Journal article
RABL6A Regulates Schwann Cell Senescence in an RB1-Dependent Manner
International journal of molecular sciences, Vol.22(10), p.5367
05/20/2021
DOI: 10.3390/ijms22105367
PMCID: PMC8161079
PMID: 34065204
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.
Details
- Title: Subtitle
- RABL6A Regulates Schwann Cell Senescence in an RB1-Dependent Manner
- Creators
- Jordan L KohlmeyerCourtney A KaemmerShaikamjad UmesalmaFrancoise A GourroncAloysius J KlingelhutzDawn E Quelle
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.22(10), p.5367
- DOI
- 10.3390/ijms22105367
- PMID
- 34065204
- PMCID
- PMC8161079
- NLM abbreviation
- Int J Mol Sci
- ISSN
- 1422-0067
- eISSN
- 1422-0067
- Grant note
- DOI: 10.13039/100001545, name: Children's Tumor Foundation, award: Synodos for Neurofibromatosis-1, Young Investigator Award; DOI: 10.13039/100011343, name: Holden Comprehensive Cancer Center, University of Iowa, award: Sarcoma Multidisciplinary Oncology Group Pilot Award; DOI: 10.13039/100000054, name: National Cancer Institute, award: P30 CA086862
- Language
- English
- Date published
- 05/20/2021
- Academic Unit
- Microbiology and Immunology; Pathology; Radiation Oncology; Neuroscience and Pharmacology
- Record Identifier
- 9984080410202771
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