Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2

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Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2

Mushtaq, M. (author): Karolinska Institutet

Kovalevska, L. (author)

Darekar, S. (author): Karolinska Institutet

Abramsson, Alexandra, 1973 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry

Zetterberg, Henrik, 1973 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology

Kashuba, V. (author): Karolinska Institutet

Klein, G. (author)

Arsenian-Henriksson, M. (author)

Kashuba, E. (author): Karolinska Institutet

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(creator_code:org_t)

2020-06-22
2020
English.
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:27, s. 15673-15683

Related links:: https://www.pnas.org...; show more...; https://gup.ub.gu.se...; https://doi.org/10.1...; http://kipublication...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

Stemness encompasses the capability of a cell for self-renewal and differentiation. The stern 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 stern 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 sternness. Here, we experimentally investigated the role of S18-2 in cell sternness 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 H2A(Lys119), a characteristic trait of ESC5, 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 sternness and differentiation and potentially also in cancerogenesis.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)

Keyword

stemness and differentiation
cell immortalization
embryogenesis
tumorigenesis
retinoblastoma protein
gene-expression
histone h2a
interacts
rnf2
differentiation
prohibitin
e2f1
immortalization
repression
Science & Technology - Other Topics

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ref (subject category)
art (subject category)

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By the author/editor: Mushtaq, M.; Kovalevska, L.; Darekar, S.; Abramsson, Alexa ...; Zetterberg, Henr ...; Kashuba, V.; show more...; Klein, G.; Arsenian-Henriks ...; Kashuba, E.; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...

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By the university: University of Gothenburg; Karolinska Institutet

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