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1.
Nat Cancer ; 3(4): 471-485, 2022 04.
Article in English | MEDLINE | ID: mdl-35484422

ABSTRACT

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.


Subject(s)
Ferroptosis , Neuroblastoma , Cell Death , Child , Cysteine/therapeutic use , Ferroptosis/genetics , Glutathione/therapeutic use , Humans , N-Myc Proto-Oncogene Protein/genetics , Neuroblastoma/genetics
2.
PLoS Genet ; 8(1): e1002433, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22242014

ABSTRACT

In mammalian cells, AU-rich elements (AREs) are well known regulatory sequences located in the 3' untranslated region (UTR) of many short-lived mRNAs. AREs cause mRNAs to be degraded rapidly and thereby suppress gene expression at the posttranscriptional level. Based on the number of AUUUA pentamers, their proximity, and surrounding AU-rich regions, we generated an algorithm termed AREScore that identifies AREs and provides a numerical assessment of their strength. By analyzing the AREScore distribution in the transcriptomes of 14 metazoan species, we provide evidence that AREs were selected for in several vertebrates and Drosophila melanogaster. We then measured mRNA expression levels genome-wide to address the importance of AREs in SL2 cells derived from D. melanogaster hemocytes. Tis11, a zinc finger RNA-binding protein homologous to mammalian tristetraprolin, was found to target ARE-containing reporter mRNAs for rapid degradation in SL2 cells. Drosophila mRNAs whose expression is elevated upon knock down of Tis11 were found to have higher AREScores. Moreover high AREScores correlate with reduced mRNA expression levels on a genome-wide scale. The precise measurement of degradation rates for 26 Drosophila mRNAs revealed that the AREScore is a very good predictor of short-lived mRNAs. Taken together, this study introduces AREScore as a simple tool to identify ARE-containing mRNAs and provides compelling evidence that AREs are widespread regulatory elements in Drosophila.


Subject(s)
Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Regulatory Sequences, Ribonucleic Acid/genetics , Transcriptome/genetics , Tristetraprolin/genetics , 3' Untranslated Regions/genetics , Animals , Computational Biology/methods , Consensus Sequence , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Evolution, Molecular , Gene Expression Regulation , Genome , Genome-Wide Association Study , RNA Stability/genetics , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Sequence Homology, Amino Acid , Software , Tristetraprolin/metabolism
3.
Nucleic Acids Res ; 39(10): 4373-86, 2011 May.
Article in English | MEDLINE | ID: mdl-21278420

ABSTRACT

The carbon catabolite repressor protein 4 (Ccr4)-Negative on TATA (Not) complex controls gene expression at two levels. In the nucleus, it regulates the basal transcription machinery, nuclear receptor-mediated transcription and histone modifications. In the cytoplasm, the complex is required for messenger RNA (mRNA) turnover through its two associated deadenylases, Ccr4 and Caf1. Not1 is the largest protein of the Ccr4-Not complex and serves as a scaffold for other subunits of the complex. Here, we provide evidence that human Not1 in the cytoplasm associates with the C-terminal domain of tristetraprolin (TTP), an RNA binding protein that mediates rapid degradation of mRNAs containing AU-rich elements (AREs). Not1 shows extensive interaction through its central region with TTP, whereas binding of Caf1 is restricted to a smaller central domain within Not1. Importantly, Not1 is required for the rapid decay of ARE-mRNAs, and TTP can recruit the Caf1 deadenylase only in presence of Not1. Thus, cytoplasmic Not1 provides a platform that allows a specific RNA binding protein to recruit the Caf1 deadenylase and thereby trigger decay of its target mRNAs.


Subject(s)
RNA, Messenger/metabolism , Ribonucleases/metabolism , Transcription Factors/metabolism , Tristetraprolin/metabolism , Cell Line , Humans , Protein Structure, Tertiary , RNA Stability , Tristetraprolin/chemistry
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