E2F6 Inhibits Cobalt Chloride-Mimetic Hypoxia-induced Apoptosis through E2F1

Yang, Weiwei; Shu, Bo; Zhu, Yi; Yang, Huang‐Tian

doi:10.1091/mbc.e08-02-0171

Cited by 28 publications

(29 citation statements)

References 35 publications

(62 reference statements)

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“…Some of them have not been described as hypoxia-responsive genes in fetal tissues in vivo. E2F6, known as a potent transcriptional repressor involved in cell cycle regulation and modification of cellular proliferation (25), recently has been shown to modify CoCl 2 -induced apoptosis via modulation of the E2F1/Apaf-1 pathway in vitro in HEK 293 cells (56). In contrast, our in vivo results demonstrate downregulation of E2f6 in response to acute hypoxia in both placenta and brain.…”

Section: Discussioncontrasting

confidence: 62%

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Late-gestational systemic hypoxia leads to a similar early gene response in mouse placenta and developing brain

Trollmann

Rehrauer

Schneider

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Late-gestational intrauterine hypoxia represents a well-known risk factor of acquired perinatal brain injury. Cell type and age-specific sensitivity of hypoxia-responsive genes to low-oxygen partial pressure is to be considered in the screening for early indicators of fetoplacental tissue hypoxia. To identify early hypoxia-induced alterations in gene expression during late-gestational hypoxia (6% O(2), 6 h; gestational day 20) we compared primary mouse placenta and brain transcriptomes using high-density oligonucleotide microarrays. Upregulation of candidate marker genes for hypoxia was confirmed by quantitative RT-PCR and immunohistochemistry. Both developing brain and placenta were highly responsive to systemic hypoxia at the level of gene expression involving hypoxia-inducible transcription factor (HIF)-dependent genes and immediate early genes (IEG) (Fos, Jun, Egr1, Bhlhb2), apoptosis-promoting factors (Bnip3, Dusp1, Ier3) that were all upregulated, and genes modulating RNA binding and translation (Rbm3, Thap2, Lig4, Rbm12b) that mainly were downregulated. Functional activity of the HIF system was obvious from elevated expression of various known HIF target genes (Adm, Vegf, Hk2, Pdk1, Bnip3, Ier3, Dusp-1), indicating immediate availability among early response to acute hypoxia. In addition, genes not yet described as being hypoxia related were identified that are involved in angiogenesis/cell differentiation (Gna13, Gab2), mRNA processing, and embryonic development. RT-PCR of placenta and brain tissues confirmed upregulation of selected HIF target genes and IEG. These data indicate that the early hypoxia-induced genomic response of the placenta mirrors that of developing brain in a temporally parallel manner. Our observations implicate future diagnostic options to identify fetal and cerebral tissue hypoxia.

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Section: Discussioncontrasting

confidence: 62%

“…In contrast, our in vivo results demonstrate downregulation of E2f6 in response to acute hypoxia in both placenta and brain. This might increase cellular sensitivity to hypoxiainduced apoptosis by upregulating E2F1-dependent proapoptotic genes (56).…”

Section: Discussionmentioning

confidence: 99%

Late-gestational systemic hypoxia leads to a similar early gene response in mouse placenta and developing brain

Trollmann

Rehrauer

Schneider

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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“…It is well established that E2F6 represses the transcription of E2F1 target genes such as p57 via competition with E2F1 for promoter binding to the p57 gene promoter. [39][40][41][42] Therefore, the increased level of E2F6 may, at least in part, account for the decreased expression of p57 in Cited2 ⌬/⌬ HSCs. It is worth noting that decreased expression of p57 in HSCs has been detected in many knockout mouse models in which HSC quiescence is affected, such as in CXCR4-, 43 JunB-, 44 Tpo-, 45 and STAT5 46 -knockout mice.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency

