Study on molecular mechanism of anti-tumor activity by splicing modulation
| Project/Area Number |
20K15420
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 37030:Chemical biology-related
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
Chhipi-Shrestha Jagat 国立研究開発法人理化学研究所, 環境資源科学研究センター, 特別研究員 (40851233)
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | spliceostatin A / splicing modulation / proteotoxic stress / aggregation / SSA / cancer / translation / Next gen sequencing / Splicing modulation / Tumor |
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| Outline of Research at the Start |
Primarily, to understand the comprehensive changes in transcriptome and translatome genome-wide upon splicing modulation in different cell lines, we will perform the simultaneous RNA sequencing and ribosome profiling respectively in the HeLa S3 cell lysate after SSA treatment.
PLAN 1 will depicts the difference in drug sensitivity to the different cell lines with respect to the normal cells whereas PLAN 2 will help in revealing the gain of function by the candidate genes that will be expressed upon splicing modulation.
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| Outline of Final Research Achievements |
Splicing modulation by Spliceostatin A (SSA) inhibit the global translation process by mTORC1 inactivation. System-wide analysis using RNA sequencing (transcriptome), ribosome profiling (translatome) and BONCAT mass spectrometry (Proteome)upon splicing inhibition produced the substantial number of exon-intron chimeric proteins from the retained introns which have the intrinsically disordered regions providing condensate-prone properties. The BONCAT and the biochemical experiments verified the production of aggregation-prone intron proteins causing cellular proteotoxic stress in tumor cell. activation of JNK pathway to disintegrate the mTORC1 components inactivating its function to reduce the mTORC1 mediated translation.
mTORC1 signaling pathway being one of the key molecular pathway upregulated in the number of cancers, and hence SSA seems to plays an important anti-tumor mechanism via mTORC1 inhibition through the proteotoxic stress from the truncated chimeric-intron proteins.
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| Academic Significance and Societal Importance of the Research Achievements |
SSA induce proteotoxicity from intron-derived truncated proteins which activates JNK inhibiting mTORC1 pathways, essential pathway in cancer cell survival. Hence, SSA ultimately attenuates global protein synthesis, this mechanism of action may not be exclusive but is vital one found from this study.
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Report
(3 results)
Research Products
(6 results)
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[Journal Article] Spliceostatin A interaction with SF3B1 limits U1 snRNP availability and causes premature cleavage and polyadenylation.2021
Author(s)
Yoshimoto, R., Chhipi-Shrestha, J.K., Schneider-Poetsch, T., Furuno, M., Burroughs, A.M., Noma, S., Suzuki, H., Hayashizaki, Y., Mayeda, A., Nakagawa, S., Kaida, D., Iwasaki, S., Yoshida, M.
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Journal Title
Cell Chem. Biol.
Volume: -
Issue: 9
Pages: 1356-1365
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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