2007
DOI: 10.1073/pnas.0708380104
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Abstract: The proteasome controls a plethora of survival factors in all mammalian cells analyzed to date. Therefore, it is puzzling that proteasome inhibitors such as bortezomib can display a preferential toxicity toward malignant cells. In fact, proteasome inhibitors have the salient feature of promoting a dramatic induction of the proapoptotic protein NOXA in a tumor cell-restricted manner. However, the molecular determinants that control this specific regulation of NOXA are unknown. Here, we show that the induction o… Show more

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Cited by 158 publications
(190 citation statements)
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“…A 1430 bp sequence spanning the region −1200 bp to +230 bp relative to the Noxa transcription start site was selected based on previous reports describing functionally important sites for binding of transcription factors (including c-Myc, hypoxia inducible factor-1α (HIF-1α), and others) within this region. 36 MLN4924 increased luciferase activity in cells transfected with this plasmid (Figure 3c), supporting the hypothesis that MLN4924 causes Noxa upregulation through transactivation of the Noxa promoter.…”
Section: Mln4924-induced Noxa Upregulation Triggers Apoptosissupporting
confidence: 81%
See 1 more Smart Citation
“…A 1430 bp sequence spanning the region −1200 bp to +230 bp relative to the Noxa transcription start site was selected based on previous reports describing functionally important sites for binding of transcription factors (including c-Myc, hypoxia inducible factor-1α (HIF-1α), and others) within this region. 36 MLN4924 increased luciferase activity in cells transfected with this plasmid (Figure 3c), supporting the hypothesis that MLN4924 causes Noxa upregulation through transactivation of the Noxa promoter.…”
Section: Mln4924-induced Noxa Upregulation Triggers Apoptosissupporting
confidence: 81%
“…9,36,37 As indicated above, p53 is not critical for MLN4924-induced Noxa upregulation, as this upregulation was seen in p53 null (HL-60) as well as p53 wild-type cells (ML-1; Figures 3a and c). NF-κB does not appear to have a critical role because, consistent with previous reports, 10,38 NF-κB levels decreased upon MLN4924 treatment and levels of the NF-κB inhibitor (I-κB) increased (Supplementary Figure S2c).…”
Section: Mln4924-induced Noxa Upregulation Triggers Apoptosismentioning
confidence: 95%
“…Importantly, p53 is not the only regulator of Noxa gene expression. Transcription factors such as c-Myc, E2F1, and HIF1a regulate Noxa expression in a p53-independent manner (Hershko and Ginsberg, 2004;Hershko et al, 2005;Nikiforov et al, 2007;Ploner et al, 2008). Interestingly, oncogenic KRAS is critical for maintaining high c-Myc levels in the HCT116/Hkh2 system (Shirasawa et al, 1993), and can promote expression of E2F1 (Berkovich and Ginsberg, 2001) and stabilisation of HIF1a (Kikuchi et al, 2009).…”
Section: Discussionmentioning
confidence: 99%
“…For example, p53-dependent and -independent transcriptional processes upregulate NOXA and PUMA, 31,32 inhibition of mitogen activated protein kinase signaling enhances BIM stability, 33,34 inhibitors of the mechanistic target of rapamycin (mTOR) induce both BIM and PUMA, 35 and inhibition of the proteasome pathway upregulates NOXA through multiple mechanisms. [36][37][38] Importantly, downregulation of the indicated BH3-only proteins impairs killing by each of the indicated treatments, [32][33][34][35]37,38 indicating the critical role of BH3-only protein upregulation in the cytotoxicity of these stresses. Despite extensive qualitative observations such as these, however, quantitative information regarding the extent of BH3-only protein upregulation required to induce apoptosis and the ability of different cells to survive this upregulation is limited.…”
mentioning
confidence: 99%