FANCD2 protein expression directly, by inhibiting FANCD2 synthesis. Finally, we demonstrate that low-dose bortezomib arrests cells in G0/G1 and also overcomes the S-phase arrest induced by melphalan, likely via inhibition of ATR. Overall, our findings provide evidence for targeting the FA/BRCA pathway, either directly or indirectly, via inhibition of NF-kappaB or ATR, to enhance chemotherapeutic response and reverse drug resistance in multiple myeloma and other cancers.
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Marten, Lara Maleen [Verfasser], and Kerstin [Akademischer Betreuer] Borgmann. "Impact of mutated p53 on homologous recombination and the FA/BRCA pathway in NSCLC H1299 cells in response to DNA cross-linking drugs / Lara Maleen Marten. Betreuer: Kerstin Borgmann." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://d-nb.info/1095766406/34.

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Marten, Lara Maleen Verfasser], and Kerstin [Akademischer Betreuer] [Borgmann. "Impact of mutated p53 on homologous recombination and the FA/BRCA pathway in NSCLC H1299 cells in response to DNA cross-linking drugs / Lara Maleen Marten. Betreuer: Kerstin Borgmann." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2016. http://nbn-resolving.de/urn:nbn:de:gbv:18-77538.

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Bottega, Roberta. "Sviluppo di una strategia per la diagnosi molecolare dell'anemia di Fanconi." Doctoral thesis, Università degli studi di Trieste, 2014. http://hdl.handle.net/10077/9981.

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2012/2013
L’anemia di Fanconi (FA) è una malattia genetica rara caratterizzata da malformazioni congenite, pancitopenia, predisposizione al cancro e aumentata sensibilità ad agenti, quali diepossibutano e mitomicina C, che formano legami tra i due filamenti di DNA. La FA è causata da almeno 16 geni che costituiscono, insieme ad altri componenti, un pathaway di riparazione del DNA. L’eterogeneità è uno dei principali motivi che complica la diagnosi molecolare della FA. E’ pertanto necessario un processo a più livelli che implica lo screening di molti esoni o, in alternativa, l’allestimento di linee cellulari e l’analisi di complementazione per la caratterizzazione del gene candidato. Gli scopi di questa tesi pertanto sono diretti a: • Ridurre i tempi per l’identificazione del gene mutato sostituendo l’analisi di complementazione con quella di espressione delle proteine FA basandosi sul presupposto che prodotti mutati siano rapidamente degradati; • Caratterizzare dal punto di vista molecolare gli effetti delle varianti identificate dall’analisi di sequenza. Per quanto riguarda il primo obiettivo, ci siamo focalizzati sullo studio della proteina FANCA in 44 linee cellulari linfoblastoidi appartenenti ai diversi gruppi di complementazione. E’ emerso che, fatta eccezione per FA-G, l’espressione di FANCA non è alterata da mutazioni nei geni FANCB, FANCC e FANCD2. Per quanto riguarda i pazienti con mutazioni in FANCA, invece, abbiamo osservato una correlazione tra il tipo di mutazione e il livello di espressione della proteina che può quelli essere paragonabile a quella dei controlli nel caso di mutazioni missenso o ampie delezioni in frame. In accordo con l’ipotesi invece, in presenza di mutazioni nonsenso e frameshift in entrambi gli alleli del gene, non si ha produzione di proteina. Sulla base di questi dati possiamo concludere che l’analisi di FANCA non è soddisfacente per assegnare ai pazienti il corrispondente gruppo di complementazione. Tuttavia, da questo studio è emersa l’ipotesi di un’associazione tra l’espressione stabile delle proteine FANCA mutate e un fenotipo meno grave nei pazienti. I dati preliminari dimostrano che queste proteine non sono traslocate nel nucleo e che quindi un’eventuale attività residua non sia da attribuire al processo di riparazione del DNA. Un potenziale ruolo andrebbe forse indagato a livello citoplasmatico dove, come sta emergendo dalla letteratura, almeno FANCG e FANCC, svolgono una funzione all’interno del mitocondrio tale da giustificare l’elevato grado di stress ossidativo delle cellule FA. Per il secondo obiettivo, lo studio dei casi arruolati nell'ambito dell'AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) ha consentito l'identificazione delle mutazioni in 100 famiglie. Dall’analisi dei dati emerge che la maggior parte delle mutazioni colpisce il gene FANCA (85%), seguito da FANCG (9%), FANCC (3%), FANCD2 (2%) e FANCB (1%). In assenza del dato di complementazione e/o in presenza di varianti alle quali non è sempre possibile attribuire un chiaro effetto patogenetico, sono state eseguite ulteriori indagini. Si citano a titolo di esempio la caratterizzazione delle ampie delezioni intrageniche mediante MLPA, l’analisi bioinformatica e a livello di RNA delle alterazioni di splicing che, qualora in frame, sono state ulteriormente confermate anche a livello proteico e, infine, lo studio bioinformatico di patogenicità delle sostituzioni aminoacidiche. La formulazione di un algoritmo efficace e rapido per la diagnosi molecolare della FA, nonché la chiara definizione del significato patogenetico delle varianti identificate, è molto importante per corretta presa in carico del paziente e della famiglia sia per l’identificazione dei portatori che per la diagnosi prenatale.
XXVI Ciclo
1984
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Neveling, Kornelia [Verfasser], and Detlev [Akademischer Betreuer] Schindler. "Molekulargenetische Ursachen und Folgen genetischer Instabilität am Beispiel des FA-BRCA Caretaker Pathways / Kornelia Neveling. Betreuer: Detlev Schindler." Würzburg : Universitätsbibliothek der Universität Würzburg, 2012. http://d-nb.info/1020361980/34.

