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5. Beta-hydroxybutyrate dampens adipose progenitors’ profibrotic activation through canonical Tgfβ signaling and non-canonical ZFP36-dependent mechanisms

Author

Simon Lecoutre, Fatiha Merabtene, Elie-Julien El Hachem, Camille Gamblin, Christine Rouault, Nataliya Sokolovska, Hedi Soula, Wi S. Lai, Perry J. Blackshear, Karine Clément, and Isabelle Dugail

Subjects
Adipocyte, Progenitors, Fibrosis, Extracellular matrix, Internal medicine, RC31-1245
Abstract

Background/Purpose: Adipose tissue contains progenitor cells that contribute to beneficial tissue expansion when needed by de novo adipocyte formation (classical white or beige fat cells with thermogenic potential). However, in chronic obesity, they can exhibit an activated pro-fibrotic, extracellular matrix (ECM)-depositing phenotype that highly aggravates obesity-related adipose tissue dysfunction. Methods: Given that progenitors' fibrotic activation and fat cell browning appear to be antagonistic cell fates, we have examined the anti-fibrotic potential of pro-browning agents in an obesogenic condition. Results: In obese mice fed a high fat diet, thermoneutral housing, which induces brown fat cell dormancy, increases the expression of ECM gene programs compared to conventionally raised animals, indicating aggravation of obesity-related tissue fibrosis at thermoneutrality. In a model of primary cultured murine adipose progenitors, we found that exposure to β-hydroxybutyrate selectively reduced Tgfβ-dependent profibrotic responses of ECM genes like Ctgf, Loxl2 and Fn1. This effect is observed in both subcutaneous and visceral-derived adipose progenitors, as well as in 3T3-L1 fibroblasts. In 30 patients with obesity eligible for bariatric surgery, those with higher circulating β-hydroxybutyrate levels have lower subcutaneous adipose tissue fibrotic scores. Mechanistically, β-hydroxybutyrate limits Tgfβ-dependent collagen accumulation and reduces Smad2-3 protein expression and phosphorylation in visceral progenitors. Moreover, β-hydroxybutyrate induces the expression of the ZFP36 gene, encoding a post-transcriptional regulator that promotes the degradation of mRNA by binding to AU-rich sites within 3′UTRs. Importantly, complete ZFP36 deficiency in a mouse embryonic fibroblast line from null mice, or siRNA knock-down in primary progenitors, indicate that ZFP36 is required for β-hydroxybutyrate anti-fibrotic effects. Conclusion: These data unravel the potential of β-hydroxybutyrate to limit adipose tissue matrix deposition, a finding that might exploited in an obesogenic context.

Published
2022
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9. Construction of the Korean VLBI Network (KVN)

Author

Kim, H. -G., Han, S. -T., Sohn, B. W., Oh, S. -J., Je, D. -H., Wi, S. -O., and Song, M. -G.

Subjects
Astrophysics
Abstract

Korea's new VLBI project to construct the Korean VLBI Network (KVN) started in 2001, as a 7-year project that is fully funded by our government. We plan to build 3 new high-precision radio telescopes of 21-m diameter in 3 places in Korea, which will be exclusively used for VLBI observations. We will install the 2/8, 22 and 43 GHz HEMT receivers within 2007 as a first target, and later we will expand the receiving frequency up to 86 and 129 GHz for astronomical, geodetic, and earth science VLBI research. The millimeter-wave VLBI will be the ultimate goal of KVN. For the front-ends, we are going to install a multi-channel receiver system that employs low-pass filters within a quasi-optical beam transportation system. This receiver system will give reliable phase calibrations for millimeter-wave VLBI as well as enable simultaneous multi-frequency band observations. The hard-disk type new Mark 5 will be used as the main recorder of KVN. We have completed the design of the KVN DAS system of 2 Gsps sampling rate, which will use 4 data streams to meet the multi-channel requirement. A VERA type DAS modified for Mark 5 recorder is also under consideration. A new correlator project for KVN was recently approved from Korean government, and will start in the second half of 2004., Comment: 4 pages. 5 figures. Proceedings of the 7th European VLBI Network Symposium held in Toledo, Spain on October 12-15, 2004. Editors: R. Bachiller, F. Colomer, J.-F. Desmurs, P. de Vicente (Observatorio Astronomico Nacional), p. 281-284. Needs evn2004.cls

Published
2004

10. PES and XAS Study on Electronic Structures of Multiferroic RMnO$_3$ (R=Y, Er)

Author

Kang, J. -S., Han, S. W., Park, J. -G., Wi, S. C., Lee, S. S., Kim, G., Song, H. J., Shin, H. J., Jo, W., and Min, B. I.

