Abstract

Pre-mRNA splicing is an essential step in gene expression in most eukaryote genes. Here we present the feasibility of a genetically encoded luciferase reporter to monitor the pre-mRNA splicing process in living cells and animals. We showed that the splicing activity change induced by isoginkgetin could be readily visualized in vitro both in a dose and time dependent manner. Moreover, the pre-mRNA splicing process could be also obviously detected in mice by bioluminescence imaging and confirmed by RT-PCR. Our work provided a reporter system that allows high-throughput screening of chemical libraries to identify potential compounds leading to aberrant patterns of splicing.

© 2018 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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  1. J. P. Staley and C. Guthrie, “Mechanical devices of the spliceosome: motors, clocks, springs, and things,” Cell 92(3), 315–326 (1998).
    [Crossref] [PubMed]
  2. M. C. Wahl, C. L. Will, and R. Lührmann, “The spliceosome: design principles of a dynamic RNP machine,” Cell 136(4), 701–718 (2009).
    [Crossref] [PubMed]
  3. D. L. Black, B. Chabot, and J. A. Steitz, “U2 as well as U1 small nuclear ribonucleoproteins are involved in premessenger RNA splicing,” Cell 42(3), 737–750 (1985).
    [Crossref] [PubMed]
  4. M. M. Konarska and P. A. Sharp, “Interactions between small nuclear ribonucleoprotein particles in formation of spliceosomes,” Cell 49(6), 763–774 (1987).
    [Crossref] [PubMed]
  5. R. A. Padgett, M. M. Konarska, P. J. Grabowski, S. F. Hardy, and P. A. Sharp, “Lariat RNA’s as intermediates and products in the splicing of messenger RNA precursors,” Science 225(4665), 898–903 (1984).
    [Crossref] [PubMed]
  6. B. Ruskin, A. R. Krainer, T. Maniatis, and M. R. Green, “Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro,” Cell 38(1), 317–331 (1984).
    [Crossref] [PubMed]
  7. T. K. Blackwell and A. K. Walker, “Transcription mechanisms,” WormBook 2006, 1–16 (2006).
    [PubMed]
  8. J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
    [Crossref] [PubMed]
  9. A. R. Krainer, T. Maniatis, B. Ruskin, and M. R. Green, “Normal and mutant human beta-globin pre-mRNAs are faithfully and efficiently spliced in vitro,” Cell 36(4), 993–1005 (1984).
    [Crossref] [PubMed]
  10. M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
    [Crossref] [PubMed]
  11. G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
    [Crossref] [PubMed]
  12. T. R. Cech, “Self-splicing of group I introns,” Annu. Rev. Biochem. 59(1), 543–568 (1990).
    [Crossref] [PubMed]
  13. B. A. Sullenger and T. R. Cech, “Ribozyme-mediated repair of defective mRNA by targeted, trans-splicing,” Nature 371(6498), 619–622 (1994).
    [Crossref] [PubMed]
  14. A. S. Gauchez, A. Du Moulinet D’Hardemare, J. Lunardi, J. P. Vuillez, and D. Fagret, “Potential use of radiolabeled antisense oligonucleotides in oncology,” Anticancer Res. 19(6B), 4989–4997 (1999).
    [PubMed]
  15. M. K. So, G. Gowrishankar, S. Hasegawa, J. K. Chung, and J. Rao, “Imaging target mRNA and siRNA-mediated gene silencing in vivo with ribozyme-based reporters,” ChemBioChem 9(16), 2682–2691 (2008).
    [Crossref] [PubMed]
  16. S. Hasegawa, G. Gowrishankar, and J. Rao, “Detection of mRNA in mammalian cells with a split ribozyme reporter,” ChemBioChem 7(6), 925–928 (2006).
    [Crossref] [PubMed]
  17. S. A. Woodson and T. R. Cech, “Alternative secondary structures in the 5′ exon affect both forward and reverse self-splicing of the Tetrahymena intervening sequence RNA,” Biochemistry 30(8), 2042–2050 (1991).
    [Crossref] [PubMed]
  18. K. O’Brien, A. J. Matlin, A. M. Lowell, and M. J. Moore, “The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing,” J. Biol. Chem. 283(48), 33147–33154 (2008).
    [Crossref] [PubMed]
  19. S. O. Yoon, S. Shin, H. J. Lee, H. K. Chun, and A. S. Chung, “Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression,” Mol. Cancer Ther. 5(11), 2666–2675 (2006).
    [Crossref] [PubMed]
  20. M. Salton and T. Misteli, “Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy,” Trends Mol. Med. 22(1), 28–37 (2016).
    [Crossref] [PubMed]
  21. S. Hasegawa, W. C. Jackson, R. Y. Tsien, and J. Rao, “Imaging Tetrahymena ribozyme splicing activity in single live mammalian cells,” Proc. Natl. Acad. Sci. U.S.A. 100(25), 14892–14896 (2003).
    [Crossref] [PubMed]
  22. S. Hasegawa, J. W. Choi, and J. Rao, “Single-cell detection of trans-splicing ribozyme in vivo activity,” J. Am. Chem. Soc. 126(23), 7158–7159 (2004).
    [Crossref] [PubMed]
  23. M. T. Nasim and I. C. Eperon, “A double-reporter splicing assay for determining splicing efficiency in mammalian cells,” Nat. Protoc. 1(2), 1022–1028 (2006).
    [Crossref] [PubMed]
  24. S. Bhaumik, Z. Walls, M. Puttaraju, L. G. Mitchell, and S. S. Gambhir, “Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing,” Proc. Natl. Acad. Sci. U.S.A. 101(23), 8693–8698 (2004).
    [Crossref] [PubMed]
  25. Z. F. Walls, M. Puttaraju, G. F. Temple, and S. S. Gambhir, “A generalizable strategy for imaging pre-mRNA levels in living subjects using spliceosome-mediated RNA trans-splicing,” J. Nucl. Med. 49(7), 1146–1154 (2008).
    [Crossref] [PubMed]

2016 (1)

M. Salton and T. Misteli, “Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy,” Trends Mol. Med. 22(1), 28–37 (2016).
[Crossref] [PubMed]

2009 (1)

M. C. Wahl, C. L. Will, and R. Lührmann, “The spliceosome: design principles of a dynamic RNP machine,” Cell 136(4), 701–718 (2009).
[Crossref] [PubMed]

2008 (3)

K. O’Brien, A. J. Matlin, A. M. Lowell, and M. J. Moore, “The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing,” J. Biol. Chem. 283(48), 33147–33154 (2008).
[Crossref] [PubMed]

M. K. So, G. Gowrishankar, S. Hasegawa, J. K. Chung, and J. Rao, “Imaging target mRNA and siRNA-mediated gene silencing in vivo with ribozyme-based reporters,” ChemBioChem 9(16), 2682–2691 (2008).
[Crossref] [PubMed]

Z. F. Walls, M. Puttaraju, G. F. Temple, and S. S. Gambhir, “A generalizable strategy for imaging pre-mRNA levels in living subjects using spliceosome-mediated RNA trans-splicing,” J. Nucl. Med. 49(7), 1146–1154 (2008).
[Crossref] [PubMed]

2007 (1)

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

2006 (4)

T. K. Blackwell and A. K. Walker, “Transcription mechanisms,” WormBook 2006, 1–16 (2006).
[PubMed]

S. Hasegawa, G. Gowrishankar, and J. Rao, “Detection of mRNA in mammalian cells with a split ribozyme reporter,” ChemBioChem 7(6), 925–928 (2006).
[Crossref] [PubMed]

S. O. Yoon, S. Shin, H. J. Lee, H. K. Chun, and A. S. Chung, “Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression,” Mol. Cancer Ther. 5(11), 2666–2675 (2006).
[Crossref] [PubMed]

M. T. Nasim and I. C. Eperon, “A double-reporter splicing assay for determining splicing efficiency in mammalian cells,” Nat. Protoc. 1(2), 1022–1028 (2006).
[Crossref] [PubMed]

2005 (1)

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

2004 (2)

S. Bhaumik, Z. Walls, M. Puttaraju, L. G. Mitchell, and S. S. Gambhir, “Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing,” Proc. Natl. Acad. Sci. U.S.A. 101(23), 8693–8698 (2004).
[Crossref] [PubMed]

S. Hasegawa, J. W. Choi, and J. Rao, “Single-cell detection of trans-splicing ribozyme in vivo activity,” J. Am. Chem. Soc. 126(23), 7158–7159 (2004).
[Crossref] [PubMed]

2003 (2)

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

S. Hasegawa, W. C. Jackson, R. Y. Tsien, and J. Rao, “Imaging Tetrahymena ribozyme splicing activity in single live mammalian cells,” Proc. Natl. Acad. Sci. U.S.A. 100(25), 14892–14896 (2003).
[Crossref] [PubMed]

1999 (1)

A. S. Gauchez, A. Du Moulinet D’Hardemare, J. Lunardi, J. P. Vuillez, and D. Fagret, “Potential use of radiolabeled antisense oligonucleotides in oncology,” Anticancer Res. 19(6B), 4989–4997 (1999).
[PubMed]

1998 (1)

J. P. Staley and C. Guthrie, “Mechanical devices of the spliceosome: motors, clocks, springs, and things,” Cell 92(3), 315–326 (1998).
[Crossref] [PubMed]

1994 (1)

B. A. Sullenger and T. R. Cech, “Ribozyme-mediated repair of defective mRNA by targeted, trans-splicing,” Nature 371(6498), 619–622 (1994).
[Crossref] [PubMed]

1991 (1)

S. A. Woodson and T. R. Cech, “Alternative secondary structures in the 5′ exon affect both forward and reverse self-splicing of the Tetrahymena intervening sequence RNA,” Biochemistry 30(8), 2042–2050 (1991).
[Crossref] [PubMed]

1990 (1)

T. R. Cech, “Self-splicing of group I introns,” Annu. Rev. Biochem. 59(1), 543–568 (1990).
[Crossref] [PubMed]

1987 (1)

M. M. Konarska and P. A. Sharp, “Interactions between small nuclear ribonucleoprotein particles in formation of spliceosomes,” Cell 49(6), 763–774 (1987).
[Crossref] [PubMed]

1985 (1)

D. L. Black, B. Chabot, and J. A. Steitz, “U2 as well as U1 small nuclear ribonucleoproteins are involved in premessenger RNA splicing,” Cell 42(3), 737–750 (1985).
[Crossref] [PubMed]

1984 (3)

R. A. Padgett, M. M. Konarska, P. J. Grabowski, S. F. Hardy, and P. A. Sharp, “Lariat RNA’s as intermediates and products in the splicing of messenger RNA precursors,” Science 225(4665), 898–903 (1984).
[Crossref] [PubMed]

B. Ruskin, A. R. Krainer, T. Maniatis, and M. R. Green, “Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro,” Cell 38(1), 317–331 (1984).
[Crossref] [PubMed]

A. R. Krainer, T. Maniatis, B. Ruskin, and M. R. Green, “Normal and mutant human beta-globin pre-mRNAs are faithfully and efficiently spliced in vitro,” Cell 36(4), 993–1005 (1984).
[Crossref] [PubMed]

An, R.

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

Armour, C. D.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

Bhaumik, S.

S. Bhaumik, Z. Walls, M. Puttaraju, L. G. Mitchell, and S. S. Gambhir, “Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing,” Proc. Natl. Acad. Sci. U.S.A. 101(23), 8693–8698 (2004).
[Crossref] [PubMed]

Black, D. L.

D. L. Black, B. Chabot, and J. A. Steitz, “U2 as well as U1 small nuclear ribonucleoproteins are involved in premessenger RNA splicing,” Cell 42(3), 737–750 (1985).
[Crossref] [PubMed]

Blackwell, T. K.

T. K. Blackwell and A. K. Walker, “Transcription mechanisms,” WormBook 2006, 1–16 (2006).
[PubMed]

Cao, W.

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

Castle, J.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

Cech, T. R.

B. A. Sullenger and T. R. Cech, “Ribozyme-mediated repair of defective mRNA by targeted, trans-splicing,” Nature 371(6498), 619–622 (1994).
[Crossref] [PubMed]

S. A. Woodson and T. R. Cech, “Alternative secondary structures in the 5′ exon affect both forward and reverse self-splicing of the Tetrahymena intervening sequence RNA,” Biochemistry 30(8), 2042–2050 (1991).
[Crossref] [PubMed]

T. R. Cech, “Self-splicing of group I introns,” Annu. Rev. Biochem. 59(1), 543–568 (1990).
[Crossref] [PubMed]

Chabot, B.

D. L. Black, B. Chabot, and J. A. Steitz, “U2 as well as U1 small nuclear ribonucleoproteins are involved in premessenger RNA splicing,” Cell 42(3), 737–750 (1985).
[Crossref] [PubMed]

Choi, J. W.

S. Hasegawa, J. W. Choi, and J. Rao, “Single-cell detection of trans-splicing ribozyme in vivo activity,” J. Am. Chem. Soc. 126(23), 7158–7159 (2004).
[Crossref] [PubMed]

Chun, H. K.

S. O. Yoon, S. Shin, H. J. Lee, H. K. Chun, and A. S. Chung, “Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression,” Mol. Cancer Ther. 5(11), 2666–2675 (2006).
[Crossref] [PubMed]

Chung, A. S.

S. O. Yoon, S. Shin, H. J. Lee, H. K. Chun, and A. S. Chung, “Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression,” Mol. Cancer Ther. 5(11), 2666–2675 (2006).
[Crossref] [PubMed]

Chung, J. K.

M. K. So, G. Gowrishankar, S. Hasegawa, J. K. Chung, and J. Rao, “Imaging target mRNA and siRNA-mediated gene silencing in vivo with ribozyme-based reporters,” ChemBioChem 9(16), 2682–2691 (2008).
[Crossref] [PubMed]

Di, L. J.

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

Du Moulinet D’Hardemare, A.

A. S. Gauchez, A. Du Moulinet D’Hardemare, J. Lunardi, J. P. Vuillez, and D. Fagret, “Potential use of radiolabeled antisense oligonucleotides in oncology,” Anticancer Res. 19(6B), 4989–4997 (1999).
[PubMed]

Eperon, I. C.

M. T. Nasim and I. C. Eperon, “A double-reporter splicing assay for determining splicing efficiency in mammalian cells,” Nat. Protoc. 1(2), 1022–1028 (2006).
[Crossref] [PubMed]

Fagret, D.

A. S. Gauchez, A. Du Moulinet D’Hardemare, J. Lunardi, J. P. Vuillez, and D. Fagret, “Potential use of radiolabeled antisense oligonucleotides in oncology,” Anticancer Res. 19(6B), 4989–4997 (1999).
[PubMed]

Gambhir, S. S.

Z. F. Walls, M. Puttaraju, G. F. Temple, and S. S. Gambhir, “A generalizable strategy for imaging pre-mRNA levels in living subjects using spliceosome-mediated RNA trans-splicing,” J. Nucl. Med. 49(7), 1146–1154 (2008).
[Crossref] [PubMed]

S. Bhaumik, Z. Walls, M. Puttaraju, L. G. Mitchell, and S. S. Gambhir, “Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing,” Proc. Natl. Acad. Sci. U.S.A. 101(23), 8693–8698 (2004).
[Crossref] [PubMed]

Gao, Z.