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Su, Wen Lynn, and 蘇文琳. "A Noval Signal Transduction Pathway of Nerve Growtth Factor via Kinase FA/GSK-3 alpha." Thesis, 1995. http://ndltd.ncl.edu.tw/handle/07895203387124553892.

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碩士
國立清華大學
生物醫學研究所
83
Using immunoprecipitation and kinase assay, we found that nerve growth factor (NGF) can stimulate upon kinase FA/GSK-3 alpha activity in rat pheochromocytoma PC12 cells under normally cultured condition. Kinase FA/GSK-3 alpha activity decreased when PC12 cells were cultured under a serum-starved condition. Nerve growth factor added into these serum-free cultures restored the activity of kinase GSK-3 alpha declined by serum starvation From Western Blotting, it has been proved that no change on the protein synthesis level of kinase FA/GSK-3 alpha caused by either serum-free cultured or normally cultured PC12 cells stimulated by NGF. Further investigation by phosphoamino acid analysis, it's shown that the activity change of kinase FA/ GSK-3 alpha is due to the phosphorylation state of tyrosine residue on kinase FA/GSK-3 alpha. These data indicate that kinase FA/GSK-3 alpha is involved in NGF-induced signal transduction pathway through tyrosine phos- phorylation that might be different from MAPK-involved cascade.
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Neveling, Kornelia. "Molecular causes and consequences of genetic instability with respect to the FA/BRCA Caretaker Pathway." Doctoral thesis, 2007. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-27383.