Subjects
Condensed Matter - Materials Science, Condensed Matter - Strongly Correlated Electrons
Abstract

Electronic structures of multiferroic RMnO$_3$ (R=Y, Er) have been investigated by employing photoemission spectroscopy (PES) and x-ray absorption spectroscopy (XAS). We have found that Mn ions in RMnO$_3$ are in the trivalent high-spin state with the total spin of S=2. The occupied Mn ($d_{xz} - d_{yz}$) states lie deep below $\rm E_F$, while the occupied Mn ($d_{xy} - d_{x^2 -y^2}$) states overlap very much with the O $2p$ states. It is observed that the PES spectral intensity of Mn 3d states is negligible above the occupied O $2p$ bands, suggesting that YMnO$_3$ is likely to be a charge-transfer insulator. The Mn $d_{3z^2 -r^2}$ state is mostly unoccupied in the ferroelectric phase of YMnO$_3$., Comment: 3 figures

Published
2004

11. Photoemission and x-ray absorption spectroscopy study of electron-doped colossal magnetoresistance manganite: La0.7Ce0.3MnO3 film

Author

Han, S. W., Kang, J. -S., Kim, K. H., Lee, J. D., Kim, J. H., Wi, S. C., Mitra, C., Raychaudhuri, P., Wirth, S., Kim, K. J., Kim, B. S., Jeong, J. I., Kwon, S. K., and Min, B. I.

Subjects
Condensed Matter - Strongly Correlated Electrons
Abstract

The electronic structure of La0.7Ce0.3MnO3 (LCeMO) thin film has been investigated using photoemission spectroscopy (PES) and x-ray absorption spectroscopy (XAS). The Ce 3d core-level PES and XAS spectra of LCeMO are very similar to those of CeO2, indicating that Ce ions are far from being trivalent. A very weak 4f resonance is observed around the Ce 4d $\to$ 4f absorption edge, suggesting that the localized Ce 4f states are almost empty in the ground state. The Mn 2p XAS spectrum reveals the existence of the Mn(2+) multiplet feature, confirming the Mn(2+)-Mn(3+) mixed-valent states of Mn ions in LCeMO. The measured Mn 3d PES/XAS spectra for LCeMO agrees reasonably well with the calculated Mn 3d PDOS using the LSDA+U method. The LSDA+U calculation predicts a half-metallic ground state for LCeMO., Comment: 7 pages, 7 figures

Published
2003
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12. Electronic structures of UTSn (T=Ni, Pd) using photoemission spectroscopy

Author

Kang, J. -S., Wi, S. C., Kim, J. H., McEwen, K. A., Olson, C. G., Shim, J. H., and Min, B. I.

Subjects
Condensed Matter - Materials Science
Abstract

The electronic structures of the localized $5f$ systems UTSn (T=Ni, Pd) have been investigated using photoemission spectroscopy (PES). The extracted U $5f$ PES spectra of UTSn (T=Ni, Pd) exhibit a broad peak centered at $\sim 0.3$ eV below $\rm E_F$ with rather small spectral weight near $\rm E_F$ (N$_f$($\rm E_F$)). The small N$_f$($\rm E_F$) in UTSn is found to be correlated with the T $d$ PES spectra that have a very low density of states (DOS) near $\rm E_F$. The high-resolution PES spectra for UTSn provide the V-shaped reduced metallic DOS near $\rm E_F$ but do not reveal any appreciable changes in their electronic structures across the magnetic phase transitions. A possible origin for the reduced N$_f$($\rm E_F$) in UTSn is ascribed to the hybridization to the very low T $d$ DOS at $\rm E_F$. Comparison of the measured PES spectra to the LSDA+$U$ band structure calculation reveals a reasonably good agreement for UPdSn, but not so for UNiSn., Comment: 7 pages, 6 figures

