Identification of the Rem-responsive element of mouse mammary tumor virus
Open accessAbstract
Mouse mammary tumor virus (MMTV) has previously been shown to encode a functional homolog of the human immunodeficiency virus-1 (HIV-1) nuclear export protein Rev, termed Rem. Here, we show that deletion of the rem gene from a MMTV molecular clone interfered with the nucleo-cytoplasmic transport of genomic length viral mRNA and resulted in a loss of viral capsid (Gag) protein production. Interestingly, nuclear export of single-spliced env mRNA was only moderately affected, suggesting that this transcript is, at least to some extent, transported via a distinct, Rem-independent export mechanism. To identify and characterize a cis-acting RNA element required for Rem responsiveness (RmRE), extensive computational and functional analyses were performed. By these means a region of 490 nt corresponding to positions nt 8517-nt 9006 in the MMTV reference strain was identified as RmRE. Deletion of this fragment, which spans the env-U3 junction region, abolished Gag expression. Furthermore, insertion of this sequence into a heterologous HIV-1-based reporter construct restored, in the presence of Rem, HIV-1 Gag expression to levels determined for the Rev/RRE export system. These results clearly demonstrate that the identified region, whose geometry resembles that of other retroviral-responsive elements, is capable to functionally substitute, in the presence of Rem, for Rev/RRE and thus provide unequivocal evidence that MMTV is a complex retrovirus.
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RmRE is predicted to form an RNA secondary structure with multiple stem loops, and one stem loop is proposed as docking site for Rem to multimerize, mediating nuclear export of unspliced RNA.
“The RmRE is predicted to form an RNA secondary structure with multiple stem loops, and it has been proposed that one of these stem loops serves as a docking site for the Rem to multimerize, mediating the nuclear export of unspliced RNA (Indik et al. 2005, Müllner et al. 2008, Mertz et al. 2009).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Müllner et al. 2008
The Results section on computational prediction (page unavailable) describes an RmRE structure with multiple stem–loops. The Discussion (page unavailable) proposes that Rem binds a primary site and then oligomerizes to recruit factors for RNA export. It does not identify one particular stem–loop as the Rem docking site; that part of the claim is more specific than the paper's proposal. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMMTV uses a mechanism similar to complex retroviruses for transport of its unspliced RNA, but not the spliced Env mRNA.
“Intriguingly, MMTV, which was previously classified as a simple retrovirus, uses a mechanism similar to complex retroviruses for the transport of its unspliced RNA, but not the spliced Env mRNA.”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Müllner et al. 2008
The Abstract and Discussion report that Rem-dependent export is essential for cytoplasmic accumulation of unspliced MMTV RNA, consistent with a complex-retrovirus-like mechanism. But the Discussion says single-spliced env mRNA is only moderately regulated by Rem/RmRE, not wholly independent of it; the claim’s unqualified “but not” overstates that distinction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRmRE is found in both unspliced and spliced RNAs.
“Like HIV-1, this element is found in both the unspliced and spliced RNAs (Fig. 9; Table 1) (Indik et al. 2005, Mertz et al. 2005, 2009, Müllner et al. 2008).”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Müllner et al. 2008
MMTV encodes Rem, which interacts with RmRE present at the 3′ end of the genome within the env gene, overlapping the 3′ LTR.
“Similarly, MMTV encodes a protein called Regulator of Export of MMTV mRNA (Rem), which interacts with the Rem Responsive Element (RmRE) present at the 3′end of the genome within the env gene, but overlapping the 3′ LTR.”
From Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication (2026) · cites this paper as Müllner et al. 2008
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Cites
Mfold web server for nucleic acid folding and hybridization prediction
Zuker, M. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg595 · Cited by 13,404 · see citing works
Malim, M. H., Hauber, J., Le, S.-Y., Maizel, J. V., & Cullen, B. R. (1989) · Nature · doi:10.1038/338254a0 · Cited by 1,280 · see citing works
Felber, B. K., Hadzopoulou‐Cladaras, M., Cladaras, C., Copeland, T. D., & Pavlakis, G. N. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.5.1495 · Cited by 624 · see citing works
Schwartz, S., Felber, B. K., Benko, D. M., Fenyö, E. M., & Pavlakis, G. N. (1990) · Journal of Virology · doi:10.1128/jvi.64.6.2519-2529.1990 · Cited by 423 · see citing works
Malim, M. H., & Cullen, B. R. (1991) · Cell · doi:10.1016/0092-8674(91)90158-u · Cited by 420 · see citing works
Hadzopoulou-Cladaras, M., Felber, B. K., Cladaras, C., Athanassopoulos, A., Tse, A., & Pavlakis, G. N. (1989) · Journal of Virology · doi:10.1128/jvi.63.3.1265-1274.1989 · Cited by 351 · see citing works
Intragenic cis-acting art gene-responsive sequences of the human immunodeficiency virus.
Rosen, C. A., Terwilliger, E., Dayton, A. I., Sodroski, J., & Haseltine, W. A. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.7.2071 · Cited by 334 · see citing works
Crandell, R. A., Fabricant, C. G., & Nelson‐Rees, W. A. (1973) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02618435 · Cited by 309 · see citing works
Identification of human endogenous retroviruses with complex mRNA expression and particle formation.
Löwer, R., Boller, K., Hasenmaier, B., Korbmacher, C., Müller-Lantzsch, N., Löwer, J., & Kurth, R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.10.4480 · Cited by 268 · see citing works
Moore, R., Dixon, M., Smith, R., Peters, G., & Dickson, C. (1987) · Journal of Virology · doi:10.1128/jvi.61.2.480-490.1987 · Cited by 256 · see citing works
Zapp, M. L., Hope, T. J., Parslow, T. G., & Green, M. R. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.17.7734 · Cited by 252 · see citing works
Kjems, J., Brown, M. A., Chang, D. D., & Sharp, P. A. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.3.683 · Cited by 225 · see citing works
Hanly, S. M., Rimsky, L. T., Malim, M. H., Kim, J. H., Hauber, J., Dodon, M. D., Le, S., Maizel, J. V., Cullen, B. R., & Greene, W. C. (1989) · Genes & Development · doi:10.1101/gad.3.10.1534 · Cited by 195 · see citing works
Tiley, L. S., Malim, M. H., Tewary, H. K., Stockley, P. G., & Cullen, B. R. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.2.758 · Cited by 162 · see citing works
Seiki, M., Inoue, J., Hidaka, M., & Yoshida, M. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.19.7124 · Cited by 151 · see citing works
Magin, C., Löwer, R., & Löwer, J. (1999) · Journal of Virology · doi:10.1128/jvi.73.11.9496-9507.1999 · Cited by 150 · see citing works
Yang, J., Bogerd, H., Peng, S., Wiegand, H. L., Truant, R., & Cullen, B. (1999) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.96.23.13404 · Cited by 147 · see citing works
Mouse mammary tumor virus encodes a self-regulatory RNA export protein and is a complex retrovirus
Mertz, J. A., Simper, M. S., Lozano, M. M., Payne, S. M., & Dudley, J. P. (2005) · Journal of Virology · doi:10.1128/jvi.79.23.14737-14747.2005 · Cited by 130 · see citing works
Mergener, K., Fäcke, M., Welker, R., Brinkmann, V., Gelderblom, H. R., & Kr√§usslich, H. G. (1992) · Virology · doi:10.1016/0042-6822(92)90058-w · Cited by 125 · see citing works
Iwai, S., Pritchard, C. E., Mann, D. A., Karn, J., & Gait, M. J. (1992) · Nucleic Acids Research · doi:10.1093/nar/20.24.6465 · Cited by 118 · see citing works
Jain, C., & Belasco, J. (2001) · Molecules and Cells · doi:10.1016/s1097-2765(01)00207-6 · Cited by 106 · see citing works
A novel, mouse mammary tumor virus encoded protein with Rev-like properties
Indik, S., Günzburg, W. H., Salmons, B., & Rouault, F. (2005) · Virology · doi:10.1016/j.virol.2005.03.040 · Cited by 99 · see citing works
Self-citationLe, S., Malim, M. H., Cullen, B. R., & Maizel, J. V. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.6.1613 · Cited by 87 · see citing works
Toyoshima, H., Ito, M., Inoue, J., Seiki, M., Takaku, F., & Yoshida, M. (1990) · Journal of Virology · doi:10.1128/jvi.64.6.2825-2832.1990 · Cited by 81 · see citing works
Daly, T. J., Doten, R. C., Rennert, P. D., Auer, M., Jaksche, H., Donner, A. L., Fisk, G., & Rusche, J. R. (1993) · Biochemistry · doi:10.1021/bi00090a028 · Cited by 77 · see citing works
Cis-acting sequences responsive to the rev gene product of the human immunodeficiency virus.
Dayton, A. I., Terwilliger, E. F., Potz, J., Kowalski, M. M., Sodroski, J., & Haseltine, W. A. (1988) · PubMed · Cited by 75 · see citing works
Sequence Requirements for Rev Multimerization in Vivo
Madore, S. J., Tiley, L. S., Malim, M. H., & Cullen, B. R. (1994) · Virology · doi:10.1006/viro.1994.1334 · Cited by 74 · see citing works
Real-time Kinetics of HIV-1 Rev-Rev Response Element Interactions
Ryk, D. I. V., & Venkatesan, S. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.25.17452 · Cited by 73 · see citing works
Wodrich, H. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.4.901 · Cited by 71 · see citing works
A method for assessing the statistical significance of RNA folding
Le, S., & Maizel, J. V. (1989) · Journal of Theoretical Biology · doi:10.1016/s0022-5193(89)80047-5 · Cited by 62 · see citing works
Salmons, B., Groner, B., Calberg‐Bacq, C. M., & Ponta, H. (1985) · Virology · doi:10.1016/0042-6822(85)90309-5 · Cited by 51 · see citing works
Self-citationSolution oligomerization of the rev protein of HIV-1: Implications for function
Cole, J. L., Gehman, J. D., Shafer, J. A., & Kuo, L. C. (1993) · Biochemistry · doi:10.1021/bi00095a004 · Cited by 47 · see citing works
Wodrich, H., Bohne, J., Gumz, E., Welker, R., & Kräusslich, H. (2001) · Journal of Virology · doi:10.1128/jvi.75.22.10670-10682.2001 · Cited by 39 · see citing works
Yang, J., Bogerd, H., Le, S., & Cullen, B. R. (2000) · RNA: A publication of the RNA Society · doi:10.1017/s135583820000100x · Cited by 29 · see citing works
Saltarelli, M. J., Schoborg, R. V., Pavlakis, G., & Clements, J. E. (1994) · Virology · doi:10.1006/viro.1994.1096 · Cited by 25 · see citing works
Structural and functional analysis of the visna virus Rev-response element
Tiley, L. S., & Cullen, B. R. (1992) · Journal of Virology · doi:10.1128/jvi.66.6.3609-3615.1992 · Cited by 24 · see citing works
Rev response elements (RRE) in lentiviruses: An RNAMotif algorithm‐based strategy for RRE prediction
Lesnik, E. A., Sampath, R., & Ecker, D. J. (2002) · Medicinal Research Reviews · doi:10.1002/med.10027 · Cited by 23 · see citing works
HIV-1 Rev can specifically interact with MMTV RNA and upregulate gene expression
Dangerfield, J. A., Hohenadl, C., Egerbacher, M., Kodajova, P., Salmons, B., & Günzburg, W. H. (2005) · Gene · doi:10.1016/j.gene.2005.05.018 · Cited by 12 · see citing works
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Ross, S. R. (2010) · Viruses · doi:10.3390/v2092000 · Cited by 106 · see citing works
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Byun, H., Gou, Y., Zook, A. E., Lozano, M. M., & Dudley, J. P. (2014) · Frontiers in Microbiology · doi:10.3389/fmicb.2014.00330 · Cited by 74 · see citing works
Identification of diverse full-length endogenous betaretroviruses in megabats and microbats
Hayward, J. A., Tachedjian, M., Cui, J., Field, H. E., Holmes, E. C., Wang, L., & Tachedjian, G. (2013) · Retrovirology · doi:10.1186/1742-4690-10-35 · Cited by 65 · see citing works
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Behrens, R. T., Aligeti, M., Pocock, G. M., Higgins, C. A., & Sherer, N. M. (2016) · Journal of Virology · doi:10.1128/jvi.02107-16 · Cited by 46 · see citing works
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Chameettachal, A., Mustafa, F., & Rizvi, T. A. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167924 · Cited by 41 · see citing works
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Mertz, J. A., Lozano, M. M., & Dudley, J. P. (2009) · Retrovirology · doi:10.1186/1742-4690-6-10 · Cited by 37 · see citing works