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In the context of this thesis, I investigated the molecular causes and functional consequences of genetic instability using a human inherited disease, Fanconi anemia. FA patients display a highly variable clinical phenotype, including congenital abnormalities, progressive bone marrow failure and a high cancer risk. The FA cellular phenotype is characterized by spontaneous and inducible chromosomal instability, and a typical S/G2 phase arrest after exposure to DNA-damaging agents. So far, 13 genes have been identified, whose biallelic (or, in the case of X-linked FANCB, hemizygous) mutations cause this multisystem disorder. The FA proteins interact in a multiprotein network, instrumental and essential in the cellular response to DNA damage. A more comprehensive summary of Fanconi anemia and its myriad clinical, cellular and molecular manifestations is provided in the introduction section of this thesis. The results of my experimental work are presented as published papers and manuscripts ready to be submitted. In the first publication, I investigated the connection between FA genes and bladder tumors. The question I tried to answer was whether a disruption of the FA/BRCA pathway may be a frequent and possibly causal event in bladder cancer, explaining the hypersensitivity of these cells to DNA-crosslinking agents. On the basis of my experimental data I arrived at the conclusion that disruption of the FA/BRCA pathway might be detrimental rather than advantageous for the majority tumor types by rendering them vulnerable towards DNA damaging agents and oxidative stress. The second publication deals with the gene coding for the core complex protein FANCE and tries to answer the question why FANCE is so rarely affected among FA-patients. The conclusion from these studies is that like FANCF, FANCE functions as a probable adaptor protein with a high tolerance towards amino acid substitutions which would explain the relative rareness of FA-E patients. I have also investigated the FANCL gene whose product functions as the catalytic subunit of the E3 ligase. The third publication addresses this issue by providing the first comprehensive description of genetic alterations and phenotypic manifestations in a series of three FA-L patients. The results of my study show that genetic alterations of FANCL are compatible with survival, these alterations may include large deletions such as so far common only in the FANCA gene, FA-L phenotypes can be mild to severe, and FANCL belongs to the group of FA genes that may undergo somatic reversion. The central protein of the FA/BRCA network, FANCD2, is the subject of the fourth publication presented in this thesis. Most importantly, we were able to show that there are no biallelic null mutations in FANCD2. Correspondingly, residual protein of both FANCD2-isotypes (FANCD2-S and FANCD2-L) was present in all available patient cell lines. This suggests that complete abrogation of the FANCD2 protein cannot be tolerated and causes early embryonic lethality. There are at least three FA proteins that are not required for the posttranslational modification of FANCD2. One of these proteins is the 5’-3’ helicase BRIP1 (BRCA1-interacting protein 1), a protein that interacts directly with the breast cancer susceptibility protein BRCA1. I participated in the identification of BRIP1 as the FA protein FANCJ. This discovery is described in the fifth publication of this thesis. The newly discovered protein BRIP1/FANCJ seems to act as one of the mediators of genomic maintenance downstream of FANCD2. Another protein identified downstream of FANCD2 is PALB2. PALB2 was originally discovered as “partner and localizer of BRCA2”. In a candidate gene approach we tested patients with early childhood cancers but without mutations in BRCA2 for mutations in PALB2 (publication 6). PALB2 was identified as a novel FA gene and designated FANCN. FA-N patients are very severely affected. The last publication included in my thesis describes the identification of the FA gene FANCI as the second monoubiquitinated member of the FA/BRCA pathway (publication 7). We identified biallelic mutations in KIAA1794 in four FA patients, thus proving the genuine FA-nature of this candidate sequence. The general discussion provides a synopsis of the results and conclusions of my work with the state of art of FA research
