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RABL6A Regulates Schwann Cell Senescence in an RB1-Dependent Manner.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 May 20; Vol. 22 (10). Date of Electronic Publication: 2021 May 20. - Publication Year :
- 2021
-
Abstract
- Schwann cells are normally quiescent, myelinating glia cells of the peripheral nervous system. Their aberrant proliferation and transformation underlie the development of benign tumors (neurofibromas) as well as deadly malignant peripheral nerve sheath tumors (MPNSTs). We discovered a new driver of MPNSTs, an oncogenic GTPase named RABL6A, that functions in part by inhibiting the RB1 tumor suppressor. RB1 is a key mediator of cellular senescence, a permanent withdrawal from the cell cycle that protects against cell immortalization and transformation. Based on the RABL6A-RB1 link in MPNSTs, we explored the hypothesis that RABL6A promotes Schwann cell proliferation and abrogates their senescence by inhibiting RB1. Using sequentially passaged normal human Schwann cells (NHSCs), we found that the induction of replicative senescence was associated with reduced expression of endogenous RABL6A. Silencing RABL6A in low passage NHSCs caused premature stress-induced senescence, which was largely rescued by co-depletion of RB1. Consistent with those findings, Rabl6 -deficient MEFs displayed impaired proliferation and accelerated senescence compared to wildtype MEFs. These results demonstrate that RABL6A is required for maintenance of proper Schwann cell proliferation and imply that aberrantly high RABL6A expression may facilitate malignant transformation.
- Subjects :
- Carcinogenesis metabolism
Cell Cycle physiology
Cell Proliferation physiology
Cell Transformation, Neoplastic metabolism
Cells, Cultured
HEK293 Cells
Humans
Neurofibroma metabolism
Neurofibrosarcoma metabolism
Cellular Senescence physiology
Oncogene Proteins metabolism
Retinoblastoma Binding Proteins metabolism
Schwann Cells metabolism
Schwann Cells physiology
Ubiquitin-Protein Ligases metabolism
rab GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 34065204
- Full Text :
- https://doi.org/10.3390/ijms22105367