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

Liang, Raymond; Rimmelé, Pauline; Bigarella, Carolina L.; Yalçın, Sakine; Ghaffari, Saghi

doi:10.1080/15384101.2015.1123355

Cited by 36 publications

(30 citation statements)

References 43 publications

(76 reference statements)

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“…It is well documented that AKT regulates FOXO1 activity by phosphorylation [23,24], and this supports our results; where p-AKT and p-FOXO1 levels are both elevated in EPS8L3 over-expression of cells but inhibited in EPS8L3silenced cells. Therefore, EPS8L3 can regulate FOXO1 through AKT which is one of the major downstream genes of the epidermal growth factor receptor (EGFR).…”

Section: Discussionsupporting

confidence: 93%

Overexpression of EPS8L3 promotes cell proliferation by inhibiting the transactivity of FOXO1 in HCC

Zeng¹,

Tang²,

Xie³

et al. 2018

neo

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The homology of epidermal growth factor receptor pathway substrate 8 (EPS8), EPS8L3, is elevated significantly in hepatocellular carcinoma (HCC) tissues and cell lines compared with the normal liver tissues and cell lines. The MTT and colony formation assays demonstrated that overexpressing EPS8L3 enhances, while silencing reduces the proliferation of HCC cells. Further experiments illustrated that overexpressing EPS8L3 promotes the expression of p-AKT, Cyclin D1, but inhibits the transcriptional activity of FOXO1. Besides, colony formation assay demonstrated that AKT inhibitor suppresses the effect of EPS8L3 on proliferation in EPS8L3-overexpressing cells, whereas AKT restores the proliferation of EPS8L3-silenced cells, suggesting that EPS8L3 might promote proliferation by hyperactivating the AKT signaling pathway and subsequently inhibiting the FOXO1 transcriptional activity. Our results provide new view between EPS8L3 and progression of human HCC, suggesting that EPS8L3 may be a novel therapeutic target for HCC.

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Section: Discussionsupporting

confidence: 93%

Overexpression of EPS8L3 promotes cell proliferation by inhibiting the transactivity of FOXO1 in HCC

Zeng¹,

Tang²,

Xie³

et al. 2018

neo

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“…its translocation to cytoplasm of primordial follicles in vitro via PI3K/Akt pathway [45,54]. However, besides phosphorylation, FOXO3 can be also regulated by acetylation, methylation, glycosylation, redox modulation, and ubiquitination, which will determine FOXO3 function [55]. The higher expression of FOXO3 in imatinib treated postnatal rat ovaries may be related to ovarian tissue fibrosis in the current study.…”

Section: Discussionmentioning

confidence: 64%

Imatinib mesylate does not counteract ovarian tissue fibrosis in postnatal rat ovary

Asadi-Azarbaijani

Braber

Duursen

et al. 2019

Reproductive Biology

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Chemotherapy may result in ovarian atrophy, a depletion of the primordial follicle pool, diminished ovarian weight, cortical and stromal fibrosis. Imatinib mesylate is an anticancer agent that inhibits competitively several receptor tyrosine kinases (RTKs). RTKs play important roles in cell metabolism, proliferation, and apoptosis. In clinic, imatinib mesylate is also known as an anti-fibrotic medicine. In the present study, the impact of imatinib on the ovarian tissue was investigated by assessing ovarian tissue fibrosis in postnatal rat administered with or without imatinib for three days. Fibrosis in the ovarian tissue was determined by histology (Picrosirius and Masson's trichrome staining) and the protein expression of vimentin and alpha-smooth muscle actin (α-SMA). Furthermore, mRNA expression of Forkhead box transcription factor O1 and O3 (FOXO1 and FOXO3), which are markers of cell proliferation was quantified. A short-term exposure to imatinib showed to increase tissue fibrosis in ovaries. This was observed by Masson's trichrome staining. Exposure to imatinib led also to a down-regulation of vimentin protein expression and up-regulation mRNA expression of FOXO3. This may indicate a role of FOXO3 in ovarian tissue fibrosis in postnatal rat ovaries.

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“…While FOXO1 increased intronic promoter activity from a luciferase reporter, FOXO1 did not significantly impact IE1 and IE2 expression in the context of the more complex MIE genomic locus. While FOXO1 and FOXO3a are both expressed in hematopoietic cells, FOXO3a more efficiently localizes to the nucleus in myeloid progenitor cells, particularly during cellular stresses such as those that induce reactivation(29, 30). Further, FOXO3a regulates monocyte to macrophage differentiation (25, 31), while FOXO1 promotes maintenance of stemness in CD34 + HPCs (25).…”

Section: Discussionmentioning

confidence: 99%

FOXO Transcription Factors Activate Alternative Major Immediate Early Promoters to Induce Human Cytomegalovirus Reactivation

Hale

Collins-McMillen

Lenarcic

et al. 2020

Preprint

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32A key step during viral reactivation from latency is the re-expression of viral genes. 33Hematopoietic progenitor cells (HPCs) support human cytomegalovirus (HCMV) 34 latency, and their differentiation triggers cellular cues that drive reactivation. A key step 35 during HCMV reactivation in latently infected HPCs is re-expression of viral genes. We 36 recently determined that the major immediate early promoter (MIEP), which is primarily 37 responsible for MIE gene expression during lytic replication, remains silent during 38 reactivation. Instead, alternative promoters in the MIE locus are induced by reactivation 39 stimuli. Here, we find that forkhead family (FOXO) transcription factors are critical for 40 activation of alternative MIE promoters during HCMV reactivation, as mutating FOXO 41 binding sites in alternative MIE promoters decreased HCMV IE gene expression upon 42 reactivation and significantly decreased the production of infectious virus from latently 43 infected primary CD34 + HPCs. These findings establish a mechanistic link by which 44 infected cells sense environmental cues to regulate latency and reactivation, and 45 emphasize the role of contextual activation of alternative MIE promoters as the primary 46 drivers of reactivation. 47 48 Significance 49 50 Human cytomegalovirus infection is lifelong and persistent. Periodic reactivation of 51 cytomegalovirus poses serious disease risk for immune-compromised patients. A critical 52 driver of reactivation is expression of viral genes from the major immediate early locus. 53Recent paradigm-shifting evidence shows that reactivation is driven from promoters 54 distinct from those that drive replication in permissive cells. Understanding the 55 contextual control of these promoters and how they specifically respond to cellular cues 56 that drive reactivation is critical for establishing future therapies that prevent 57 reactivation. Our findings mechanistically define a previously enigmatic relationship 58 between differentiation and reactivation, and provide potential targets for therapeutic 59 intervention to prevent HCMV reactivation and disease. 60 61 virology 89(Pt 2):359-368.

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

Cited by 36 publications

References 43 publications

Overexpression of EPS8L3 promotes cell proliferation by inhibiting the transactivity of FOXO1 in HCC

Overexpression of EPS8L3 promotes cell proliferation by inhibiting the transactivity of FOXO1 in HCC

Imatinib mesylate does not counteract ovarian tissue fibrosis in postnatal rat ovary

FOXO Transcription Factors Activate Alternative Major Immediate Early Promoters to Induce Human Cytomegalovirus Reactivation

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