RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage
RNA-binding protein HuR modulates the stability and translational efficiency of messenger RNAs (mRNAs) encoding essential components of the cellular proliferation, growth and survival pathways. Consistent with these functions, HuR levels are often elevated in cancer cells and reduced in senescent an...
| Main Authors: | , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2013
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/96896 http://hdl.handle.net/10220/10011 |
| _version_ | 1811689692497707008 |
|---|---|
| author | Dai, Weijun Zhang, Gen Makeyev, Eugene V. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Dai, Weijun Zhang, Gen Makeyev, Eugene V. |
| author_sort | Dai, Weijun |
| collection | NTU |
| description | RNA-binding protein HuR modulates the stability and translational efficiency of messenger RNAs (mRNAs) encoding essential components of the cellular proliferation, growth and survival pathways. Consistent with these functions, HuR levels are often elevated in cancer cells and reduced in senescent and quiescent cells. However, the molecular mechanisms that control HuR expression are poorly understood. Here we show that HuR protein autoregulates its abundance through a negative feedback loop that involves
interaction of the nuclear HuR protein with a GU-rich element (GRE) overlapping with the HuR major polyadenylation signal (PAS2). An increase in the cellular HuR protein levels stimulates the expression of long HuR mRNA species containing an AU-rich element (ARE) that destabilizes the mRNAs and thus reduces the protein production output. The PAS2 read-through occurs due to a reduced recruitment of the CstF-64 subunit of the pre-mRNA cleavage stimulation factor in the presence of the GRE-bound HuR. We propose that this mechanism maintains HuR homeostasis in proliferating cells. Since only the nuclear HuR is expected to contribute to the auto-regulation, our model may explain the longstanding observation that the increase in the total HuR expression in cancer cells often correlates with the accumulation of its substantial fraction in the cytoplasm. |
| first_indexed | 2024-10-01T05:52:09Z |
| format | Journal Article |
| id | ntu-10356/96896 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:52:09Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | ntu-10356/968962023-02-28T17:03:21Z RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage Dai, Weijun Zhang, Gen Makeyev, Eugene V. School of Biological Sciences DRNTU::Science::Biological sciences DRNTU::Science::Biological sciences::Human anatomy and physiology::Deoxyribonucleic acids RNA-binding protein HuR modulates the stability and translational efficiency of messenger RNAs (mRNAs) encoding essential components of the cellular proliferation, growth and survival pathways. Consistent with these functions, HuR levels are often elevated in cancer cells and reduced in senescent and quiescent cells. However, the molecular mechanisms that control HuR expression are poorly understood. Here we show that HuR protein autoregulates its abundance through a negative feedback loop that involves interaction of the nuclear HuR protein with a GU-rich element (GRE) overlapping with the HuR major polyadenylation signal (PAS2). An increase in the cellular HuR protein levels stimulates the expression of long HuR mRNA species containing an AU-rich element (ARE) that destabilizes the mRNAs and thus reduces the protein production output. The PAS2 read-through occurs due to a reduced recruitment of the CstF-64 subunit of the pre-mRNA cleavage stimulation factor in the presence of the GRE-bound HuR. We propose that this mechanism maintains HuR homeostasis in proliferating cells. Since only the nuclear HuR is expected to contribute to the auto-regulation, our model may explain the longstanding observation that the increase in the total HuR expression in cancer cells often correlates with the accumulation of its substantial fraction in the cytoplasm. Published version 2013-05-28T01:23:16Z 2019-12-06T19:36:26Z 2013-05-28T01:23:16Z 2019-12-06T19:36:26Z 2011 2011 Journal Article Dai, W., Zhang, G., & Makeyev, E. V. (2011). RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage. Nucleic Acids Research, 40(2), 787-800. https://hdl.handle.net/10356/96896 http://hdl.handle.net/10220/10011 10.1093/nar/gkr783 21948791 en Nucleic acids research © 2011 The Author(s). This paper was published in Nucleic Acids Research and is made available as an electronic reprint (preprint) with permission of The Author(s). The paper can be found at the following official DOI: [http://dx.doi.org/10.1093/nar/gkr783]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences DRNTU::Science::Biological sciences::Human anatomy and physiology::Deoxyribonucleic acids Dai, Weijun Zhang, Gen Makeyev, Eugene V. RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage |
| title | RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage |
| title_full | RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage |
| title_fullStr | RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage |
| title_full_unstemmed | RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage |
| title_short | RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage |
| title_sort | rna binding protein hur autoregulates its expression by promoting alternative polyadenylation site usage |
| topic | DRNTU::Science::Biological sciences DRNTU::Science::Biological sciences::Human anatomy and physiology::Deoxyribonucleic acids |
| url | https://hdl.handle.net/10356/96896 http://hdl.handle.net/10220/10011 |
| work_keys_str_mv | AT daiweijun rnabindingproteinhurautoregulatesitsexpressionbypromotingalternativepolyadenylationsiteusage AT zhanggen rnabindingproteinhurautoregulatesitsexpressionbypromotingalternativepolyadenylationsiteusage AT makeyeveugenev rnabindingproteinhurautoregulatesitsexpressionbypromotingalternativepolyadenylationsiteusage |