Im Rahmen der vorliegenden Dissertation wurden molekulare Ursachen und funktionale Konsequenzen genetischer Instabilität am Beispiel der menschlichen Erbkrankheit Fanconi Anämie (FA) untersucht. FA Patienten zeigen einen sehr variablen klinischen Phänotyp, der in der Regel angeborene Fehlbildungen, progressives Knochenmarkversagen und ein hohes Risiko für Tumorerkrankungen beinhaltet. Der zelluläre Phänotyp der FA ist durch eine spontane und induzierbare chromosomale Instabilität und einen typischen S/G2-Phasen-Arrest nach Exposition mit DNA-schädigenden Agentien charakterisiert. Biallelische oder -im Fall des X-chromosomalen FANCB- hemizygote Mutationen, die zu dieser Erkrankung führen, wurden in bislang 13 Genen identifiziert. Die FA Proteine arbeiten in einem gemeinsamen Netzwerk und sind essentiell beteiligt an der zellulären Antwort auf DNA Schädigung. Eine umfassendere Übersicht über Fanconi Anämie und ihre vielfältigen klinischen, zellulären und molekularen Erscheinungsformen ist in der Einleitung dieser Dissertation gegeben. Die Ergebnisse meiner experimentellen Arbeiten sind in Form von publizierten Fachartikeln und fertigen Manuskripten dargestellt. In der ersten Publikation habe ich den Zusammenhang von FA Genen und Harnblasentumoren untersucht. Die Frage, die ich zu beantworten versucht habe, war, ob ein Defekt im FA/BRCA Weg eine mögliche Ursache für die Entstehung von Blasentumoren sein könnte. Aufgrund meiner experimentellen Daten bin ich zu dem Schluss gekommen, dass ein Defekt im FA/BRCA Weg für einen Tumor vermutlich eher schädlich als vorteilhaft ist, da so ein Defekt den Tumor gegenüber DNA-schädigenden Agentien und oxidativem Stress anfällig machen würde. Meine zweite Publikation befasst sich mit dem Kern-Komplex Protein FANCE und versucht die Frage zu beantworten, warum das FANCE Gen in so wenigen FA Patienten betroffen ist. Die Schlussfolgerung dieser Arbeit war, dass FANCE vermutlich genauso wie FANCF im Kern-Komplex die Rolle eines Adaptor-Proteins mit einer hohen Toleranz gegenüber Aminosäure-Austauschen innehat, was die relative Seltenheit von Patienten dieser Untergruppe erklären könnte. Ich habe weiterhin das FANCL Gen untersucht, dessen Produkt als katalytische Untereinheit der E3-Ligase fungiert. Die dritte Publikation in dieser Dissertation befasst sich mit diesem Thema und enthält eine umfassende Beschreibung von genetischen Veränderungen und phänotypischen Auswirkungen in einer Gruppe von 3 FA-L Patienten. Die Ergebnisse meiner Arbeit haben allerdings gezeigt, dass genetische Veränderungen in FANCL mit dem Leben vereinbar sind, dass diese Veränderungen sehr große Deletionen beinhalten können, was bisher nur für FANCA gezeigt werden konnte, dass FA-L Phänotypen von mild bis schwer betroffen reichen können und dass FANCL zu den Genen gehört, in denen somatische Reversionen stattfinden. Das Schlüsselprotein des FA/BRCA Netzwerks, FANCD2, ist das Thema der vierten Publikation in dieser Dissertation. Insbesondere konnten wir zeigen, dass es keine biallelischen Nullmutationen in FANCD2 zu geben scheint. Dementsprechend war Restprotein von beiden FANCD2-Isoformen, FANCD2-L und FANCD2-S, in allen verfügbaren Patienten-Zelllinien nachweisbar. Dies ließ vermuten, dass ein komplettes Fehlen des FANCD2 Proteins nicht tolerierbar ist und frühe embryonale Letalität verursacht. Es mindestens drei Proteine, die nicht für diese posttranslationale Modifikation benötigt werden. Eines dieser Proteine ist die 5’-3’ Helikase BRIP1 (BRCA1-interagierendes Protein 1), ein Protein, das direkt mit dem Brustkrebs-assoziierten Protein BRCA1 interagiert. Ich war an der Identifizierung von BRIP1 als FA Protein (FANCJ) beteiligt. Diese Entdeckung ist in der fünften Publikation meiner Dissertation beschrieben. Das neu entdeckte Protein BRIP1/FANCJ, das direkt mit BRCA1 interagiert, scheint als einer der Mediatoren zur Aufrechterhaltung genomischer Stabilität downstream von FANCD2 zu wirken. Ein weiteres Protein downstream von FANCD2 ist PALB2. PALB2 wurde ursprünglich als „Partner und Lokalisierer von BRCA2“ entdeckt. In einer Kandidatengen-Studie haben wir Patienten mit frühkindlichen Tumoren, aber ohne Mutationen in BRCA2, auf Mutationen in PALB2 untersucht (Publikation 6). Aufgrund unserer Ergebnisse haben wir PALB2 als ein neues FA Gen identifiziert und haben es FANCN genannt. Genauso wie FA-D1 Patienten sind FA-N Patienten sehr schwer betroffen. Die letzte Publikation meiner Dissertation beschreibt die Identifikation des FA Genes FANCI, dessen Produkt das zweite monoubiquitinierte Mitglied des FA/BRCA Weges darstellt (Publikation 7). Wir haben in vier Patienten biallelische Mutationen in KIAA1794 gefunden, und so zeigen können, dass KIAA1794 wirklich ein FA Gen ist. Die generelle Diskussion birgt eine Synopsis der Ergebnisse und Schlussfolgerungen meiner Forschung mit dem aktuellen Wissensstand über FA
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Books on the topic "Pathway FA"