Vallejos, M., Ramdohr, P., Valiente‐Echeverría, F., Tapia, K., Rodríguez, F., Lowy, F., Huidobro-Toro, J. P., Dangerfield, J. A., & López‐Lastra, M. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp890 · Cited by 37 · see citing works
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Gales, J. P., Kubina, J., Geldreich, A., & Dimitrova, M. (2020) · Viruses · doi:10.3390/v12091014 · Cited by 31 · see citing works
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Feldman, D., Roniger, M., Bar-Sinai, A., Braitbard, O., Natan, C., Love, D. C., Hanover, J. A., & Hochman, J. (2012) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-11-0581 · Cited by 29 · see citing works
Konstantoulas, C. J., & Indik, S. (2014) · Retrovirology · doi:10.1186/1742-4690-11-34 · Cited by 27 · see citing works
Self-citationMertz, J. A., Chadee, A. B., Byun, H., Russell, R., & Dudley, J. P. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.012476 · Cited by 26 · see citing works
Bevilacqua, G. (2022) · Viruses · doi:10.3390/v14081704 · Cited by 25 · see citing works
Mustafa, F., Amri, D. A., Ali, F. A., Sari, N. A., Suwaidi, S. A., Jayanth, P., Philips, P. S., & Rizvi, T. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047088 · Cited by 23 · see citing works
Konstantoulas, C. J., & Indik, S. (2014) · Journal of General Virology · doi:10.1099/jgv.0.000006 · Cited by 24 · see citing works
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Pilkington, G. R., Purzycka, K. J., Bear, J., Grice, S. F. J. L., & Felber, B. K. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku798 · Cited by 16 · see citing works
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Boeras, I., Sakalian, M., & West, J. T. (2012) · Retrovirology · doi:10.1186/1742-4690-9-8 · Cited by 10 · see citing works
Pocock, G. M., Zimdars, L. L., Yuan, M., Eliceiri, K. W., Ahlquist, P., & Sherer, N. M. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e16-08-0612 · Cited by 9 · see citing works
Ren, X., Wang, H., Li, C., Jiang, J.-F., Xiong, S.-D., Jin, X., Wu, L. J., & Wang, J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.706135 · Cited by 9 · see citing works
Hohenadl, C., Gunzburg, W. H., Salmons, B., & Indik, S. (2012) · Journal of General Virology · doi:10.1099/vir.0.035196-0 · Cited by 8 · see citing works
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“9 ; Table 1 ) (Müllner et al. 2008 , Boeras et al. 2012 , Hohenadl et al. 2012 ).”
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- Authors
- Mullner, M., Salmons, B., Gunzburg, W. H., & Indik, S.
- Affiliations
- University of Veterinary Medicine Vienna (AT)
- Corresponding author
- Indik, S.
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-09-27
- Volume
- 36
- Issue
- 19
- Pages
- 6284-6294
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC2577329
- OpenAlex
- W2117623434
- Cited by
- 34
- References
- 38
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 3 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 1 · 2014: 5 · 2013: 2 · 2012: 3
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- mouse mammary tumor virus, nuclear export, cis-acting RNA elements
- MeSH terms
- Animals, Binding Sites, Cats, Cell Line, Cell Nucleus, Mammary Tumor Virus, Mouse, RNA, Viral, Viral Proteins, HIV-1, RNA-Binding Proteins, Sequence Deletion, Genes, Reporter, Computational Biology, Active Transport, Cell Nucleus, Regulatory Sequences, Ribonucleic Acid, gag Gene Products, Human Immunodeficiency Virus
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