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

Garrett-Engele, P.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

Gauchez, A. S.

A. S. Gauchez, A. Du Moulinet D’Hardemare, J. Lunardi, J. P. Vuillez, and D. Fagret, “Potential use of radiolabeled antisense oligonucleotides in oncology,” Anticancer Res. 19(6B), 4989–4997 (1999).
[PubMed]

Gowrishankar, G.

M. K. So, G. Gowrishankar, S. Hasegawa, J. K. Chung, and J. Rao, “Imaging target mRNA and siRNA-mediated gene silencing in vivo with ribozyme-based reporters,” ChemBioChem 9(16), 2682–2691 (2008).
[Crossref] [PubMed]

S. Hasegawa, G. Gowrishankar, and J. Rao, “Detection of mRNA in mammalian cells with a split ribozyme reporter,” ChemBioChem 7(6), 925–928 (2006).
[Crossref] [PubMed]

Grabowski, P. J.

R. A. Padgett, M. M. Konarska, P. J. Grabowski, S. F. Hardy, and P. A. Sharp, “Lariat RNA’s as intermediates and products in the splicing of messenger RNA precursors,” Science 225(4665), 898–903 (1984).
[Crossref] [PubMed]

Green, M. R.

A. R. Krainer, T. Maniatis, B. Ruskin, and M. R. Green, “Normal and mutant human beta-globin pre-mRNAs are faithfully and efficiently spliced in vitro,” Cell 36(4), 993–1005 (1984).
[Crossref] [PubMed]

B. Ruskin, A. R. Krainer, T. Maniatis, and M. R. Green, “Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro,” Cell 38(1), 317–331 (1984).
[Crossref] [PubMed]

Guo, F. Q.

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

Guthrie, C.

J. P. Staley and C. Guthrie, “Mechanical devices of the spliceosome: motors, clocks, springs, and things,” Cell 92(3), 315–326 (1998).
[Crossref] [PubMed]

Hardy, S. F.

R. A. Padgett, M. M. Konarska, P. J. Grabowski, S. F. Hardy, and P. A. Sharp, “Lariat RNA’s as intermediates and products in the splicing of messenger RNA precursors,” Science 225(4665), 898–903 (1984).
[Crossref] [PubMed]

Hasegawa, S.

M. K. So, G. Gowrishankar, S. Hasegawa, J. K. Chung, and J. Rao, “Imaging target mRNA and siRNA-mediated gene silencing in vivo with ribozyme-based reporters,” ChemBioChem 9(16), 2682–2691 (2008).
[Crossref] [PubMed]

S. Hasegawa, G. Gowrishankar, and J. Rao, “Detection of mRNA in mammalian cells with a split ribozyme reporter,” ChemBioChem 7(6), 925–928 (2006).
[Crossref] [PubMed]

S. Hasegawa, J. W. Choi, and J. Rao, “Single-cell detection of trans-splicing ribozyme in vivo activity,” J. Am. Chem. Soc. 126(23), 7158–7159 (2004).
[Crossref] [PubMed]

S. Hasegawa, W. C. Jackson, R. Y. Tsien, and J. Rao, “Imaging Tetrahymena ribozyme splicing activity in single live mammalian cells,” Proc. Natl. Acad. Sci. U.S.A. 100(25), 14892–14896 (2003).
[Crossref] [PubMed]

Jackson, W. C.

S. Hasegawa, W. C. Jackson, R. Y. Tsien, and J. Rao, “Imaging Tetrahymena ribozyme splicing activity in single live mammalian cells,” Proc. Natl. Acad. Sci. U.S.A. 100(25), 14892–14896 (2003).
[Crossref] [PubMed]

Johnson, J. M.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

Kan, Z.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

Konarska, M. M.

M. M. Konarska and P. A. Sharp, “Interactions between small nuclear ribonucleoprotein particles in formation of spliceosomes,” Cell 49(6), 763–774 (1987).
[Crossref] [PubMed]

R. A. Padgett, M. M. Konarska, P. J. Grabowski, S. F. Hardy, and P. A. Sharp, “Lariat RNA’s as intermediates and products in the splicing of messenger RNA precursors,” Science 225(4665), 898–903 (1984).
[Crossref] [PubMed]

Krainer, A. R.

A. R. Krainer, T. Maniatis, B. Ruskin, and M. R. Green, “Normal and mutant human beta-globin pre-mRNAs are faithfully and efficiently spliced in vitro,” Cell 36(4), 993–1005 (1984).
[Crossref] [PubMed]

B. Ruskin, A. R. Krainer, T. Maniatis, and M. R. Green, “Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro,” Cell 38(1), 317–331 (1984).
[Crossref] [PubMed]

Lee, H. J.

S. O. Yoon, S. Shin, H. J. Lee, H. K. Chun, and A. S. Chung, “Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression,” Mol. Cancer Ther. 5(11), 2666–2675 (2006).
[Crossref] [PubMed]

Li, G.

