E2F1 and E2F2 have opposite effects on radiation-induced p53-independent apoptosis in Drosophila

Wichmann, Anita; Uyetake, Lyle; Su, Tin Tin

doi:10.1016/j.ydbio.2010.07.023

Cited by 29 publications

(45 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…42,57,58 Within 4 h after IR, hid-GFP expression was induced in larval imaginal discs of wild-type, but not p53 mutant, animals consistent with previous reports (Figures 7a and b). 57,58 The Ch-p53BSTOP (encodes p53A, C, D/E) but not GFP-p53ASTOP (encodes p53B, C, D/E) rescued induction of hid-GFP expression in the p53 null strain, consistent with the results of the cleaved Caspase labeling that p53A is required for the early apoptotic response to radiation (Figures 7c and d).…”

Section: Resultssupporting

confidence: 92%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

View full text Add to dashboard Cite

The p53 protein is a major mediator of the cellular response to genotoxic stress and is a crucial suppressor of tumor formation. In a variety of organisms, p53 and its paralogs, p63 and p73, each encode multiple protein isoforms through alternative splicing, promoters, and translation start sites. The function of these isoforms in development and disease are still being defined. Here, we evaluate the apoptotic potential of multiple isoforms of the single p53 gene in the genetic model Drosophila melanogaster. Most previous studies have focused on the p53A isoform, but it has been recently shown that a larger p53B isoform can induce apoptosis when overexpressed. It has remained unclear, however, whether one or both isoforms are required for the apoptotic response to genotoxic stress. We show that p53B is a much more potent inducer of apoptosis than p53A when overexpressed. Overexpression of two newly identified short isoforms perturbed development and inhibited the apoptotic response to ionizing radiation. Analysis of physiological protein expression indicated that p53A is the most abundant isoform, and that both p53A and p53B can form a complex and co-localize to sub-nuclear compartments. In contrast to the overexpression results, new isoformspecific loss-of-function mutants indicated that it is the shorter p53A isoform, not full-length p53B, that is the primary mediator of pro-apoptotic gene transcription and apoptosis after ionizing radiation. Together, our data show that it is the shorter p53A isoform that mediates the apoptotic response to DNA damage, and further suggest that p53B and shorter isoforms have specialized functions.

show abstract

Section: Resultssupporting

confidence: 92%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Consistent with our results, E2F2 was found to have a protective role in radiation-induced, p53-independent apoptosis in Drosophila third-instar larvae (37). ID1 has recently been shown to be necessary for prostaglandin E2-mediated radiation resistance in mouse glioblastoma cells, and ID1 + human GSCs appear to be relatively radiation resistant (33).…”

Section: Discussionsupporting

confidence: 90%

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD + ). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD + synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD + levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD + -dependent network. Accordingly, we demonstrate E2F2 is required for GSC selfrenewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD + metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.T he prognosis for glioblastoma, the most common malignant intrinsic brain tumor in adults, remains poor despite aggressive multidisciplinary therapy, including maximal safe surgical resection, radiation therapy, and temozolomide (1, 2). The failure of these interventions to generate a durable response stems in part from inadequate understanding of the metabolic and molecular mechanisms underlying malignant behavior and therapeutic resistance (3, 4). Nicotinamide adenine dinucleotide (NAD + ) has a well-known role in cellular metabolism and is an important cofactor for signaling pathways that regulate aging, inflammation, diabetes mellitus, axonal injury, and cancer (5, 6). Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD + synthesis, produces NAD + precursor nicotinamide mononucleotide (NMN) to drive NAD + -dependent processes. Interestingly, NAMPT expression is extremely low in the mammalian brain compared with other organs (7,8). However, NAMPT is highly expressed in several cancers, and features of cancer cells, including proliferation, invasion, and tumor growth, exhibit a dependence on NAD + (9-11). In noncancer cells, NAD + plays a critical role in transcriptional control, providing a metabolic basis for epigenetic reprogramming (12-16). Enzymes using NAD + as a cofactor, including the sirtuins and poly-ADP ribosyl transferases, regulate transcription factor activity and chromatin structure (13-15). Additionally, NAD + can control transcription by altering DNA methylation in neurons (12). However, in glioblastoma, little is known about NAD + -dependent transcriptional events and whether these even...

show abstract

“…This deletion was originally described by Rong et al 16 ; homozygous deletion flies are viable and fertile, but they display reduced apoptosis in response to DNA damage caused by ionizing radiation. [17][18][19] Genomic PCRs verified that the modified parental lines were in fact deleted for p53 (Fig. 4A).…”

Section: Resultsmentioning

confidence: 92%

Nucleolar stress in Drosophila melanogaster

James

Cindass²,

Mayer³

et al. 2013

Nucleus

View full text Add to dashboard Cite

E2F1 and E2F2 have opposite effects on radiation-induced p53-independent apoptosis in Drosophila

Cited by 29 publications

References 46 publications

The function of Drosophila p53 isoforms in apoptosis

The function of Drosophila p53 isoforms in apoptosis

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Nucleolar stress in Drosophila melanogaster

Contact Info

Product

Resources

About

E2F1 and E2F2 have opposite effects on radiation-induced p53-independent apoptosis in Drosophila

Cited by 29 publications

References 46 publications

The function of Drosophila p53 isoforms in apoptosis

The function of Drosophila p53 isoforms in apoptosis

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Nucleolar stress in Drosophila melanogaster

Contact Info

Product

Resources

About

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma