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Long non-coding RNA TILR constitutively represses TP53 and apoptosis in lung cancer
Mika Iwai1, Taisuke Kajino1,2, Masahiro Nakatochi3
1Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Abstract:
Non-coding RNAs have an integral regulatory role in numerous functions related to lung cancer development. Here, we report identification of a novel lncRNA, termed TP53-inhibiting lncRNA (TILR), which was found to function as a constitutive negative regulator of p53 expression, including activation of downstream genes such as p21 and MDM2, and induction of apoptosis. A proteomic search for TILR-associated proteins revealed an association with PCBP2, while the mid-portion of TILR was found to be required for both PCBP2 and p53 mRNA binding. In addition, depletion of PCBP2 resulted in phenocopied effects of TILR silencing. TILR was also shown to suppress p53 expression in a post-transcriptional manner, as well as via a positive feedback loop involving p53 and Fanconi anemia pathway genes. Taken together, the present findings clearly demonstrate that TILR constitutively inhibits p53 expression in cooperation with PCBP2, thus maintaining p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.
Insights
A novel long non-coding RNA, TP53-inhibiting lncRNA (TILR), suppresses p53 expression in lung cancer. TILR, with PCBP2, maintains low p53 activity, preventing unnecessary apoptosis.
Area of Science:
- Molecular Biology
- Cancer Research
- RNA Biology
Background:
- Non-coding RNAs play crucial roles in lung cancer development.
- The precise regulatory mechanisms involving non-coding RNAs and tumor suppressors like p53 are not fully understood.
Purpose of the Study:
- To identify and characterize novel non-coding RNAs involved in lung cancer regulation.
- To elucidate the function of a newly discovered lncRNA, TP53-inhibiting lncRNA (TILR), in controlling p53 expression.
Main Methods:
- Proteomic analysis to identify TILR-interacting proteins.
- RNA binding assays to determine TILR's interaction with p53 mRNA.
- Gene silencing experiments (siRNA) to assess the functional impact of TILR and PCBP2.
- Analysis of downstream gene expression and apoptosis induction.
Main Results:
- Identification of a novel long non-coding RNA, TP53-inhibiting lncRNA (TILR).
- TILR acts as a negative regulator of p53 expression, affecting p21 and MDM2.
- TILR binds to p53 mRNA via PCBP2, suppressing p53 post-transcriptionally.
- TILR influences p53 and Fanconi anemia pathway genes, creating a feedback loop.
Conclusions:
- TILR constitutively inhibits p53 expression in conjunction with PCBP2.
- This inhibition maintains low p53 transcriptional activity, preventing spurious apoptosis.
- TILR represents a potential therapeutic target in lung cancer.
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