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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
A Nucleolar Stress-Specific p53-miR-101 Molecular Circuit Functions as an Intrinsic Tumor-Suppressor Network
Yuko Fujiwara1, Motonobu Saito2, Ana I Robles3
1Laboratory of Molecular Carcinogenesis, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Background:
Activation of intrinsic p53 tumor-suppressor (TS) pathways is an important principle underlying cancer chemotherapy. It is necessary to elucidate the precise regulatory mechanisms of these networks to create new treatment strategies.
Methods:
Comprehensive analyses were carried out by microarray. Expression of miR-101 was analyzed by clinical samples of lung adenocarcinomas.
Findings:
We discovered a functional link between p53 and miR-101, which form a molecular circuit in response to nucleolar stress. Inhibition of RNA polymerase I (Pol I) transcription resulted in the post-transcriptional activation of miR-101 in a p53-dependent manner. miR-101 induced G2 phase-specific feedback regulation of p53 through direct repression of its target, EG5, resulting in elevated phosphorylation of ATM. In lung cancer patients, low expression of miR-101 was associated with significantly poorer prognosis exclusively in p53 WT cases. miR-101 sensitized cancer cells to Pol I transcription inhibitors and strongly repressed xenograft growth in mice. Interestingly, the most downstream targets of this circuit included the inhibitor of apoptosis proteins (IAPs). Repression of cIAP1 by a selective inhibitor, birinapant, promoted activation of the apoptosis induced by Pol I transcription inhibitor in p53 WT cancer cells.
Interpretation:
Our findings indicate that the p53-miR-101 circuit is a component of an intrinsic TS network formed by nucleolar stress, and that mimicking activation of this circuit represents a promising strategy for cancer therapy. FUND: National Institute of Biomedical Innovation, Ministry of Education, Culture, Sports & Technology of Japan, Japan Agency for Medical Research and Development.
Insights
A new p53-miR-101 molecular circuit activates tumor suppression in response to nucleolar stress. Activating this circuit shows promise for cancer therapy by sensitizing cells to inhibitors and repressing tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p53 tumor-suppressor (TS) pathway is crucial in cancer chemotherapy.
- Understanding regulatory mechanisms of p53 networks is vital for developing novel cancer treatments.
Purpose of the Study:
- To elucidate the functional link between p53 and miR-101 in response to nucleolar stress.
- To investigate the therapeutic potential of activating the p53-miR-101 circuit in cancer.
Main Methods:
- Comprehensive gene expression analysis using microarrays.
- Analysis of miR-101 expression in clinical lung adenocarcinoma samples.
- Investigated p53-dependent regulation of miR-101 following RNA polymerase I (Pol I) inhibition.
Main Results:
- Discovered a p53-miR-101 molecular circuit activated by nucleolar stress.
- miR-101 represses EG5, leading to feedback regulation of p53 and elevated ATM phosphorylation.
- Low miR-101 expression correlated with poor prognosis in p53 wild-type (WT) lung cancer patients.
- miR-101 sensitized cancer cells to Pol I inhibitors and inhibited xenograft growth.
- The circuit targets inhibitor of apoptosis proteins (IAPs), and cIAP1 inhibition enhanced apoptosis.
Conclusions:
- The p53-miR-101 circuit is part of an intrinsic tumor-suppressor network activated by nucleolar stress.
- Mimicking the activation of this circuit presents a promising strategy for cancer therapy.
- Combined inhibition of Pol I transcription and IAPs may enhance efficacy in p53 WT cancers.
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