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

Li, S.

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

Liu, H. J.

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

Liu, M.

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

Loerch, P. M.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

Lowell, A. M.

K. O’Brien, A. J. Matlin, A. M. Lowell, and M. J. Moore, “The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing,” J. Biol. Chem. 283(48), 33147–33154 (2008).
[Crossref] [PubMed]

Lührmann, R.

M. C. Wahl, C. L. Will, and R. Lührmann, “The spliceosome: design principles of a dynamic RNP machine,” Cell 136(4), 701–718 (2009).
[Crossref] [PubMed]

Lunardi, J.

A. S. Gauchez, A. Du Moulinet D’Hardemare, J. Lunardi, J. P. Vuillez, and D. Fagret, “Potential use of radiolabeled antisense oligonucleotides in oncology,” Anticancer Res. 19(6B), 4989–4997 (1999).
[PubMed]

Maniatis, T.

B. Ruskin, A. R. Krainer, T. Maniatis, and M. R. Green, “Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro,” Cell 38(1), 317–331 (1984).
[Crossref] [PubMed]

A. R. Krainer, T. Maniatis, B. Ruskin, and M. R. Green, “Normal and mutant human beta-globin pre-mRNAs are faithfully and efficiently spliced in vitro,” Cell 36(4), 993–1005 (1984).
[Crossref] [PubMed]

Matlin, A. J.

K. O’Brien, A. J. Matlin, A. M. Lowell, and M. J. Moore, “The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing,” J. Biol. Chem. 283(48), 33147–33154 (2008).
[Crossref] [PubMed]

Misteli, T.

M. Salton and T. Misteli, “Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy,” Trends Mol. Med. 22(1), 28–37 (2016).
[Crossref] [PubMed]

Mitchell, L. G.

S. Bhaumik, Z. Walls, M. Puttaraju, L. G. Mitchell, and S. S. Gambhir, “Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing,” Proc. Natl. Acad. Sci. U.S.A. 101(23), 8693–8698 (2004).
[Crossref] [PubMed]

Moore, M. J.

K. O’Brien, A. J. Matlin, A. M. Lowell, and M. J. Moore, “The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing,” J. Biol. Chem. 283(48), 33147–33154 (2008).
[Crossref] [PubMed]

Nasim, M. T.

M. T. Nasim and I. C. Eperon, “A double-reporter splicing assay for determining splicing efficiency in mammalian cells,” Nat. Protoc. 1(2), 1022–1028 (2006).
[Crossref] [PubMed]

O’Brien, K.

K. O’Brien, A. J. Matlin, A. M. Lowell, and M. J. Moore, “The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing,” J. Biol. Chem. 283(48), 33147–33154 (2008).
[Crossref] [PubMed]

Padgett, R. A.

R. A. Padgett, M. M. Konarska, P. J. Grabowski, S. F. Hardy, and P. A. Sharp, “Lariat RNA’s as intermediates and products in the splicing of messenger RNA precursors,” Science 225(4665), 898–903 (1984).
[Crossref] [PubMed]

Puttaraju, M.

Z. F. Walls, M. Puttaraju, G. F. Temple, and S. S. Gambhir, “A generalizable strategy for imaging pre-mRNA levels in living subjects using spliceosome-mediated RNA trans-splicing,” J. Nucl. Med. 49(7), 1146–1154 (2008).
[Crossref] [PubMed]

S. Bhaumik, Z. Walls, M. Puttaraju, L. G. Mitchell, and S. S. Gambhir, “Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing,” Proc. Natl. Acad. Sci. U.S.A. 101(23), 8693–8698 (2004).
[Crossref] [PubMed]

Qin, G.

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

Rao, J.

M. K. So, G. Gowrishankar, S. Hasegawa, J. K. Chung, and J. Rao, “Imaging target mRNA and siRNA-mediated gene silencing in vivo with ribozyme-based reporters,” ChemBioChem 9(16), 2682–2691 (2008).
[Crossref] [PubMed]

S. Hasegawa, G. Gowrishankar, and J. Rao, “Detection of mRNA in mammalian cells with a split ribozyme reporter,” ChemBioChem 7(6), 925–928 (2006).
[Crossref] [PubMed]

S. Hasegawa, J. W. Choi, and J. Rao, “Single-cell detection of trans-splicing ribozyme in vivo activity,” J. Am. Chem. Soc. 126(23), 7158–7159 (2004).
[Crossref] [PubMed]

S. Hasegawa, W. C. Jackson, R. Y. Tsien, and J. Rao, “Imaging Tetrahymena ribozyme splicing activity in single live mammalian cells,” Proc. Natl. Acad. Sci. U.S.A. 100(25), 14892–14896 (2003).
[Crossref] [PubMed]

Ruskin, B.

A. R. Krainer, T. Maniatis, B. Ruskin, and M. R. Green, “Normal and mutant human beta-globin pre-mRNAs are faithfully and efficiently spliced in vitro,” Cell 36(4), 993–1005 (1984).
[Crossref] [PubMed]

B. Ruskin, A. R. Krainer, T. Maniatis, and M. R. Green, “Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro,” Cell 38(1), 317–331 (1984).
[Crossref] [PubMed]

Salton, M.

M. Salton and T. Misteli, “Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy,” Trends Mol. Med. 22(1), 28–37 (2016).
[Crossref] [PubMed]

Santos, R.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

Schadt, E. E.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

Sharp, P. A.

M. M. Konarska and P. A. Sharp, “Interactions between small nuclear ribonucleoprotein particles in formation of spliceosomes,” Cell 49(6), 763–774 (1987).
[Crossref] [PubMed]

R. A. Padgett, M. M. Konarska, P. J. Grabowski, S. F. Hardy, and P. A. Sharp, “Lariat RNA’s as intermediates and products in the splicing of messenger RNA precursors,” Science 225(4665), 898–903 (1984).
[Crossref] [PubMed]

Shin, S.

S. O. Yoon, S. Shin, H. J. Lee, H. K. Chun, and A. S. Chung, “Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression,” Mol. Cancer Ther. 5(11), 2666–2675 (2006).
[Crossref] [PubMed]

Shoemaker, D. D.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

So, M. K.

M. K. So, G. Gowrishankar, S. Hasegawa, J. K. Chung, and J. Rao, “Imaging target mRNA and siRNA-mediated gene silencing in vivo with ribozyme-based reporters,” ChemBioChem 9(16), 2682–2691 (2008).
[Crossref] [PubMed]

Staley, J. P.

J. P. Staley and C. Guthrie, “Mechanical devices of the spliceosome: motors, clocks, springs, and things,” Cell 92(3), 315–326 (1998).
[Crossref] [PubMed]

Steitz, J. A.

D. L. Black, B. Chabot, and J. A. Steitz, “U2 as well as U1 small nuclear ribonucleoproteins are involved in premessenger RNA splicing,” Cell 42(3), 737–750 (1985).
[Crossref] [PubMed]

Stoughton, R.

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

Sullenger, B. A.

B. A. Sullenger and T. R. Cech, “Ribozyme-mediated repair of defective mRNA by targeted, trans-splicing,” Nature 371(6498), 619–622 (1994).
[Crossref] [PubMed]

Temple, G. F.

Z. F. Walls, M. Puttaraju, G. F. Temple, and S. S. Gambhir, “A generalizable strategy for imaging pre-mRNA levels in living subjects using spliceosome-mediated RNA trans-splicing,” J. Nucl. Med. 49(7), 1146–1154 (2008).
[Crossref] [PubMed]

Tsien, R. Y.

S. Hasegawa, W. C. Jackson, R. Y. Tsien, and J. Rao, “Imaging Tetrahymena ribozyme splicing activity in single live mammalian cells,” Proc. Natl. Acad. Sci. U.S.A. 100(25), 14892–14896 (2003).
[Crossref] [PubMed]

Vuillez, J. P.

A. S. Gauchez, A. Du Moulinet D’Hardemare, J. Lunardi, J. P. Vuillez, and D. Fagret, “Potential use of radiolabeled antisense oligonucleotides in oncology,” Anticancer Res. 19(6B), 4989–4997 (1999).
[PubMed]

Wahl, M. C.

M. C. Wahl, C. L. Will, and R. Lührmann, “The spliceosome: design principles of a dynamic RNP machine,” Cell 136(4), 701–718 (2009).
[Crossref] [PubMed]

Walker, A. K.

T. K. Blackwell and A. K. Walker, “Transcription mechanisms,” WormBook 2006, 1–16 (2006).
[PubMed]

Walls, Z.

S. Bhaumik, Z. Walls, M. Puttaraju, L. G. Mitchell, and S. S. Gambhir, “Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing,” Proc. Natl. Acad. Sci. U.S.A. 101(23), 8693–8698 (2004).
[Crossref] [PubMed]

Walls, Z. F.

Z. F. Walls, M. Puttaraju, G. F. Temple, and S. S. Gambhir, “A generalizable strategy for imaging pre-mRNA levels in living subjects using spliceosome-mediated RNA trans-splicing,” J. Nucl. Med. 49(7), 1146–1154 (2008).
[Crossref] [PubMed]

Wang, R. F.

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

Will, C. L.

M. C. Wahl, C. L. Will, and R. Lührmann, “The spliceosome: design principles of a dynamic RNP machine,” Cell 136(4), 701–718 (2009).
[Crossref] [PubMed]

Woodson, S. A.

S. A. Woodson and T. R. Cech, “Alternative secondary structures in the 5′ exon affect both forward and reverse self-splicing of the Tetrahymena intervening sequence RNA,” Biochemistry 30(8), 2042–2050 (1991).
[Crossref] [PubMed]

Xu, W.

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

Yan, P.

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

Yoon, S. O.

S. O. Yoon, S. Shin, H. J. Lee, H. K. Chun, and A. S. Chung, “Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression,” Mol. Cancer Ther. 5(11), 2666–2675 (2006).
[Crossref] [PubMed]

Yu, M. M.

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

Zhang, C. L.

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

Zhang, K.

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

Zhang, Y.

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

Annu. Rev. Biochem. (1)

T. R. Cech, “Self-splicing of group I introns,” Annu. Rev. Biochem. 59(1), 543–568 (1990).
[Crossref] [PubMed]

Anticancer Res. (1)

A. S. Gauchez, A. Du Moulinet D’Hardemare, J. Lunardi, J. P. Vuillez, and D. Fagret, “Potential use of radiolabeled antisense oligonucleotides in oncology,” Anticancer Res. 19(6B), 4989–4997 (1999).
[PubMed]

Biochemistry (1)

S. A. Woodson and T. R. Cech, “Alternative secondary structures in the 5′ exon affect both forward and reverse self-splicing of the Tetrahymena intervening sequence RNA,” Biochemistry 30(8), 2042–2050 (1991).
[Crossref] [PubMed]

Cell (6)

J. P. Staley and C. Guthrie, “Mechanical devices of the spliceosome: motors, clocks, springs, and things,” Cell 92(3), 315–326 (1998).
[Crossref] [PubMed]

M. C. Wahl, C. L. Will, and R. Lührmann, “The spliceosome: design principles of a dynamic RNP machine,” Cell 136(4), 701–718 (2009).
[Crossref] [PubMed]

D. L. Black, B. Chabot, and J. A. Steitz, “U2 as well as U1 small nuclear ribonucleoproteins are involved in premessenger RNA splicing,” Cell 42(3), 737–750 (1985).
[Crossref] [PubMed]

M. M. Konarska and P. A. Sharp, “Interactions between small nuclear ribonucleoprotein particles in formation of spliceosomes,” Cell 49(6), 763–774 (1987).
[Crossref] [PubMed]

B. Ruskin, A. R. Krainer, T. Maniatis, and M. R. Green, “Excision of an intact intron as a novel lariat structure during pre-mRNA splicing in vitro,” Cell 38(1), 317–331 (1984).
[Crossref] [PubMed]

A. R. Krainer, T. Maniatis, B. Ruskin, and M. R. Green, “Normal and mutant human beta-globin pre-mRNAs are faithfully and efficiently spliced in vitro,” Cell 36(4), 993–1005 (1984).
[Crossref] [PubMed]

ChemBioChem (2)

M. K. So, G. Gowrishankar, S. Hasegawa, J. K. Chung, and J. Rao, “Imaging target mRNA and siRNA-mediated gene silencing in vivo with ribozyme-based reporters,” ChemBioChem 9(16), 2682–2691 (2008).
[Crossref] [PubMed]

S. Hasegawa, G. Gowrishankar, and J. Rao, “Detection of mRNA in mammalian cells with a split ribozyme reporter,” ChemBioChem 7(6), 925–928 (2006).
[Crossref] [PubMed]

Eur. J. Nucl. Med. Mol. Imaging (1)

G. Qin, Y. Zhang, W. Cao, R. An, Z. Gao, G. Li, W. Xu, K. Zhang, and S. Li, “Molecular imaging of atherosclerotic plaques with technetium-99m-labelled antisense oligonucleotides,” Eur. J. Nucl. Med. Mol. Imaging 32(1), 6–14 (2005).
[Crossref] [PubMed]

J. Am. Chem. Soc. (1)

S. Hasegawa, J. W. Choi, and J. Rao, “Single-cell detection of trans-splicing ribozyme in vivo activity,” J. Am. Chem. Soc. 126(23), 7158–7159 (2004).
[Crossref] [PubMed]

J. Biol. Chem. (1)

K. O’Brien, A. J. Matlin, A. M. Lowell, and M. J. Moore, “The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing,” J. Biol. Chem. 283(48), 33147–33154 (2008).
[Crossref] [PubMed]

J. Nucl. Med. (2)

M. Liu, R. F. Wang, C. L. Zhang, P. Yan, M. M. Yu, L. J. Di, H. J. Liu, and F. Q. Guo, “Noninvasive imaging of human telomerase reverse transcriptase (hTERT) messenger RNA with 99mTc-radiolabeled antisense probes in malignant tumors,” J. Nucl. Med. 48(12), 2028–2036 (2007).
[Crossref] [PubMed]

Z. F. Walls, M. Puttaraju, G. F. Temple, and S. S. Gambhir, “A generalizable strategy for imaging pre-mRNA levels in living subjects using spliceosome-mediated RNA trans-splicing,” J. Nucl. Med. 49(7), 1146–1154 (2008).
[Crossref] [PubMed]

Mol. Cancer Ther. (1)

S. O. Yoon, S. Shin, H. J. Lee, H. K. Chun, and A. S. Chung, “Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression,” Mol. Cancer Ther. 5(11), 2666–2675 (2006).
[Crossref] [PubMed]

Nat. Protoc. (1)

M. T. Nasim and I. C. Eperon, “A double-reporter splicing assay for determining splicing efficiency in mammalian cells,” Nat. Protoc. 1(2), 1022–1028 (2006).
[Crossref] [PubMed]

Nature (1)

B. A. Sullenger and T. R. Cech, “Ribozyme-mediated repair of defective mRNA by targeted, trans-splicing,” Nature 371(6498), 619–622 (1994).
[Crossref] [PubMed]

Proc. Natl. Acad. Sci. U.S.A. (2)

S. Bhaumik, Z. Walls, M. Puttaraju, L. G. Mitchell, and S. S. Gambhir, “Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing,” Proc. Natl. Acad. Sci. U.S.A. 101(23), 8693–8698 (2004).
[Crossref] [PubMed]

S. Hasegawa, W. C. Jackson, R. Y. Tsien, and J. Rao, “Imaging Tetrahymena ribozyme splicing activity in single live mammalian cells,” Proc. Natl. Acad. Sci. U.S.A. 100(25), 14892–14896 (2003).
[Crossref] [PubMed]

Science (2)

J. M. Johnson, J. Castle, P. Garrett-Engele, Z. Kan, P. M. Loerch, C. D. Armour, R. Santos, E. E. Schadt, R. Stoughton, and D. D. Shoemaker, “Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays,” Science 302(5653), 2141–2144 (2003).
[Crossref] [PubMed]

R. A. Padgett, M. M. Konarska, P. J. Grabowski, S. F. Hardy, and P. A. Sharp, “Lariat RNA’s as intermediates and products in the splicing of messenger RNA precursors,” Science 225(4665), 898–903 (1984).
[Crossref] [PubMed]

Trends Mol. Med. (1)

M. Salton and T. Misteli, “Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy,” Trends Mol. Med. 22(1), 28–37 (2016).
[Crossref] [PubMed]

WormBook (1)

T. K. Blackwell and A. K. Walker, “Transcription mechanisms,” WormBook 2006, 1–16 (2006).
[PubMed]

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Figures (6)

Fig. 1
Fig. 1 Characterization of the splicing reporter. (a) Schematic diagram of the intron-containing (Luc-intron) and intronless (Luc-control) luciferase reporters. Both luciferase genes are under the control of a CMV promoter. GT and AG represent the 5′ and 3′ splice site of intron, respectively. (b) The A549 cells were transfected with the Luc-intron or Luc-control plasmid, together with an internal control plasmid pRL-TK that expresses renilla luciferase. Mock indicates that the cells were added only transfection reagent. Dual luciferase reporter assay was performed 24 h after transfection. Error bars represent the standard deviations for three independent experiments. ***p < 0.001 (c) RT-PCR analysis of total RNA isolated from the cells treated by the same method as described in (b). M indicates DNA marker.
Fig. 2
Fig. 2 Correlation between bioluminescence signal and cell numbers in cells. The A549-luc-control cells (a) or A549-luc-intron cells (b) were seeded with different cell numbers in a 24-well plate. Then the in vitro bioluminescence imaging was performed following the addition of D-luciferin (150 μg/ml) substrate to the cells. The correlation curves were plotted for each cell line and the square of the correlation coefficients were 0.9685 and 0.9632, respectively.
Fig. 3
Fig. 3 Measuring of splicing activity at different doses of ISO treatment. (a) The A549-luc-control cells or A549-luc-intron cells were treated with ISO (10 μM) or DMSO for 24 h. Then the luciferase activities were measured. (b) RT-PCR analysis of total RNA isolated from the cells treated with the same method described in (a). Sizes of unspliced and spliced products were indicated. (c) The A549-luc-intron cells were treated with DMSO or different doses of ISO (10, 50, 80 μM) for 24 h. Then the luciferase activities were measured. (d) RT-PCR analysis of total RNA isolated from the cells treated with the different doses of ISO used in (c). Error bars represent the standard deviations for three independent experiments. *p < 0.05, **p < 0.01.
Fig. 4
Fig. 4 In vitro real time monitor splicing activity induced by ISO. Luciferase activity versus time for A549-luc-intron cells (a) or A549-luc-control cells (b) treated with 10 μM or 40 μM of ISO. (c) The normalization of luciferase activity from A549-luc-intron cells to that from A549-luc-control cells treated with 10 μM or 40 μM ISO at the same period of time. (d) RT-PCR analysis of total RNA isolated from A549-luc-intron cells treated with 10 or 40 μM ISO for 0, 4 or 8 h.
Fig. 5
Fig. 5 Monitor the inhibition of cell proliferation and splicing by ISO in a reversible fashion. (a) CKK-8 assay for the A549 cells treated with 10 μM or 40 μM of ISO over time. (b) The A549 cells were treated with 40 μM of ISO for 24 h. Then the ISO was removed and the fresh medium was added for CKK-8 assay at the indicated time. (c, d) The luciferase activity from A549-luc-intron cells or A549-luc-control cells exposed to fresh medium after 24 h treatment with (c) 10 μM or (d) 40 μM of ISO.
Fig. 6
Fig. 6 In vivo imaging of splicing by ISO. (a) The xenograft mice were intraperitoneally injected with 15 mg/kg ISO. The bioluminescence imaging was performed at the 0 h time point and 24 h time point after ISO treatment. A representative image was shown. (b) The quantification of the bioluminescence signal from the region of interest in mice treated by ISO at 0 or 24 h as described in (a). (c) RT-PCR analysis of total RNA isolated from tumors of the xenograft mice receiving ISO treatment at 0 h and 24 h time point.

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