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Zhongguo 2050 nian di tan fa zhan zhi lu: Neng yuan xu qiu ji tan pai fang qing jing fen xi = China's low carbon development pathways by 2050 : scenario analysis of energy demand and carbon emissions. Beijing: Ke xue chu ban she, 2009.

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Book chapters on the topic "Pathway FA"

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"CELL-BASED SCREENING SUGGESTS EFFICACY OF NON-SPECIFIC CHEMICAL INHIBITION OF THE FA PATHWAY." In DNA Repair and Cancer, 337–42. CRC Press, 2013. http://dx.doi.org/10.1201/b14587-31.

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Ježek, Petr, Blanka Holendová, Martin Jabůrek, Jan Tauber, Andrea Dlasková, and Lydie Plecitá-Hlavatá. "Redox Signaling is Essential for Insulin Secretion." In Type 2 Diabetes [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.94312.

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In this review, we place redox signaling in pancreatic β-cells to the context with signaling pathways leading to insulin secretion, acting for example upon the action of incretins (GLP-1, GIP) and the metabotropic receptor GPR40. Besides a brief description of ion channel participation in depolarization/repolarization of the plasma membrane, we emphasize a prominent role of the elevated glucose level in pancreatic β-cells during glucose-stimulated insulin secretion (GSIS). We focus on our recent findings, which revealed that for GSIS, not only elevated ATP synthesis is required, but also fundamental redox signaling originating from the NADPH oxidase 4- (NOX4-) mediated H2O2 production. We hypothesized that the closing of the ATP-sensitive K+ channel (KATP) is only possible when both ATP plus H2O2 are elevated in INS-1E cells. KATP alone or with synergic channels provides an element of logical sum, integrating both metabolic plus redox homeostasis. This is also valid for other secretagogues, such as branched chain ketoacids (BCKAs); and partly for fatty acids (FAs). Branched chain aminoacids, leucine, valine and isoleucine, after being converted to BCKAs are metabolized by a series of reactions resembling β-oxidation of FAs. This increases superoxide formation in mitochondria, including its portion elevated due to the function of electron transfer flavoprotein ubiquinone oxidoreductase (ETF:QOR). After superoxide conversion to H2O2 the oxidation of BCKAs provides the mitochondrial redox signaling extending up to the plasma membrane to induce its depolarization together with the elevated ATP. In contrast, experimental FA-stimulated insulin secretion in the presence of non-stimulating glucose concentrations is predominantly mediated by GPR40, for which intramitochondrial redox signaling activates phospholipase iPLA2γ, cleaving free FAs from mitochondrial membranes, which diffuse to the plasma membrane and largely amplify the GPR40 response. These events are concomitant to the insulin release due to the metabolic component. Hypothetically, redox signaling may proceed by simple H2O2 diffusion or via an SH-relay enabled by peroxiredoxins to target proteins. However, these aspects have yet to be elucidated.
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Conference papers on the topic "Pathway FA"

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Ramaswamy, B., V. Srividya, DA Mullins, S. Carothers, G. Young, D. Wenrui, W. Zhao, et al. "PD10-01: Prevalence of Dysfunctional Fanconi Anemia (FA) DNA Repair Pathway in Breast Cancer." In Abstracts: Thirty-Fourth Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 6‐10, 2011; San Antonio, TX. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/0008-5472.sabcs11-pd10-01.

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Gao, Li, Wenrui Duan, Xin Wu, Gregory A. Otterson, and Miguel A. Villalona-Calero. "Abstract 5500: Inhibition of poly(ADP-ribose) polymerase in lung cancer cells with defective Fanconi anemia (FA) pathway." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-5500.

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Gao, Li, Wenrui Duan, Brittany Barnwell, Arjun Kalvala, Gregory A. Otterson, and Miguel A. Villalona-Calero. "Abstract 4365: Sensitivity of small cell lung cancer cells with defective Fanconi Anemia (FA) pathway to BCL2 inhibitors.." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-4365.

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Lambert, Muriel W., Deepa Sridharan, and Pan Zhang. "Abstract 2380: Separate but important roles of αSpII and FANCD2 in the FA pathway after DNA interstrand crosslink damage." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-2380.

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Duan, Wenrui, Shirley Tang, Li Gao, Kathleen Dotts, Andrew Fink, Arjun Kalvala, Brittany Aguila, and Miguel A. Villalona-Calero. "Abstract 1361: Micro RNA-200C is one of the important Fanconi Anemia (FA) pathway downstream regulators in lung cancer." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1361.

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Rego, Meghan A., Maurizio Mauro, Julie A. Harney, Mae Shen, Frederick W. Kolling, and Niall G. Howlett. "Abstract LB-102: The p21Cip1/Waf1cyclin-dependent kinase inhibitor is required for the activation of the FA-BRCA pathway." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-lb-102.

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Villalona-Calero, Miguel A., Wenrui Duan, Weiqiang Zhao, Li Gao, Jennifer Thurmond, Marino Leon, Konstantin Shilo, et al. "Abstract A99: Phase I trial of veliparib or mitomycin C + veliparib in pts with Fanconi anemia pathway (FA) repair defects." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-a99.

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Fink, Andrew, Arjun Kalvala, Li Gao, Kathleen Dotts, Brittany Aguila, Shirley Tang, Gregory A. Otterson, Miguel A. Villalona-Calero, and Wenrui Duan. "Abstract 4438: Promoter hypermethylation status of Fanconi Anemia (FA) pathway genes FANCF, FANCL and FANCS in non-small cell lung cancer (NSCLC)." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4438.

