ROLE OF AU-RICH ELEMENT (ARE) BINDING PROTEIN HuR IN POST-TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION IN MAMMALIAN CELLS
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
ROLE OF AU-RICH ELEMENT (ARE) BINDING PROTEIN HuR
IN POST-TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION IN
MAMMALIAN CELLS
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| Creator |
Mukherjee, Kamalika
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| Subject |
Molecular & Human Genetics
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| Description |
miRNAs, the 22 nucleotide long but stable non-coding RNAs, form miRNP
complexes with Argonaute proteins which thereby bind to the 3’UTR of target
messages. miRNPs not only cause translational repression of target genes but
also destabilize them. During stress, RNA binding protein, HuR, binds to the
AU-rich elements of target mRNAs, stabilises them and facilitates their
translation. Interestingly, a reduction in cellular miR-122 level of Huh7 cells
upon amino acid starvation was observed, with an increase in extracellular
vesicle (EV)-associated miR-122 level of starved cells. In this context a new
role of ELAV protein HuR was identified. HuR accelerates the EVs-mediated
export of miRNAs in human cells. The protein is both necessary and sufficient
for the export of corresponding miRNAs.
The mechanism behind this phenomenon was studied and it was found
that in amino acid starved cells, HuR and miRNPs bind to the common target
mRNAs in a mutually exclusive manner. HuR replaces miRNPs from target
messages. HuR also reversibly binds with miRNAs and replaces them from
Ago2 on endoplasmic reticulum. This HuR-miR-122 binding is specific for
miR-122 and in this context and RRMIII of HuR is necessary for this HuRmiRNA
binding.
In this study it was also found that HuR undergoes ubiquitination on
multivesicular bodies (MVBs). This ubiquitination further helps in HuRmiRNA
unbinding on MVBs and the resulting HuR-unloaded miRNAs get
exported out via EVs. It was known that, the 110 amino acids long segment
required for ubiquitination of HuR, spans to its hinge region. Interestingly, the
deletion mutant of HuR devoid of hinge region, failed to promote EV-mediated
2
miR-122 export. Therefore, both HuR-miR-122 binding and ubiquitinationmediated
release are necessary for HuR-mediated extracellular export of miR122
via EVs.
This EV-mediated extracellular export of miRNAs delimits the cellularmiRNA levels not only in starved hepatic cells but also in breast cancer cells and macrophage cells. Therefore, HuR, by modulating extracellular export of miRNAs, controls stress response in amino acid starved Huh7 cells. It further
controls cell senescence in MDA-MB-231 breast cancer cells and proinflammatory
miRNA levels in RAW 264.7 macrophage like cells.
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| Date |
2017
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2770/1/PhD_Thesis_Kamalika_Mukherjee.pdf
Mukherjee, Kamalika (2017) ROLE OF AU-RICH ELEMENT (ARE) BINDING PROTEIN HuR IN POST-TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION IN MAMMALIAN CELLS. PhD thesis, University of Calcutta. |
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| Relation |
http://www.eprints.iicb.res.in/2770/
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