Cytoplasmic Metadherin (MTDH) Provides Survival Advantage under Conditions of Stress by Acting as RNA-binding Protein

Meng, Xiangjun; Zhu, Danlin; Yang, Shujie; Wang, Xinjun; Xiong, Zhi Gang; Zhang, Yuping; Brachova, Pavla; Leslie, Kimberly K.

doi:10.1074/jbc.c111.291518

Cited by 50 publications

(82 citation statements)

References 31 publications

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“…These are based on RNA-binding proteins in combination with micro-RNAs binding mainly to UTRs thereby regulating the initiation step. As examples, selective regulations serve diminished translation of mRNAs with 5Ј terminal oligopyrimidine tracts (44), the usage of iron responsive elements (45), and more recently described the function of cytosolic metadherin as a regulatory RNA-binding protein (46). Especially the regulation by metadherin might be interesting for our observation as it is highly expressed in solid tumors and even further up-regulated by hypoxia (47).…”

Section: Discussionmentioning

confidence: 88%

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

Tholen

Wolanski

Stolze

et al. 2015

Journal of Biological Chemistry

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Background: Translational regulation might underlie the high expression levels of the protease cathepsin L (CTSL) associated with poor breast cancer prognosis. Results: Translation of CTSL mRNA is highly stress-resistant and promotes metastasis of murine breast cancer. Conclusion: CTSL mRNA circumvents translational shutdown in cancer-associated stress conditions. Significance: High expression of a metastasis promoting protease is maintained by translational regulation.

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Section: Discussionmentioning

confidence: 88%

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

Tholen

Wolanski

Stolze

et al. 2015

Journal of Biological Chemistry

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“…Metadherin/AEG-1 is upregulated in many types of cancer including glioma, breast, prostate, and liver, and has been linked to increased proliferation, migration, cell survival, chemoresistance, and a poor clinical outcome (14,22). Emerging evidence is suggesting, it acts to coordinate many signaling pathways to impart these diverse effects.…”

Section: Discussionmentioning

confidence: 99%

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Kochanek

Wells

2013

Molecular Cancer Research

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Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is an mRNA-binding protein present in both neurons and glia. CPEB1 is capable of both repressing mRNA translation and activating it depending upon its phosphorylation state. CPEB1-bound mRNAs are held in translational dormancy until CPEB1 is phosphorylated, leading to the cytoplasmic polyadenylation of the bound mRNA that triggers translation. Here, we show that CPEB1 can bind to and regulate translation of the mRNA-encoding metadherin (MTDH, also known as AEG-1 and Lyric) in the rat glioblastoma cell line CNS1. MTDH/AEG-1 is being revealed as a critical signaling molecule in tumor progression, playing roles in invasion, metastasis, and chemoresistance. By using a mutant of CPEB1 that cannot be phosphorylated (thereby holding target mRNAs in translational arrest), we show that inhibiting CPEB1-mediated translation blocks MTDH/AEG-1 expression in vitro and inhibits glioblastomas tumor growth in vivo. CPEB1-mediated translation is likely to impact several signaling pathways that may promote tumor progression, but we present evidence suggesting a role in directed cell migration in glioblastoma cells. In addition, reporter mRNA containing CPEB1-binding sites is transported to the leading edge of migrating cells and translated, whereas the same mRNA with point mutations in the binding sites is synthesized perinuclearly. Our findings show that CPEB1 is hyperactive in rat glioblastoma cells and is regulating an important cohort of mRNAs whose increased translation is fueling the progression of tumor proliferation and dispersal in the brain. Thus, targeting CPEB1-mediated mRNA translation might be a sound therapeutic approach. Mol Cancer Res; 11(2); 149-60. Ó2012 AACR.

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“…We argue that these findings point to biological processes used by the parasite to survive drug pressure or circumvent the action of antimalarial compounds. Other genes of interest include those encoding three ABC transporters-a class of transporters known to modulate drug responses in other organisms (28)-and genes proposed to modulate chromatin (29,30), DNA repair (31, 32), or RNA binding (33), pathways that have been shown to potentially be altered in response to drug pressure.…”

Section: Discussionmentioning

confidence: 99%

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

Park

Lukens

Neafsey

et al. 2012

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

108

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Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite-the deadliest of those that cause malaria-is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites' in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.

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Cytoplasmic Metadherin (MTDH) Provides Survival Advantage under Conditions of Stress by Acting as RNA-binding Protein

Cited by 50 publications

References 31 publications

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

CPEB1 Regulates the Expression of MTDH/AEG-1 and Glioblastoma Cell Migration

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

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