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Karanam, Narasimha Kumar, Lianghao Ding, Brock Sishc, Debabrata Saha, and Michael D. Story. "Abstract 2138: Tumor treatment fields downregulate the BRCA1/FA pathway genes leading to reduced DNA repair capacity, the inhibition of mitophagy and enhanced cell death." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-2138.

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Villalona-Calero, Miguel A., Wenrui Duan, Weiqiang Zhao, Konstantin Shilo, Jiuping Ji, Jennifer Thurmond, Adam Norris, et al. "Abstract LB-139: Phase I trial of veliparib or mitomycin (MMC) + veliparib in patients with sporadic solid tumors screened for somatic deficiency in the Fanconi Anemia (FA) pathway." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-lb-139.

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Reports on the topic "Pathway FA"

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Barg, Rivka, Kendal D. Hirschi, Avner Silber, Gozal Ben-Hayyim, Yechiam Salts, and Marla Binzel. Combining Elevated Levels of Membrane Fatty Acid Desaturation and Vacuolar H+ -pyrophosphatase Activity for Improved Drought Tolerance. United States Department of Agriculture, December 2012. http://dx.doi.org/10.32747/2012.7613877.bard.

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Background to the topic: In previous works we have shown that Arabidopsis and tomato over-expressing H+-pyrophosphatase show increased tolerance to drought imposed by withholding irrigation of young plants in pots (Park et al. 2005). In addition, young tobacco plants over-expressing fatty acid desaturase 3 (OEX-FAD3) also showed increasing tolerance to drought stress (Zhang et al 2005), and similarly OEX-FAD3 young tomato plants (unpublished data from ARO), hence raising the possibility that pyramiding the two could further improve drought tolerance in tomato. Based on these findings the specific objects originally set were: 1. To analyze the impact of pyramiding transgenes for enhanced fatty acid desaturation and for elevated H+-PPase activity on tomato yielding under water deficit stress conditions. 2. To elucidate the biochemical relationship between elevated desaturation of the membrane lipids and the activities of selected vacuolar transporters in the context of drought responses. 3. To explore the S. pennellii introgression lines as alternative genetic sources for drought tolerance related to enhanced fatty acid desaturation and/or H+-PPase activity. 4. Since OEX-FAD3 increases the levels of linolenic acid which is the precursor of various oxylipins including the stress hormone Jasmonate. (JA), study of the effect of this transgene on tolerance to herbivore pests was added as additional goal. The Major conclusions, solutions, and achievements are: (1) The facts that ectopic over-expression of vacuolarH+-PPases (in line OEX-AVP1) does not change the fatty acid profile compared to the parental MoneyMaker (MM) line and that elevated level of FA desaturation (by OEX-FAD3) does not change the activity of either H+-PPase, H+-ATPaseor Ca2+ /H+ antiport, indicate that the observed increased drought tolerance reported before for increase FA desaturation in tobacco plants and increased H+PPase in tomato plants involves different mechanisms. (2) After generating hybrid lines bringing to a common genetic background (i.e. F1 hybrids between line MP-1 and MM) each of the two transgenes separately and the two transgenes together the effect of various drought stress regimes including recovery from a short and longer duration of complete water withhold as well as performance under chronic stresses imposed by reducing water supply to 75-25% of the control irrigation regime could be studied. Under all the tested conditions in Israel, for well established plants grown in 3L pots or larger, none of the transgenic lines exhibited a reproducible significantly better drought tolerance compare to the parental lines. Still, examining the performance of these hybrids under the growth practices followed in the USA is called for. (3) Young seedlings of none of the identified introgression lines including the S. pennellii homologs of two of the H+-PPase genes and one of the FAD7 genes performed better than line M82 upon irrigation withhold. However, differences in the general canopy structures between the IL lines and M82 might mask such differences if existing. (4). Over-expression of FAD3 in the background of line MP-1 was found to confer significant tolerance to three important pest insects in tomato: Bordered Straw (Heliothis peltigera), Egyptian cotton leafworm (Spodoptera littoralis) and Western Flower Thrips (Frankliniella occidentalis). Implications: Although the original hypothesis that pyramiding these two trasgenes could improve drought tolerance was not supported, the unexpected positive impact on herbivore deterring, as well as the changes in dynamics of JA biosynthesis in response to wounding and the profound changes in expression of wound response genes calls for deciphering the exact linolenic acid derived signaling molecule mediating this response. This will further facilitate breeding for herbivore pest and mechanical stress tolerance based on this pathway.
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