Journal article
RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21
Journal of translational medicine, Vol.22(1), pp.204-18
02/26/2024
DOI: 10.1186/s12967-024-04985-3
PMCID: PMC10895901
PMID: 38409136
Abstract
Prior evidence demonstrated that Regulator of G protein Signaling 6 (RGS6) translocates to the nucleolus in response to cytotoxic stress though the functional significance of this phenomenon remains unknown.
Utilizing in vivo gene manipulations in mice, primary murine cardiac cells, human cell lines and human patient samples we dissect the participation of a RGS6-nucleolin complex in chemotherapy-dependent cardiotoxicity.
Here we demonstrate that RGS6 binds to a key nucleolar protein, Nucleolin, and controls its expression and activity in cardiomyocytes. In the human myocyte AC-16 cell line, induced pluripotent stem cell derived cardiomyocytes, primary murine cardiomyocytes, and the intact murine myocardium tuning RGS6 levels via overexpression or knockdown resulted in diametrically opposed impacts on Nucleolin mRNA, protein, and phosphorylation.RGS6 depletion provided marked protection against nucleolar stress-mediated cell death in vitro, and, conversely, RGS6 overexpression suppressed ribosomal RNA production, a key output of the nucleolus, and triggered death of myocytes. Importantly, overexpression of either Nucleolin or Nucleolin effector miRNA-21 counteracted the pro-apoptotic effects of RGS6. In both human and murine heart tissue, exposure to the genotoxic stressor doxorubicin was associated with an increase in the ratio of RGS6/Nucleolin. Preventing RGS6 induction via introduction of RGS6-directed shRNA via intracardiac injection proved cardioprotective in mice and was accompanied by restored Nucleolin/miRNA-21 expression, decreased nucleolar stress, and decreased expression of pro-apoptotic, hypertrophy, and oxidative stress markers in heart.
Together, these data implicate RGS6 as a driver of nucleolar stress-dependent cell death in cardiomyocytes via its ability to modulate Nucleolin. This work represents the first demonstration of a functional role for an RGS protein in the nucleolus and identifies the RGS6/Nucleolin interaction as a possible new therapeutic target in the prevention of cardiotoxicity.
Details
- Title: Subtitle
- RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21
- Creators
- Abhishek Singh Sengar - Centre of Biomedical ResearchManish Kumar - Centre of Biomedical ResearchChetna Rai - Centre of Biomedical Research (CBMR), SGPGI Campus, Raebareli Road, Lucknow, Uttar Pradesh, 226014, IndiaSreemoyee Chakraborti - Centre of Biomedical ResearchDinesh Kumar - Centre of Biomedical ResearchPranesh Kumar - University of LucknowSukhes Mukherjee - All India Institute of Medical Sciences BhopalKausik Mondal - University of KalyaniAdele Stewart - Florida Atlantic UniversityBiswanath Maity - Centre of Biomedical Research
- Resource Type
- Journal article
- Publication Details
- Journal of translational medicine, Vol.22(1), pp.204-18
- DOI
- 10.1186/s12967-024-04985-3
- PMID
- 38409136
- PMCID
- PMC10895901
- ISSN
- 1479-5876
- eISSN
- 1479-5876
- Grant note
- 5/4/1-22/CVD/2022-NCD-I / Indian Council of Medical Research CRG/2022/003455 / Science and Engineering Research Board
- Language
- English
- Date published
- 02/26/2024
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618506002771
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