Chen

et al. 2012

Blood

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Cited2 is a transcriptional modulator involved in various biologic processes including fetal liver hematopoiesis. In the present study, the function of Cited2 in adult hematopoiesis was investigated in conditional knockout mice. Deletion of Cited2 using Mx1-Cre resulted in increased hematopoietic stem cell (HSC) apoptosis, loss of quiescence, and increased cycling, leading to a severely impaired reconstitution capacity as assessed by 5-fluorouracil treatment and long-term transplantation. Transcriptional profiling revealed that multiple HSC quiescence-and hypoxia-related genes such as Egr1, p57, and Hes1 were affected in Cited2-deficient HSCs. Because Cited2 is a negative regulator of HIF-1, which is essential for maintaining HSC quiescence, and because we demonstrated previously that decreased HIF-1␣ gene dosage partially rescues both cardiac and lens defects caused by Cited2 deficiency, we generated Cited2 and HIF-1␣ doubleknockout mice. Additional deletion of HIF-1␣ in Cited2-knockout BM partially rescued impaired HSC quiescence and reconstitution capacity. At the transcriptional level, deletion of HIF-1␣ restored expression of p57 and Hes1 but not Egr1 to normal levels. Our results suggest that Cited2 regulates HSC quiescence through both HIF-1-dependent and HIF-1-independent pathways. (Blood. 2012;119(12):2789-2798) IntroductionHematopoietic stem cells (HSCs) are thought to be localized in the hypoxic microenvironment of the BM and remain quiescent or differentiate into multiple blood cell lineages. Several factors have been found to regulate HSC quiescence in either a cell-intrinsic (eg, p21, p57, Bmi1, Egr1, GATA2, Gfi1, Pbx1, and others) or a cell-extrinsic (eg, Tie2/Angpt1, c-Mpl/Tpo, CXCR4/CXCL12, and others) manner.CBP/p300-interacting transactivator with glutamic acid (E) and aspartic acid (D)-rich tail 2 (Cited2), a member of the Cited family of transcriptional modulators, is a cytokine-inducible gene 1 that plays various roles during mouse development. [2][3][4][5][6] In particular, Cited2 plays an important role in fetal liver hematopoiesis, which is supported by severely impaired fetal liver HSC function and decreased expression of genes known to be essential for hematopoiesis in Cited2-deficient fetal liver HSC/progenitors. 7 Cited2 has also been implicated in tumor cell invasion and progression. 8,9 Cited2 is a negative regulator of hypoxia-inducible factor 1 (HIF-1). Bhattacharya et al first demonstrated in vitro that Cited2 competes with HIF-1␣ for binding to p300-CH1 and inhibits HIF-1-mediated transactivation. 10 Bakker et al also showed that FOXO3a inhibits HIF-1-induced apoptosis by stimulating the transcription of Cited2, which reduces the expression of the pro-apoptotic HIF-1 target genes NIX (also called "Bnip3l") and RTP801 (also called "Ddit4"). 11 In our previous studies, we showed that deletion of HIF-1␣ partially rescues defects in heart and lens caused by Cited2 deficiency. 4,12 In addition, at the structural level, Freedman et al revealed that Cited2 and HIF-1␣ share a conserved...

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“…In agreement, while ERK is often associated with hypertrophy, ERK1 −/− ERK2 +/− mice can elicit cardiac growth in response to hypertrophic stimuli, but show increased cell death indicating that ERK is required for survival, but not growth in response to hypertrophic insult [44]. Consistent with the activation of a survival pathway, no apoptosis was detected in E2F6 mice at this stage, and further, E2F6 has been demonstrated to inhibit apoptosis in cell culture [19,45,46]. We observed an increase in apoptosis in much older mice (6 months), at which point less than 40% of mice are alive, suggesting that apoptosis was a consequence of end stage heart failure and not the underlying cause of the DCM [19].…”

Section: Discussionmentioning

confidence: 55%

Interplay between the E2F pathway and β-adrenergic signaling in the pathological hypertrophic response of myocardium

Major¹,

Salih²,

Tuana³

2015

Journal of Molecular and Cellular Cardiology

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E2F6 Inhibits Cobalt Chloride-Mimetic Hypoxia-induced Apoptosis through E2F1

Cited by 28 publications

References 35 publications

Late-gestational systemic hypoxia leads to a similar early gene response in mouse placenta and developing brain

Late-gestational systemic hypoxia leads to a similar early gene response in mouse placenta and developing brain

HIF-1α deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency

Interplay between the E2F pathway and β-adrenergic signaling in the pathological hypertrophic response of myocardium

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