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IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells.

ABSTRACT: RNA binding proteins mediate global regulation at the level of transcriptome and translatome of a cell. We studied the global level expression changes regulated by IMP3 in transcriptome and translatome by performing microarray using total cellular RNA and heavy polysome derived RNA of IMP3 silenced glioma cells respectively. Differentially regulated transcripts at the transcriptome level (n = 2388) and at the level of translatome (n = 479) were identified. Further, these transcripts were classified as direct and indirect targets on the basis of presence of IMP3 binding site. Additional investigation revealed that direct targets at transcriptome level were found to be associated with processes related to cell cycle, whereas direct targets at the translatome level participated in apoptosis related pathways. Probable mechanism of indirect regulation at both the levels is also investigated. Collectively, our study reveals multi-level gene expression regulation imposed by IMP3 in glioma cells.

SUBMITTER: Bhargava S

PROVIDER: S-EPMC5790340 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells.

Bhargava Shruti S Patil Vikas V Shah Riyaz Ahmad RA Somasundaram Kumaravel K

Cancer biology & therapy 20171219 1

RNA binding proteins mediate global regulation at the level of transcriptome and translatome of a cell. We studied the global level expression changes regulated by IMP3 in transcriptome and translatome by performing microarray using total cellular RNA and heavy polysome derived RNA of IMP3 silenced glioma cells respectively. Differentially regulated transcripts at the transcriptome level (n = 2388) and at the level of translatome (n = 479) were identified. Further, these transcripts were classif ...[more]

PMID: 28485999

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Project description:BackgroundMEK1/ERK signaling pathway plays an important role in most tumor progression, including colorectal cancer (CRC), however, MEK1-targeting therapy has little effective in treating CRC patients, indicating there may be a complex mechanism to activate MEK1/ERK signaling pathway except RAS activated mechanism.MethodsTo investigate the clinical significance of IMP3, we analyzed its expression levels in publicly available dataset and samples from Fudan University Shanghai Cancer Center. The effects of IMP3 on proliferation, migration, and invasion were determined by in vitro and in vivo experiments. To investigate the role of IMP3 in colon carcinogenesis, conditional IMP3 knockout C57BL/6 mice was generated. The IMP3/MEKK1/MEK/ERK signaling axis in CRC was screened and validated by RNA-sequencing, RNA immunoprecipitation, luciferase reporter and western blot assays.ResultsWe find RNA binding protein IMP3 directly bind to MEKK1 mRNA 3'-UTR, which regulates its stability, promote MEKK1 expression and sequentially activates MEK1/ERK signaling. Functionally, IMP3 promote the malignant biological process of CRC cells via MEKK1/MEK1/ERK signaling pathway both in vitro and in vivo, Moreover, IMP3-/- mice show decreased the expression of MEKK1 as well as colorectal tumors compared with wild-type mice after treatment with azoxymethane/dextran sodium sulfate. Clinically, the expression of IMP3 and MEKK1 are positive correlated, and concomitant IMP3 and MEKK1 protein levels negatively correlate with metastasis in CRC patients. In addition, MEK1 inhibitor in combination with shRNA-IMP3 have a synergistic effect both in vitro and in vivo.ConclusionOur study demonstrates that IMP3 regulates MEKK1 in CRC, thus activating the MEK1/ERK signaling in the progression of colorectal cancer, Furthermore, these results provide new insights into potential applications for combining MEK1 inhibitors with other target therapy such as IMP3 in preclinical trials for CRC patients.

Dataset Information

IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells.

Publications

IGF2 mRNA binding protein 3 (IMP3) mediated regulation of transcriptome and translatome in glioma cells.

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