Published
2003

13. Electronic structures of Zn$_{1-x}$Co$_x$O using photoemission and x-ray absorption spectroscopy

Author

Wi, S. C., Kang, J. -S., Kim, J. H., Cho, S. -B., Kim, B. J., Yoon, S., Suh, B. J., Han, S. W., Kim, K. H., Kim, K. J., Kim, B. S., Song, H. J., Shin, H. J., Shim, J. H., and Min, B. I.

Subjects
Condensed Matter - Materials Science
Abstract

Electronic structures of Zn$_{1-x}$Co$_x$O have been investigated using photoemission spectroscopy (PES) and x-ray absorption spectroscopy (XAS). The Co 3d states are found to lie near the top of the O $2p$ valence band, with a peak around $\sim 3$ eV binding energy. The Co $2p$ XAS spectrum provides evidence that the Co ions in Zn$_{1-x}$Co$_{x}$O are in the divalent Co$^{2+}$ ($d^7$) states under the tetrahedral symmetry. Our finding indicates that the properly substituted Co ions for Zn sites will not produce the diluted ferromagnetic semiconductor property., Comment: 3 pages, 2 figures

Published
2003
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14. Control of cytokine mRNA degradation by the histone deacetylase inhibitor ITF2357 in rheumatoid arthritis fibroblast-like synoviocytes: beyond transcriptional regulation

Author

Chiara Angiolilli, Pawel A. Kabala, Aleksander M. Grabiec, Marzia Rossato, Wi S. Lai, Gianluca Fossati, Paolo Mascagni, Christian Steinkühler, Perry J. Blackshear, Kris A. Reedquist, Dominique L. Baeten, and Timothy R. D. J. Radstake

Subjects
Rheumatoid arthritis, Fibroblast-like synoviocytes, Inflammation, mRNA stability, Tristetraprolin, Histone deacetylase inhibitor, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background Histone deacetylase inhibitors (HDACi) suppress cytokine production in immune and stromal cells of patients with rheumatoid arthritis (RA). Here, we investigated the effects of the HDACi givinostat (ITF2357) on the transcriptional and post-transcriptional regulation of inflammatory markers in RA fibroblast-like synoviocytes (FLS). Methods The effects of ITF2357 on the expression and messenger RNA (mRNA) stability of IL-1β-inducible genes in FLS were analyzed using array-based qPCR and Luminex. The expression of primary and mature cytokine transcripts, the mRNA levels of tristetraprolin (TTP, or ZFP36) and other AU-rich element binding proteins (ARE-BP) and the cytokine profile of fibroblasts derived from ZFP36 +/+ and ZFP36 −/− mice was measured by qPCR. ARE-BP silencing was performed by small interfering RNA (siRNA)-mediated knockdown, and TTP post-translational modifications were analyzed by immunoblotting. Results ITF2357 reduced the expression of 85% of the analyzed IL-1β-inducible transcripts, including cytokines (IL6, IL8), chemokines (CXCL2, CXCL5, CXCL6, CXCL10), matrix-degrading enzymes (MMP1, ADAMTS1) and other inflammatory mediators. Analyses of mRNA stability demonstrated that ITF2357 accelerates IL6, IL8, PTGS2 and CXCL2 mRNA degradation, a phenomenon associated with the enhanced transcription of TTP, but not other ARE-BP, and the altered post-translational status of TTP protein. TTP knockdown potentiated cytokine production in RA FLS and murine fibroblasts, which in the latter case was insensitive to inhibition by ITF2357 treatment. Conclusions Our study identifies that regulation of cytokine mRNA stability is a predominant mechanism underlying ITF2357 anti-inflammatory properties, occurring via regulation of TTP. These results highlight the therapeutic potential of ITF2357 in the treatment of RA.

Published
2018
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18. Beta-hydroxybutyrate dampens adipose progenitors’ profibrotic activation through canonical Tgfβ signaling and non-canonical ZFP36-dependent mechanisms

Author

Lecoutre, Simon, primary, Merabtene, Fatiha, additional, El Hachem, Elie-Julien, additional, Gamblin, Camille, additional, Rouault, Christine, additional, Sokolovska, Nataliya, additional, Soula, Hedi, additional, Lai, Wi S., additional, Blackshear, Perry J., additional, Clément, Karine, additional, and Dugail, Isabelle, additional

Published
2022
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22. A post-transcriptional regulon controlled by TtpA, the single tristetraprolin family member expressed in Dictyostelium discoideum

Author

Lalith Perera, Alan R. Kimmel, Perry J. Blackshear, Stephanie N. Hicks, Melissa L. Wells, Wenli Bai, Adam B. Burkholder, and Wi S. Lai

Subjects
Untranslated region, Zinc finger, RNA Stability, Tristetraprolin, Protozoan Proteins, RNA, RNA-binding protein, Biology, Regulon, Cell biology, Membrane protein, Gene expression, Mutation, Genetics, RNA and RNA-protein complexes, Dictyostelium, RNA, Messenger, 3' Untranslated Regions
Abstract

Post-transcriptional processes mediated by mRNA binding proteins represent important control points in gene expression. In eukaryotes, mRNAs containing specific AU-rich motifs are regulated by binding of tristetraprolin (TTP) family tandem zinc finger proteins, which promote mRNA deadenylation and decay, partly through interaction of a conserved C-terminal CNOT1 binding (CNB) domain with CCR4–NOT protein complexes. The social ameba Dictyostelium discoideum shared a common ancestor with humans more than a billion years ago, and expresses only one TTP family protein, TtpA, in contrast to three members expressed in humans. Evaluation of ttpA null-mutants identified six transcripts that were consistently upregulated compared to WT during growth and early development. The 3′-untranslated regions (3′-UTRs) of all six ‘TtpA-target’ mRNAs contained multiple TTP binding motifs (UUAUUUAUU), and one 3′-UTR conferred TtpA post-transcriptional stability regulation to a heterologous mRNA that was abrogated by mutations in the core TTP-binding motifs. All six target transcripts were upregulated to similar extents in a C-terminal truncation mutant, in contrast to less severe effects of analogous mutants in mice. All six target transcripts encoded probable membrane proteins. In Dictyostelium, TtpA may control an ‘RNA regulon’, where a single RNA binding protein, TtpA, post-transcriptionally co-regulates expression of several functionally related proteins.

Published
2021

26. Inhibiting transcription in cultured metazoan cells with actinomycin D to monitor mRNA turnover

Author

Aaron C. Goldstrohm, Wi S. Lai, Perry J. Blackshear, and René M. Arvola

Subjects
Transcription, Genetic, RNA Stability, Primary Cell Culture, Endogeny, RNA-binding protein, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, Tristetraprolin, Transcription (biology), Animals, RNA, Messenger, Molecular Biology, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Protein Synthesis Inhibitors, 0303 health sciences, Messenger RNA, Insect cell, Sequence Analysis, RNA, Chemistry, Macrophages, 030302 biochemistry & molecular biology, High-Throughput Nucleotide Sequencing, Promoter, Fibroblasts, Cell biology, Drosophila melanogaster, Mrna level, Dactinomycin, History of use
Abstract

Decay of transcribed mRNA is a key determinant of steady state mRNA levels in cells. Global analysis of mRNA decay in cultured cells has revealed amazing heterogeneity in rates of decay under normal growth conditions, with calculated half-lives ranging from several minutes to many days. The factors that are responsible for this wide range of decay rates are largely unknown, although our knowledge of trans-acting RNA binding proteins and non-coding RNAs that can control decay rates is increasing. Many methods have been used to try to determine mRNA decay rates under various experimental conditions in cultured cells, and transcription inhibitors like actinomycin D have probably the longest history of any technique for this purpose. Despite this long history of use, the actinomycin D method has been criticized as prone to artifacts, and as ineffective for some promoters. With appropriate guidelines and controls, however, it can be a versatile, effective technique for measuring endogenous mRNA decay in cultured mammalian and insect cells, as well as the decay of exogenously-expressed transcripts. It can be used readily on a genome-wide level, and is remarkably cost-effective. In this short review, we will discuss our utilization of this approach in these cells; we hope that these methods will allow more investigators to apply this useful technique to study mRNA decay under the appropriate conditions.

Published
2019

33. Importance of the Conserved Carboxyl-Terminal CNOT1 Binding Domain to Tristetraprolin Activity In Vivo

Author

Stephanie N. Hicks, Roberta Faccio, Michael W. Webster, Deborah J. Stumpo, Melissa L. Wells, Wi S. Lai, Lori A. Passmore, Perry J. Blackshear, Artiom Gruzdev, Zhengfeng Yang, and Cindo O Nicholson

Subjects
Male, Untranslated region, RNA Stability, Tristetraprolin, RNA-binding protein, Biology, law.invention, Gene Knockout Techniques, Mice, 03 medical and health sciences, 0302 clinical medicine, law, hemic and lymphatic diseases, Schizosaccharomyces, Animals, Humans, heterocyclic compounds, RNA, Messenger, neoplasms, Molecular Biology, Adaptor Proteins, Signal Transducing, Sequence Deletion, 030304 developmental biology, Zinc finger, 0303 health sciences, RNA-Binding Proteins, Cell Biology, respiratory system, biology.organism_classification, Phenotype, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, Schizosaccharomyces pombe, Recombinant DNA, Female, Schizosaccharomyces pombe Proteins, therapeutics, Transcription Factors, Research Article, Binding domain
Abstract

Tristetraprolin (TTP) is an anti-inflammatory protein that modulates the stability of certain cytokine/chemokine mRNAs. After initial high-affinity binding to AU-rich elements in 3′ untranslated regions of target mRNAs, mediated through its tandem zinc finger (TZF) domain, TTP promotes the deadenylation and ultimate decay of target transcripts. These transcripts and their encoded proteins accumulate abnormally in TTP knockout (KO) mice, leading to a severe inflammatory syndrome. To assess the importance of the highly conserved C-terminal CNOT1 binding domain (CNBD) of TTP to the TTP deficiency phenotype in mice, we created a mouse model in which TTP lacked its CNBD. CNBD deletion mice exhibited a less severe phenotype than the complete TTP KO mice. In macrophages, the stabilization of target transcripts seen in KO mice was partially normalized in the CNBD deletion mice. In cell-free experiments, recombinant TTP lacking its CNBD could still activate target mRNA deadenylation by purified recombinant Schizosaccharomyces pombe CCR4/NOT complexes, although to a lesser extent than full-length TTP. Thus, TTP lacking its CNBD can still act to promote target mRNA instability in vitro and in vivo. These data have implications for TTP family members throughout the eukarya, since species from all four kingdoms contain proteins with linked TZF and CNOT1 binding domains.

Published
2019

34. The tandem zinc finger RNA binding domain of members of the tristetraprolin (TTP) protein family

Author

Perry J. Blackshear, Wi S. Lai, Lalith Perera, and Melissa L. Wells

Subjects
Zinc finger, 0303 health sciences, Messenger RNA, Protein family, RNA Stability, 030302 biochemistry & molecular biology, Protein domain, Tristetraprolin, RNA, RNA-binding protein, Zinc Fingers, Biology, Biochemistry, Article, Cell biology, 03 medical and health sciences, Eukaryotic Cells, Gene Expression Regulation, RNA-Binding Motifs, Molecular Biology, 030304 developmental biology, Binding domain
Abstract

Tristetraprolin (TTP), the prototype member of the protein family of the same name, was originally discovered as the product of a rapidly inducible gene in mouse cells. Development of a knockout (KO) mouse established that absence of the protein led to a severe inflammatory syndrome, due in part to elevated levels of tumor necrosis factor (TNF). TTP was found to bind directly and with high affinity to specific AU-rich sequences in the 3'-untranslated region of the TNF mRNA. This initial binding led to promotion of TNF mRNA decay and inhibition of its translation. Many additional TTP target mRNAs have since been identified, some of which are cytokines and chemokines involved in the inflammatory response. There are three other proteins in the mouse with similar activities and domain structures, but whose KO phenotypes are remarkably different. Moreover, proteins with similar domain structures and activities have been found throughout eukaryotes, demonstrating that this protein family arose from an ancient ancestor. The defining characteristic of this protein family is the tandem zinc finger (TZF) domain, a 64 amino acid sequence with many conserved residues that is responsible for the direct RNA binding. We discuss here many aspects of this protein domain that have been elucidated since the original discovery of TTP, including its sequence conservation throughout eukarya; its apparent continued evolution in some lineages; its functional dependence on many key conserved residues; its "interchangeability" among evolutionarily distant species; and the evidence that RNA binding is required for the physiological functions of the proteins. This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.

Published
2019

36. Contributors

Author

Abrams, John M., primary, Adelman, John P., additional, Alcorn, Joseph L., additional, Alessi, Dario R., additional, Alexov, Emil, additional, Alford, Simon, additional, Alitalo, Kari, additional, Allison, James P., additional, Almo, Steven C., additional, Alory, Christelle, additional, Al-Shamkhani, Aymen, additional, Amundson, Sally A., additional, Anderson, Carl W., additional, Andersen, Jannik N., additional, Angel, Peter, additional, Appella, Ettore, additional, Arendshorst, William J., additional, Arkinstall, Steve, additional, Audhya, Anjon, additional, Avruch, Joseph, additional, Bader, Gary D., additional, Bagala, Cinzia, additional, Balch, William E., additional, Balsinde, Jesus, additional, Banerjee, Utpal, additional, Barford, David, additional, Bar-Sagi, Dafna, additional, Bartlett, Perry F., additional, Bastiaens, Philippe I.H., additional, Battelli, Chiara, additional, Baudhuin, Linnea M., additional, Beavil, Andrew J., additional, Beavil, Rebecca L., additional, Beavo, Joseph A., additional, Bello-Reuss, Elsa, additional, Bellum, Stephen, additional, Belmonte, Juan Carlos Izpisúa, additional, Bennett, Craig B., additional, Benovic, Jeffrey L., additional, Berridge, Michael J., additional, Beuning, Penny J., additional, Bhandari, Rashna, additional, Bhattacharya, Ananya, additional, Biel, Martin, additional, Bielinski, Vincent A., additional, Bilak, Hana, additional, Birnbaumer, Lutz, additional, Birrell, Geoff, additional, Bishop, Gail A., additional, Blackmer, Trillium, additional, Blackshear, Perry J., additional, Blattner, Christine, additional, Blaustein, Mordecai P., additional, Bokoch, Gary M., additional, Bonewald, Lynda F., additional, Bonomi, Marco, additional, Booden, Michelle A., additional, Boone, Charles, additional, Bootman, Martin D., additional, Bos, Johannes L., additional, Bradbury, Jane M., additional, Bradshaw, Ralph A., additional, Bresnick, Anne R., additional, Brevnova, Lena, additional, Brinkworth, Ross I., additional, Brown, Michael S., additional, Brown, Steven A., additional, Brunet, Anne, additional, Bucki, Robert, additional, Burgoyne, Robert D., additional, Buss, Janice E., additional, Butow, Ronald A., additional, Capdevila, Javier, additional, Carafoli, Ernesto, additional, Carlson, Cathrine R., additional, Carpenter, Graham, additional, Carrillo, Juan J., additional, Casey, Patrick J., additional, Catterall, William A., additional, Cerione, Richard A., additional, Cesareni, Gianni, additional, Chan, Andrew C., additional, Chang, Geoffrey, additional, Chao, Moses V., additional, Charbonneau, Harry, additional, Chen, Philip, additional, Cheng, Alan, additional, Chiu, Chris, additional, Chow, Dar-chone, additional, Chrisman, Ted D., additional, Christensen, Anne Elisabeth, additional, Chung, Jee Y., additional, Churchill, Grant C., additional, Ciechanover, Aaron, additional, Cingolani, Gino, additional, Claeysen, Sylvie, additional, Closset, Jean, additional, Cockcroft, Shamshad, additional, Cohen, Patricia T.W., additional, Cohen, Philip, additional, Colbran, Roger J., additional, Comstock, Clay E.S., additional, Conti, Marco, additional, Corbin, Jackie D., additional, Corda, Daniela, additional, Costagliola, Sabine, additional, Cote, Rick H., additional, Coughlin, Shaun R., additional, Cowart, L. Ashley, additional, Cox, Adrienne D., additional, Cragg, Mark S., additional, Crespo, José L., additional, Crosio, Claudia, additional, Daly, Christopher, additional, Damak, Sami, additional, Dasso, Mary, additional, David, Michael, additional, Davis, Anthony J., additional, Davis, Roger J., additional, Day, Richard N., additional, Degerman, Eva, additional, DeLano, Warren L., additional, Dell'Acqua, Mark L., additional, Délot, Emmanuèle, additional, Demple, Bruce, additional, Dennis, Edward A., additional, Denu, John M., additional, DePaoli-Roach, Anna A., additional, Der, Channing J., additional, de Rooij, Johan, additional, de Sauvage, Frederic, additional, Devreotes, Peter N., additional, Dewaste, Valérie, additional, Dickson, Robert B., additional, Diebold, Becky A., additional, Fiori, Pier Paolo Di, additional, Girolamo, Maria Di, additional, Diplexcito, Julie, additional, Dixon, Jack E., additional, Doms, Robert W., additional, Donoghue, Daniel J., additional, Doolittle, Russell F., additional, Døskeland, Stein Ove, additional, Dostmann, Wolfgang R.G., additional, Dreyer, Matthias K., additional, Du, Guo Guang, additional, Du, Keyong, additional, Duchen, Michael R., additional, Dunphy, William G., additional, Durgan, Joanne, additional, Dustin, Michael L., additional, Edwards, Peter A., additional, Egen, Jackson G., additional, Eiden, Lee E., additional, Elion, Elaine A., additional, Emr, Scott, additional, Engelhardt, Othmar G., additional, Erneux, Christophe, additional, Espenshade, Peter J., additional, Esplin, Edward D., additional, Evers, B. Mark, additional, Eyles, Joanne L., additional, Fame, Sheelagh, additional, Farquhar, Marilyn, additional, Feil, Robert, additional, Feng, Gui-Jie, additional, Fields, Stanley, additional, Fiordalisi, James J., additional, Firtel, Richard A., additional, Fitzgerald, Garret A., additional, Flint, Andrew, additional, Foiani, Marco, additional, Forman, Barry Marc, additional, Fornace, Albert J., additional, Francis, Sharron H., additional, Fritz, Günter, additional, Fruman, David A., additional, Galione, Antony, additional, Gandhi, Chris S., additional, Garbers, David L., additional, Garcia, K. Christopher, additional, Geiger, Benjamin, additional, Gerace, Larry, additional, Gerstner, Andrea, additional, Giaccia, Amato J., additional, Giannattasio, Michele, additional, Giguère, Vincent, additional, Glass, Christopher K., additional, Glennie, Martin J., additional, Glick, Jennifer L., additional, Goldstein, Joseph L., additional, Gopal, Venkatesh, additional, Gorospe, Myriam, additional, Govaerts, Cedric, additional, Graves, Paul R., additional, Gray, Patrick W., additional, Graziani, Irene, additional, Green, Douglas R., additional, Greenberg, Michael E., additional, Greenwald, Iva, additional, Gu, Haihua, additional, Gueven, Nuri, additional, Gutkind, J. Silvio, additional, Haeggström, Jesper Z., additional, Hall, Alan, additional, Hall, Michael N., additional, Haller, Otto, additional, Hamm, Heidi E., additional, Hannun, Yusef A., additional, Hansen, Carl A., additional, Harden, T. Kendall, additional, Hardie, D. Grahame, additional, Hasegawa, Kiminori, additional, Hawkins, Phillip T., additional, Haystead, Timothy A.J., additional, He, Xiao-lin, additional, Heizmann, Claus W., additional, Heldin, Carl-Henrik, additional, Hermiston, