Ei24, a Novel E2F Target Gene, Affects p53-independent Cell Death upon Ultraviolet C Irradiation

Sung, Young Hoon; Jin, Yoonhee; Kang, Yunhwa; Devkota, Sushil; Lee, Jae‐Hoon; Roh, Jae Il; Lee, Han Woong

doi:10.1074/jbc.m113.477570

Cited by 15 publications

(13 citation statements)

References 37 publications

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“…Total RNA was isolated with Trizol (Invitrogen) according to the manufacturer’s instructions. Superscript III (Invitrogen) was used for cDNA synthesis as previously described [ 31 ]. iQ5 (Bio-Rad) was used for RT-qPCR with the following primers: human HK2 , and ; human TERT , and ; human TERC , ; and human ACTIN , and .…”

Section: Methodsmentioning

confidence: 99%

Hexokinase 2 is a molecular bridge linking telomerase and autophagy

Roh

Kim

et al. 2018

PLoS ONE

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Autophagy is systematically regulated by upstream factors and nutrients. Recent studies reported that telomerase and hexokinase 2 [HK2) regulate autophagy through mTOR and that telomerase has the capacity to bind to the HK2 promoter. However, the molecular linkage among telomerase, HK2, and autophagy is not fully understood. Here, we show that HK2 connects telomerase to autophagy. HK2 inhibition in HepG2 cells suppressed TERT-induced autophagy activation and further enhancement by glucose deprivation. The HK2 downstream factor mTOR was responsible for the TERT-induced autophagy activation under glucose deprivation, implying that TERT promotes autophagy through an HK2-mTOR pathway. TERC played a role similar to that of TERT, and simultaneous expression of TERT and TERC synergistically enhanced HK2 expression and autophagy. At the gene level, TERT bound to the HK2 promoter at a specific region harboring the telomerase-responsive sequence ‘.’ Mutagenesis of TERC and the TERT-responsive element in the HK2 promoter revealed that TERC is required for the binding of TERT to the HK2 promoter. We demonstrate the existence of a telomerase-HK2-mTOR-autophagy axis and suggest that inhibition of the interaction between telomerase and the HK2 promoter diminishes glucose starvation-induced autophagy.

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Section: Methodsmentioning

confidence: 99%

Hexokinase 2 is a molecular bridge linking telomerase and autophagy

Roh

Kim

et al. 2018

PLoS ONE

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“…FACS analysis was performed as described previously 47 . Briefly, B16F10 control and Ei24 knockdown cells grown in normal medium or in HBSS (48 h) were fixed in 70% ethanol, treated with RNase A (Sigma-Aldrich, R4875), and stained with propidium iodide (Sigma-Aldrich, P4170) to stain DNA.…”

Section: Methodsmentioning

confidence: 99%

Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases

et al. 2016

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Historically, the ubiquitin-proteasome system (UPS) and autophagy pathways were believed to be independent; however, recent data indicate that these pathways engage in crosstalk. To date, the players mediating this crosstalk have been elusive. Here, we show experimentally that EI24 (EI24, autophagy associated transmembrane protein), a key component of basal macroautophagy/autophagy, degrades 14 physiologically important E3 ligases with a RING (really interesting new gene) domain, whereas 5 other ligases were not degraded. Based on the degradation results, we built a statistical model that predicts the RING E3 ligases targeted by EI24 using partial least squares discriminant analysis. Of 381 RING E3 ligases examined computationally, our model predicted 161 EI24 targets. Those targets are primarily involved in transcription, proteolysis, cellular bioenergetics, and apoptosis and regulated by TP53 and MTOR signaling. Collectively, our work demonstrates that EI24 is an essential player in UPS-autophagy crosstalk via degradation of RING E3 ligases. These results indicate a paradigm shift regarding the fate of E3 ligases.

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“…Although this biological role has been known for some time, the mechanisms affecting cell death in stem and progenitor cells due to deregulation of E2Fs or PPs is not fully clarified. Nevertheless, p53-dependent mechanisms have been highly implicated, and while recent evidence suggested a non-transcriptional role for pRb in apoptotic induction ( Hilgendorf et al, 2013 ), a number of genes that are involved in both the mitochondrial apoptotic signaling cascade as well as autophagy regulation have been demonstrated as downstream or direct targets of E2Fs and/or PPs ( Hiebert et al, 1995 ; Sherr, 1998 ; Irwin et al, 2000 ; Moroni et al, 2001 ; Nahle et al, 2002 ; Vorburger et al, 2002 ; Hershko and Ginsberg, 2004 ; Hershko et al, 2005 ; Tracy et al, 2007 ; Ianari et al, 2009 ; Conklin et al, 2012 ; Bertin-Ciftci et al, 2013 ; Sung et al, 2013 ; Benson et al, 2014 ). Furthermore, a specific biochemical interaction between pRB and E2F1 is required for regulation of both E2F1-induced apoptosis and expression of E2F-dependent apoptotic genes ( Dick and Dyson, 2003 ; Julian et al, 2008 ; Carnevale et al, 2012 ), strongly suggesting that transcriptional regulation by E2F/PP is a primary mechanism by which this pathway controls cell death.…”

Section: Functional Evidence That E2fs and Pps Control Transcription mentioning

confidence: 99%

Transcriptional control of stem cell fate by E2Fs and pocket proteins

Julian

Blais

2015

Front. Genet.

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E2F transcription factors and their regulatory partners, the pocket proteins (PPs), have emerged as essential regulators of stem cell fate control in a number of lineages. In mammals, this role extends from both pluripotent stem cells to those encompassing all embryonic germ layers, as well as extra-embryonic lineages. E2F/PP-mediated regulation of stem cell decisions is highly evolutionarily conserved, and is likely a pivotal biological mechanism underlying stem cell homeostasis. This has immense implications for organismal development, tissue maintenance, and regeneration. In this article, we discuss the roles of E2F factors and PPs in stem cell populations, focusing on mammalian systems. We discuss emerging findings that position the E2F and PP families as widespread and dynamic epigenetic regulators of cell fate decisions. Additionally, we focus on the ever expanding landscape of E2F/PP target genes, and explore the possibility that E2Fs are not simply regulators of general ‘multi-purpose’ cell fate genes but can execute tissue- and cell type-specific gene regulatory programs.

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Ei24, a Novel E2F Target Gene, Affects p53-independent Cell Death upon Ultraviolet C Irradiation

Abstract: Background: Rb loss deregulates E2F and thus induces the expressions of E2F target genes. Results: Ei24 is an E2F target up-regulated in Rb Ϫ/Ϫ MEFs and affects susceptibility of p53-deficient MEFs against UVC.

Cited by 15 publications

References 37 publications

Hexokinase 2 is a molecular bridge linking telomerase and autophagy

Hexokinase 2 is a molecular bridge linking telomerase and autophagy

Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases

Transcriptional control of stem cell fate by E2Fs and pocket proteins

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