| 1. |
- Kashuba, E, et al.
(författare)
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EBV-encoded EBNA-6 binds and targets MRS18-2 to the nucleus, resulting in the disruption of pRb-E2F1 complexes
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 105:14, s. 5489-5494
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Tidskriftsartikel (refereegranskat)abstract
- Epstein–Barr virus (EBV), like other DNA tumor viruses, induces an S-phase in the natural host cell, the human B lymphocyte. This is linked with blast transformation. It is believed that the EBV-encoded nuclear antigen 6 (EBNA-6) is involved in the regulation of cell cycle entry. However, the possible mechanism of this regulation is not approached. In our current study, we found that EBNA-6 binds to a MRPS18-2 protein, and targets it to the nucleus. We found that MRPS18-2 binds to both hypo- and hyperphosphorylated forms of Rb protein specifically. This binding targets the small pocket of pRb, which is a site of interaction with E2F1. The MRPS18-2 competes with the binding of E2F1 to pRb, thereby raising the level of free E2F1. Our experimental data suggest that EBNA-6 may play a major role in the entry of EBV infected B cells into the S phase by binding to and raising the level of nuclear MRPS18-2, protein. This would inhibit pRb binding to E2F1 competitively and lift the block preventing S-phase entry.
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| 2. |
- Kashuba, E, et al.
(författare)
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MRPS18-2 protein immortalizes primary rat embryonic fibroblasts and endows them with stem cell-like properties
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 106:47, s. 19866-19871
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Tidskriftsartikel (refereegranskat)abstract
- We report that the overexpression of mitochondrial ribosomal protein MRPS18–2 (S18–2) can immortalize primary rat embryonic fibroblasts (REFs). The immortalized cells (18IM) lose contact inhibition, form foci, and are capable of anchorage-independent growth. Concurrently, mesodermal markers, such as vimentin, smooth muscle actin, and Fut4, disappear completely. 18IM cells express embryonic stem cell markers, such as SSEA-1, Sox2, and Oct3/4. In confluent cultures, a portion of cells also express ectoderm- and endoderm-specific pan-keratin, ectoderm-specific beta-III-tubulin, mesoderm-specific MHC class II, and become stainable for fat with Oil red O. None of these changes was detected in c-myc+Ha-ras (MR)-transformed cells. In immunodeficient mice, 18IM cells formed small transiently growing tumors that have down-regulated SSEA-1 and showed pan-keratin staining. We conclude that S18–2 can immortalize REFs and induces them to express stem cell traits.
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| 3. |
- Klein, G
(författare)
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Rejection antigens in chemically induced tumors
- 1997
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 94:12, s. 5991-5992
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Klein, G
(författare)
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Reply to Bredberg: The voice of the whale
- 2009
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Ingår i: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 106:20, s. E52-E52
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Klein, G
(författare)
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Simian virus 40 and the human mesothelium
- 2000
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 97:18, s. 9830-9831
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Klein, G
(författare)
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Toward a genetics of cancer resistance
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 106:3, s. 859-863
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Tidskriftsartikel (refereegranskat)abstract
- Two of three humans never get cancer. Even the majority of heavy smokers remain cancer free. Is this a matter of chance, or are there cancer-resistant genotypes? Based on the evidence discussed, it would appear that evolution has favored a limited number of relatively common resistance genes that may nip incipient cancerous foci in the bud, i.e., to stop them at their inception. It is further suggested that resistance genes may act at the level of tissue organization in a dominant fashion.
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| 7. |
- Mushtaq, M., et al.
(författare)
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Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2
- 2020
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Ingår i: 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
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- WENNBORG, A, et al.
(författare)
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A human RNase E-like activity that cleaves RNA sequences involved in mRNA stability control
- 1995
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 92:16, s. 7322-7326
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Tidskriftsartikel (refereegranskat)abstract
- We have detected an endoribonucleolytic activity in human cell extracts that processes the Escherichia coli 9S RNA and outer membrane protein A (ompA) mRNA with the same specificity as RNase E from E. coli. The human enzyme was partially purified by ion-exchange chromatography, and the active fractions contained a protein that was detected with antibodies shown to recognize E. coli RNase E. RNA containing four repeats of the destabilizing motif AUUUA and RNA from the 3' untranslated region of human c-myc mRNA were also found to be cleaved by E. coli RNase E and its human counterpart in a fashion that may suggest a role of this activity in mammalian mRNA decay. It was also found that RNA containing more than one AUUUA motif was cleaved more efficiently than RNA with only one or a mutated motif. This finding of a eukaryotic endoribonucleolytic activity corresponding to RNase E indicates an evolutionary conservation of the components of mRNA degradation systems.
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