PUBLICATION
Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2
- Authors
- Mushtaq, M., Kovalevska, L., Darekar, S., Abramsson, A., Zetterberg, H., Kashuba, V., Klein, G., Arsenian-Henriksson, M., Kashuba, E.
- ID
- ZDB-PUB-200624-6
- Date
- 2020
- Source
- Proceedings of the National Academy of Sciences of the United States of America 117(27): 15673-15683 (Journal)
- Registered Authors
- Zetterberg, Henrik
- Keywords
- cell immortalization, embryogenesis, stemness and differentiation, tumorigenesis
- MeSH Terms
-
- Animals
- Cell Differentiation/genetics
- Cell Proliferation/genetics
- Cell Self Renewal/genetics
- Fibroblasts/metabolism
- Gene Expression Regulation, Developmental/genetics
- Histones/genetics
- Human Embryonic Stem Cells/metabolism
- Humans
- Kruppel-Like Transcription Factors/genetics
- Mice
- Mitochondria/genetics*
- Mitochondria/metabolism
- Mouse Embryonic Stem Cells/metabolism*
- Polycomb Repressive Complex 1/genetics
- Retinoblastoma Binding Proteins/genetics*
- Ribosomal Proteins/chemistry
- Ribosomal Proteins/genetics*
- Tumor Microenvironment/genetics
- Ubiquitin-Protein Ligases/genetics
- PubMed
- 32571933 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Mushtaq, M., Kovalevska, L., Darekar, S., Abramsson, A., Zetterberg, H., Kashuba, V., Klein, G., Arsenian-Henriksson, M., Kashuba, E. (2020) Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2. Proceedings of the National Academy of Sciences of the United States of America. 117(27):15673-15683.
Abstract
Stemness encompasses the capability of a cell for self-renewal and differentiation. The stem cell maintains a balance between proliferation, quiescence, and regeneration via interactions with the microenvironment. Previously, we showed that ectopic expression of the mitochondrial ribosomal protein S18-2 (MRPS18-2) led to immortalization of primary fibroblasts, accompanied by induction of an embryonic stem cell (ESC) phenotype. Moreover, we demonstrated interaction between S18-2 and the retinoblastoma-associated protein (RB) and hypothesized that the simultaneous expression of RB and S18-2 is essential for maintaining cell stemness. Here, we experimentally investigated the role of S18-2 in cell stemness and differentiation. Concurrent expression of RB and S18-2 resulted in immortalization of Rb1-/- primary mouse embryonic fibroblasts and in aggressive tumor growth in severe combined immunodeficiency mice. These cells, which express both RB and S18-2 at high levels, exhibited the potential to differentiate into various lineages in vitro, including osteogenic, chondrogenic, and adipogenic lineages. Mechanistically, S18-2 formed a multimeric protein complex with prohibitin and the ring finger protein 2 (RNF2). This molecular complex increased the monoubiquitination of histone H2ALys119, a characteristic trait of ESCs, by enhanced E3-ligase activity of RNF2. Furthermore, we found enrichment of KLF4 at the S18-2 promoter region and that the S18-2 expression is positively correlated with KLF4 levels. Importantly, knockdown of S18-2 in zebrafish larvae led to embryonic lethality. Collectively, our findings suggest an important role for S18-2 in cell stemness and differentiation and potentially also in cancerogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping