The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Huard, Caroline; Tremblay, Cédric; Magron, Audrey; Lévesque, Georges; Carreau, Madeleine

doi:10.1073/pnas.1314226111

Cited by 15 publications

(12 citation statements)

References 33 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, knockdown of FANCC, a member of the Fanconi anemia complex (Huard et al, 2014; Marathi et al, 1996), promoted HIV reactivation. Most of the 25 shRNAs for FANCC were relatively enriched in the double-positive population (i.e., FANCC is latency-promoting) (Figure 1D).…”

Section: Resultsmentioning

confidence: 99%

The mTOR Complex Controls HIV Latency

Besnard

Hakre

Kampmann

et al. 2016

Cell Host & Microbe

176

197

View full text Add to dashboard Cite

SUMMARY A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR complex subunits or pharmacological inhibition of mTOR activity suppresses reversal of latency in various HIV-1 latency models and HIV-infected patient cells. mTOR inhibitors suppress HIV transcription both through the viral transactivator Tat as well as via Tat-independent mechanisms. This inhibition occurs at least in part via blocking the phosphorylation of, CDK9, a p-TEFb complex member that serves as a cofactor for Tat-mediated transcription. The control of HIV latency by mTOR signaling identifies a pathway that may have significant therapeutic opportunities.

show abstract

Section: Resultsmentioning

confidence: 99%

The mTOR Complex Controls HIV Latency

Besnard

Hakre

Kampmann

et al. 2016

Cell Host & Microbe

176

197

View full text Add to dashboard Cite

show abstract

“…The upper band (slightly larger form) is monoubiquitinated FANCD2 (FANCD2-L), and the lower band is unubiquitinated FANCD2 (FANCD2-S) (40, 41). The ratio of FANCD2-L to FANCD2-S (L/S) was calculated by densitometry.…”

Section: Methodsmentioning

confidence: 99%

Leukemic survival factor SALL4 contributes to defective DNA damage repair

Wang

Gao

et al. 2016

Oncogene

View full text Add to dashboard Cite

SALL4 is aberrantly expressed in human myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We have generated a SALL4 transgenic (SALL4B Tg) mouse model with pre-leukemic MDS-like symptoms that transform to AML over time. This makes our mouse model applicable for studying human MDS/AML diseases. Characterization of the leukemic initiation population in this model leads to the discovery that Fancl (Fanconi anemia, complementation group L) is down-regulated in SALL4B Tg leukemic and pre-leukemic cells. Similar to the reported Fanconi anemia (FA) mouse model, chromosomal instability with radial changes that can be detected in pre-leukemic SALL4B Tg bone marrow (BM) cells after DNA damage challenge. Results from additional studies using DNA damage repair reporter assays support a role of SALL4 in inhibiting the homologous recombination pathway. Intriguingly, unlike the FA mouse model, after DNA damage challenge, SALL4B Tg BM cells can survive and generate hematopoietic colonies. We further elucidated that the mechanism by which SALL4 promotes cell survival is through Bcl2 activation. Overall, our studies demonstrate for the first time that SALL4 has a negative impact in DNA damage repair, and support the model of dual functional properties of SALL4 in leukemogenesis through inhibiting DNA damage repair and promoting cell survival.

show abstract

“…Interestingly, we also observed a significant enrichment of genes involved in Wnt signaling (Figure 3A). We decided to evaluate this pathway, as previous studies have suggested a possible interaction of Fancc with Wnt signaling (15, 16) and the involvement of Wnt signaling in B cell development (28, 29). Up-regulation and down-regulation of both inhibitors (Camk2b, Ankrd6, Sfrp1, Axin2, Nkd1, Tax1bp3) and activators (Dlg2, Fhl2) of the Wnt pathway and deregulated expression of Wnt receptor genes (Fzd-9, 2 and 4) were detected in Fancc −/− B cells (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, two recent studies have shown that FANCC is able to interact with Ctbp1 and β-catenin and regulates the expression of the Wnt inhibitor Dkk1 and that the integrity of the FA core complex is indispensable for a normal Wnt activity (15, 16). We observed no alteration in Dkk1 expression in our transcriptome analysis but found deregulation of several genes implicated in the Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Loss of Fancc Impairs Antibody-Secreting Cell Differentiation in Mice through Deregulating the Wnt Signaling Pathway

Sertorio

Amarachintha

Wilson

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

Fanconi anemia (FA) is characterized by a progressive bone marrow failure and an increased incidence of cancer. FA patients have high susceptibility to immune-related complications such as infection and post-transplant graft-versus-host-disease. Here we investigated the effect of FA deficiency in B cell function using the Fancc mouse model. Fancc−/− B cells show a specific defect in IgG2a switch and impaired Antibody-Secreting-Cell (ASC) differentiation. Global transcriptome analysis of naïve B cells by RNAseq demonstrates that FA deficiency deregulates a network of genes involved in immune function. Significantly, many genes implicated in Wnt signaling were aberrantly expressed in Fancc−/− B cells. Consistently, Fancc−/− B cells accumulate high levels of β-catenin under both resting and stimulated conditions, suggesting hyper-active Wnt signaling. Using an in-vivo Wnt GFP reporter assay, we verified the up-regulation of Wnt signaling as a potential mechanism responsible for the impaired Fancc−/− B cell differentiation. Further, we showed that Wnt signaling inhibits ASC differentiation possibly through repression of Blimp1 and that Fancc−/− B cells are hypersensitive to Wnt activation during ASC differentiation. Our findings identify Wnt signaling as a physiological regulator of ASC differentiation and establish a role for the Wnt pathway in normal B cell function and FA immune deficiency.

show abstract

The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression

Cited by 15 publications

References 33 publications

The mTOR Complex Controls HIV Latency

The mTOR Complex Controls HIV Latency

Leukemic survival factor SALL4 contributes to defective DNA damage repair

Loss of Fancc Impairs Antibody-Secreting Cell Differentiation in Mice through Deregulating the Wnt Signaling Pathway

Contact Info

Product

Resources

About