Inactivation of <i>Rb</i> and <i>E2f8</i> Synergizes To Trigger Stressed DNA Replication during Erythroid Terminal Differentiation

Ghazaryan, Seda; Sy, Chandler B.; Hu, Tinghui; An, Xiuli; Mohandas, Narla; Fu, Haiqing; Aladjem, Mirit I.; Chang, Victor; Opavský, René; Wu, Lizhao

doi:10.1128/mcb.01651-13

Cited by 15 publications

(21 citation statements)

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“…It has been shown that inactivation of both Rb and E2F8 works synergistically to trigger DNA replication. 50 In addition, E2F8 is essential for polyploidization in mammalian cells. 51 The detailed information for the role of E2F family in cancer has been described in a recent review.…”

Section: P16/rb/e2f Pathway In Liver Proliferation After Ph and In LImentioning

confidence: 99%

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Timchenko

Lewis²

2014

Cancer Stud Mol Med Open J

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Liver cancer is one of the most lethal cancers. Quiescent liver expresses up to 20 tumor suppressor proteins including Rb, p53, CCAAT-Enhancer-Binding Protein (C/EBP)α, Hepatocyte Nuclear Factor (HNF4)α and p16 and it is well protected from development of liver cancer. However, the negative control of liver proliferation by these factors and other tumor suppressor genes is eliminated in liver cancer. Studies of liver regeneration after surgery and injury have provided fundamental mechanisms on how liver neutralizes tumor suppressor proteins for the time of regeneration; however, studies of liver cancer in animal models and in human samples showed several additional pathways of this neutralization. One of these additional pathways includes activation of a small subunit of the proteasome, Gankyrin. Gankyrin is dramatically increased in human hepatocellular carcinoma (HCC) and in animal models of carcinogenesis. Once activated Gankyrin triggers degradation of main tumor suppressor proteins during development of liver cancer using slightly different mechanisms. Recent studies identified mechanisms which repress Gankyrin in quiescent livers and mechanisms of activation of Gankyrin in liver cancer. These mechanisms involve a communication between Farnesoid X Receptor (FXR) signaling and chromatin remodelling proteins mediated by members of C/EBP family. It has been recently shown that C/EBPα plays a critical role in this network and that the activation of C/EBPα in cirrhotic livers with HCC inhibits cancer progression. This C/EBPα-dependent inhibition of liver cancer involves activation of a majority of tumor suppressor genes and repression of tumor initiating pathways such as β-catenin and c-myc. These recent findings provide a background for FXR-based and C/EBPα-based approaches to treat liver cancer.

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Section: P16/rb/e2f Pathway In Liver Proliferation After Ph and In LImentioning

confidence: 99%

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Timchenko

Lewis²

2014

Cancer Stud Mol Med Open J

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“…Previously, gene expression studies have demonstrated that, of all E2F transcription factor genes, E2f2 is most significantly induced in terminally differentiating cells of the definitive erythroid lineage (in bone marrow and fetal liver) (7,21). In agreement with these gene expression data, we found that E2F-2 protein is significantly upregulated in primary bone marrow erythroid cells, sorted based on CD44/Ter119/forward scatter (FSC) (22) to distinguish basophilic erythroblasts (RII), polychromatic erythroblasts (RIII), and orthochromatic erythroblasts (RIV) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Erythroblasts exit the mitotic cell cycle before undergoing enucleation; this exit occurs concomitantly with the induction of cyclindependent kinase (Cdk) inhibitors, including p21 Cip1 and p27 Kip1 (2)(3)(4). Loss of retinoblastoma (Rb), the master regulator of G 1 -to-S-phase progression, results in ineffective erythropoiesis in vivo (5)(6)(7)(8). Upstream mitogen-stimulated pathway signaling converges upon the G 1 cyclin-Cdks, leading to Rb hyperphosphorylation and E2F transcription factor activation (9-11).…”

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confidence: 99%

“…Germ line deletion of another E2F transcription factor, E2F-4, results in fetal anemia due to impaired expansion (19,20). One of the Rb-independent E2F family members, E2F-8, collaborates with Rb to restrain E2F-2 transcriptional activity during erythroid maturation and prevent DNA damage, permitting normal red blood cell (RBC) production (7). Moreover, E2F-2 loss alleviates erythroid differentiation defects seen with Rb loss alone or in combination with deletion of E2f8 (7,8).…”

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confidence: 99%

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E2F-2 Promotes Nuclear Condensation and Enucleation of Terminally Differentiated Erythroblasts

