DNA-binding independent cell death from a minimal proapoptotic region of E2F-1

Bell, L. Andrew; O’Prey, Jim; Ryan, Kevin M.

doi:10.1038/sj.onc.1209580

Cited by 34 publications

(42 citation statements)

References 65 publications

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“…All cell cultures were grown in D-MEM (Gibco, 21969) supplemented with 10% FCS and were, where indicated, either infected with adenoviral lysates or transfected using X-fect (Clontech, 631316) or calcium phosphate transfection as previously described. 32 TetOn-p53 cells were induced with 1 mg/ml doxycycline (Dox) (Sigma, D9891). Endogenous p53 was activated in wild-type MEFs with 10 mM Nutlin-3 (Sigma, N6287) for 48 h. E1aER-expressing cells were activated by incubation in 500 nM 4-hydoxytamoxifen (Sigma, H7904).…”

Section: Methodsmentioning

confidence: 99%

DRAM-1 encodes multiple isoforms that regulate autophagy

et al. 2012

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Keywords: DRAM-1, mRNA splice variants, p53, cell death, autophagy Abbreviations: RNAi, RNA interference; siRNA, small interfering RNA; GFP, green fluorescent protein; LC3, microtubule-associated protein 1 light chain 3; SV, splice variant; DRAM-1, damage-regulated autophagy modulator-1; MEF, mouse embryo fibroblast; Dox, doxycyclineMacro(autophagy) is a cellular mechanism which delivers cytoplasmic constituents to lysosomes for degradation. Due to its role in maintaining cellular integrity, autophagy protects against various diseases including cancer. p53 is a major tumor suppressor gene which can modulate autophagy both positively and negatively. p53 induces autophagy via transcriptional activation of damage-regulated autophagy modulator (DRAM-1). We report here that DRAM-1 encodes not just one mRNA, but a series of p53-inducible splice variants which are expressed at varying levels in multiple human and mouse cell lines. Two of these new splice variants, termed SV4 and SV5, result in mature mRNA species. Different from 'full-length' DRAM-1 (SV1), SV4 and SV5 do not localize to lysosomes or endosomes, but instead partially localize to peroxisomes and autophagosomes respectively. In addition, SV4 and SV5 can also be found co-localized with certain markers of the endoplasmic reticulum. Similar to SV1, SV4 and SV5 do not appear to be inducers of programmed cell death, but they do modulate autophagy. In summary, these findings identify new autophagy regulators that provide insight into the control of autophagy downstream of p53.

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Section: Methodsmentioning

confidence: 99%

DRAM-1 encodes multiple isoforms that regulate autophagy

et al. 2012

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“…Where indicated, cells were transfected by CaPO 4 precipitation as previously described. 39 Western blotting. Cells were lysed in a 2 Â Western sample buffer and transferred to nitrocellulose membranes as described previously.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were lysed in a 2 Â Western sample buffer and transferred to nitrocellulose membranes as described previously. 39 Membranes were probed using standard immunoblotting techniques with antibodies that recognize p73 (HRP-conjugated HA, Roche), p53 (DO-1, Pharmingen), p21 (sc-397G, Santa Cruz) and actin (clone 1A4, Sigma).…”

Section: Methodsmentioning

confidence: 99%

p73 regulates DRAM-independent autophagy that does not contribute to programmed cell death

et al. 2007

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Evading programmed cell death is a common event in tumour development. The p53 family member, p73, is a potent inducer of death and a determinant of chemotherapeutic response, but different to p53, is rarely mutated in cancer. Understanding cell death pathways downstream of p53 and p73 is therefore pivotal to understand both the development and treatment of malignant disease. Recently, p53 has been shown to modulate autophagy -a membrane trafficking process, which degrades long-lived proteins and organelles. This requires a p53 target gene, DRAM, and both DRAM and autophagy are critical for p53-mediated death. We report here that TA-p73 also regulates DRAM and autophagy, with different TA-p73 isoforms regulating DRAM and autophagy to varying extents. RNAi knockdown of DRAM, however, revealed that p73's modulation of autophagy is DRAMindependent. Also, p73's ability to induce death, again different to p53, is neither dependent on DRAM nor autophagy. In contrast to TA-p73, DN-p73 is a negative regulator of p53-induced and p73-induced autophagy, but does not affect autophagy induced by amino-acid starvation. These studies, therefore, represent not only the first report that p73 modulates autophagy but also highlight important differences in the mechanism by which starvation, p53 and p73 regulate autophagy and how this contributes to programmed cell death.

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“…11 This intriguingly revealed that the highest E2F1-induced messenger RNA (mRNA) encodes the multidrug transporter ABCG2 (see Supplementary Information for microarray dataset). Direct mRNA and protein analyses in these cells showed that ABCG2 was strongly induced by wild-type E2F1 but not the mutant E2F1-E132 (Figures 1a and b and Supplementary Figures S1a and S1b).…”

Section: Resultsmentioning

confidence: 99%

E2F1 drives chemotherapeutic drug resistance via ABCG2

et al. 2013

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Multidrug resistance is a major barrier against successful chemotherapy, and this has been shown in vitro to be often caused by ATP-binding cassette (ABC) transporters. These transporters are frequently overexpressed in human cancers and confer an adverse prognosis in many common malignancies. The genetic factors, however, that initiate their expression in cancer are largely unknown. Here we report that the major multidrug transporter ABCG2 (BCRP/MXR) is directly and specifically activated by the transcription factor E2F1-a factor perturbed in the majority of human cancers. E2F1 regulates ABCG2 expression in multiple cell systems, and, importantly, we have identified a significant correlation between elevated E2F1 and ABCG2 expression in human lung cancers. We show that E2F1 causes chemotherapeutic drug efflux both in vitro and in vivo via ABCG2. Furthermore, the E2F1-ABCG2 axis suppresses chemotherapy-induced cell death that can be restored by the inhibition of ABCG2. These findings therefore identify a new axis in multidrug resistance and highlight a radical new function of E2F1 that is relevant to tumor therapy.

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DNA-binding independent cell death from a minimal proapoptotic region of E2F-1

Cited by 34 publications

References 65 publications

DRAM-1 encodes multiple isoforms that regulate autophagy

DRAM-1 encodes multiple isoforms that regulate autophagy

p73 regulates DRAM-independent autophagy that does not contribute to programmed cell death

E2F1 drives chemotherapeutic drug resistance via ABCG2

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