Fancd2 Is Required for Nuclear Retention of Foxo3a in Hematopoietic Stem Cell Maintenance

Li, Xiaoli; Li, Jie; Wilson, Andrew; Sipple, Jared; Schick, Jonathan; Pang, Qishen

doi:10.1074/jbc.m114.619536

Cited by 17 publications

(18 citation statements)

References 39 publications

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“…These results combined with previous findings suggest that post-translational modification of FOXO3 by acetylation (by PCAF or CBP/ p300) among others or association with different partners, might be important for HSPC activity and its generation of downstream progenitor cells with more restricted lineage specificity. 1,9,20,42 Together, our data supports the hypothesis that in HSPCs SIRT1 (deacetylation) is dominant over AKT (phosphorylation) in the regulation of FOXO3. FOXO1 remained relatively cytoplasmic regardless of SIRT1 or AKT activity, suggesting other signals may regulate FOXO1 in HSPCs.…”

Section: Discussionsupporting

confidence: 86%

Evidence for AKT-independent regulation of FOXO1 and FOXO3 in haematopoietic stem and progenitor cells

et al. 2016

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Transcription factors FOXOs (1, 3, 4) are essential for the maintenance of haematopoietic stem cells. FOXOs are evolutionary conserved substrates of the AKT serine threonine protein kinase that are also phosphorylated by several kinases other than AKT. Specifically, phosphorylation by AKT is known to result in the cytosolic localization of FOXO and subsequent inhibition of FOXO transcriptional activity. In addition to phosphorylation, FOXOs are regulated by a number of other post-translational modifications including acetylation, methylation, redox modulation, and ubiquitination that altogether determine these factors' output. Cumulating evidence raises the possibility that in stem cells, including in haematopoietic stem cells, AKT may not be the dominant regulator of FOXO. To address this question in more detail, we examined gene expression, subcellular localization, and response to AKT inhibition of FOXO1 and FOXO3, the main FOXO expressed in HSPCs (haematopoietic stem and progenitor cells). Here we show that while FOXO1 and FOXO3 transcripts are expressed at similar levels, endogenous FOXO3 protein is mostly nuclear compared to the cytoplasmic localization of FOXO1 in HSPCs. Furthermore, inhibition of AKT does not enhance nuclear localization of FOXO1 nor FOXO3. Nonetheless AKT inhibition in the context of loss of NAD-dependent SIRT1 deacetylase modulates FOXO3 localization in HSPCs. Together, these data suggest that FOXO3 is more active than FOXO1 in primitive haematopoietic stem and multipotent progenitor cells. In addition, they indicate that upstream regulators other than AKT, such as SIRT1, maintain nuclear FOXO localization and activity in HSPCs.

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Section: Discussionsupporting

confidence: 86%

Evidence for AKT-independent regulation of FOXO1 and FOXO3 in haematopoietic stem and progenitor cells

et al. 2016

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“…shRNA knockdown of Pparγ in WT LSKs did not change the GFP + proportion of BM cells in recipient mice compared with shScramble -transduced cells. Consistent with previous reports (Ceccaldi et al., 2012, Li et al., 2015, Parmar et al., 2010), recipient mice transplanted with the s hScramble -transduced Fancd2 − / − LSKs had a decreased total number of donor-derived mononuclear cells as well as a decreased proportion and absolute number of LSKs and HSCs (SLAM, CD150 + CD48 − LSK) in the BM at 16 weeks after transplantation compared with mice receiving the s hScramble -transduced WT LSKs (Figures 3D and 3E). Importantly, shRNA inhibition of Pparγ in Fancd2 − / − LSKs led to not only a significant increase in total BM cells but also an augmentation of proportion and absolute number of LSKs and HSCs in the transplanted mice compared with shScramble -transduced Fancd2 − / − LSKs (Figures 3D and 3E).…”

Section: Resultsmentioning

confidence: 99%

In Vivo RNAi Screen Unveils PPARγ as a Regulator of Hematopoietic Stem Cell Homeostasis

Sertorio

Amarachintha

et al. 2017

Stem Cell Reports

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SummaryHematopoietic stem cell (HSC) defects can cause repopulating impairment leading to hematologic diseases. To target HSC deficiency in a disease setting, we exploited the repopulating defect of Fanconi anemia (FA) HSCs to conduct an in vivo short hairpin RNA (shRNA) screen. We exposed Fancd2−/− HSCs to a lentiviral shRNA library targeting 947 genes. We found enrichment of shRNAs targeting genes involved in the PPARγ pathway that has not been linked to HSC homeostasis. PPARγ inhibition by shRNA or chemical compounds significantly improves the repopulating ability of Fancd2−/− HSCs. Conversely, activation of PPARγ in wild-type HSCs impaired hematopoietic repopulation. In mouse HSCs and patient-derived lymphoblasts, PPARγ activation is manifested in upregulating the p53 target p21. PPARγ and co-activators are upregulated in total bone marrow and stem/progenitor cells from FA patients. Collectively, this work illustrates the utility of RNAi technology coupled with HSC transplantation for the discovery of novel genes and pathways involved in stress hematopoiesis.

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“…4) might constitute only a transient response, in agreement with our recent report showing that NAC treatment is unable to rescue the long term reconstitution ability of Foxo3 Ϫ/Ϫ HSC (36). Data presented here, combined with published work (33,34,36,52,53), depict FOXO3 as a molecular node that wires together mitochondrial metabolism (36), ROS signaling, and DNA damage repair mechanisms for the maintenance of healthy HSPC. These collective findings join growing evidence in support of the notion that FOXO3 serves as a barrier to genomic instability in HSPC (52, 53).…”

Section: Foxo3 Is Key To Hsc Oxidative Dna Damage Responsementioning

confidence: 99%

FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage

Bigarella

Rimmelé

et al. 2017

Journal of Biological Chemistry

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Edited by Xiao-Fan WangAccumulation of damaged DNA in hematopoietic stem cells (HSC) is associated with chromosomal abnormalities, genomic instability, and HSC aging and might promote hematological malignancies with age. Despite this, the regulatory pathways implicated in the HSC DNA damage response have not been fully elucidated. One of the sources of DNA damage is reactive oxygen species (ROS) generated by both exogenous and endogenous insults. Balancing ROS levels in HSC requires FOXO3, which is an essential transcription factor for HSC maintenance implicated in HSC aging. Elevated ROS levels result in defective

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Fancd2 Is Required for Nuclear Retention of Foxo3a in Hematopoietic Stem Cell Maintenance

Cited by 17 publications

References 39 publications

Evidence for AKT-independent regulation of FOXO1 and FOXO3 in haematopoietic stem and progenitor cells

Evidence for AKT-independent regulation of FOXO1 and FOXO3 in haematopoietic stem and progenitor cells

In Vivo RNAi Screen Unveils PPARγ as a Regulator of Hematopoietic Stem Cell Homeostasis

FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage

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