Swartz

Wood

Murthy

et al. 2017

Molecular and Cellular Biology

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E2F-2 is a retinoblastoma (Rb)-regulated transcription factor induced during terminal erythroid maturation. Cyclin E-mediated Rb hyperphosphorylation induces E2F transcriptional activator functions. We previously reported that deregulated cyclin E activity causes defective terminal maturation of nucleated erythroblasts in vivo. Here, we found that these defects are normalized by E2F-2 deletion; however, anemia in mice with deregulated cyclin E is not improved by E2F-2-loss, which itself causes reduced peripheral red blood cell (RBC) counts without altering relative abundances of erythroblast subpopulations. To determine how E2F-2 regulates RBC production, we comprehensively studied erythropoiesis using knockout mice and hematopoietic progenitors. We found that efficient stress erythropoiesis in vivo requires E2F-2, and we also identified an unappreciated role for E2F-2 in erythroblast enucleation. In particular, E2F-2 deletion impairs nuclear condensation, a morphological feature of maturing erythroblasts. Transcriptome profiling of E2F-2-null, mature erythroblasts demonstrated widespread changes in gene expression. Notably, we identified citron Rho-interacting kinase (CRIK), which has known functions in mitosis and cytokinesis, as induced in erythroblasts in an E2F-2-dependent manner, and we found that CRIK activity promotes efficient erythroblast enucleation and nuclear condensation. Together, our data reveal novel, lineage-specific functions for E2F-2 and suggest that some mitotic kinases have specialized roles supporting enucleation of maturing erythroblasts.

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“…Although E2F8 has previously been shown to promote erythroid terminal differentiation by collaborating with Rb protein where Rb binds and sequesters E2F2 and E2F8 competes with E2F2 for E2F2-binding sites on target gene promoters (Ghazaryan, Sy et al 2014), to our knowledge, there is no reported data showing the participation of E2F8 in the differentiation program in KCs. Dysregulation of squamous differentiation is a key event in malignant conversion of KCs and is evident in early forms of SCC (Sugiyama, Speight et al 1993;Watanabe, Ichikawa et al 1995;Gasparoni, Fonzi et al 2004).…”

Section: Atypical E2f Proteins and Differentiationmentioning

confidence: 81%

The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

Rethinam¹

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Among keratinocyte-derived squamous cell carcinoma (SCC), cutaneous SCC (CSCC) is the second most common cutaneous cancer type and the most common of the potentially fatal skin cancers. Approximately 90% of head and neck cancers are SCC (HNSCC) and HNSCC worldwide is the sixth most common cancer type afflicting mankind. While resectable disease may be treated by surgery with radiation or chemoradiation, there are still no curative options for advanced, unresectable disease. However, chemotherapy alone may offer a hope for unresectable, disseminated SCC, where 50-60% of patients have disease recurrence within 2 years and approximately 30% of these develop metastatic disease. The mainstay of chemotherapeutic treatment in SCC is the platinum-based drug, cisplatin, 5-fluorouracil (5-FU), taxanes, and anti-EGFR monoclonal antibody such as Cetuximab. Nonetheless, despite advances in treatment techniques, the 5-year survival rate still remains at around 55%.Therefore, there remains a lack of options for recurrent or metastatic disease.The E2F family of transcription factors has emerged as key regulators of proliferation, differentiation and response to stress and apoptotic stimuli in keratinocytes. Consistent with these roles, dysregulation of E2F expression/activity is a common occurrence in cancer and SCC in particular. Thus, better understanding of the E2F family of proteins is essential to establish how these processes are disrupted during SCC genesis. The E2F network exists as a complex map of interacting pathways, and the complete understanding of the E2F family will not be possible until physiological functions of newly identified inhibitory E2F proteins, E2F7 and E2F8, are fully revealed. I provide strong evidence, from in vitro experiments, that E2F7 plays a unique and non-redundant role in modulating UV-or chemotherapy-induced cytotoxicity whereas E2F8 has a unique and non-redundant capacity to regulate squamous differentiation. In addition, I report on a unique feedback loop between E2F1, E2F7 and E2F8 that highlights a previously unreported interdependent axis.With respect to E2F7-specific functions, my work characterised two previously unidentified pathways as therapeutic targets, E2F7/Sphk1/S1P/AKT and E2F7/RacGAP1/AKT, by which the transcription factor E2F7 suppresses doxorubicin specific sensitivity in SCC cells.Targeting these pathways has the potential to expand the clinical activity of existing chemotherapeutics. I provide, in vitro, in vivo and patient data in this study that shows that E2F7-dependent repression of doxorubicin sensitivity is mediated via the induction of Sphingosine kinase 1 (Sphk1) and Rac GTPase activating protein 1 (RacGAP1). These are iii both novel findings and have significant implications for drug resistant SCC. Specifically, Ishowed that (i) E2F7 is overexpressed in patient SCCs and inhibits sensitivity to doxorubicin, (ii) that E2F7-dependent doxorubicin resistance is mediated via E2F-dependent induction of Sphk1 leading to overproduction of Sphingosine-1-phosphate ...

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Inactivation of Rb and E2f8 Synergizes To Trigger Stressed DNA Replication during Erythroid Terminal Differentiation

Cited by 15 publications

References 50 publications

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

E2F-2 Promotes Nuclear Condensation and Enucleation of Terminally Differentiated Erythroblasts

The role of E2F7 and E2F8 in squamous differentiation, UV- and chemotherapy-induced responses in keratinocytes

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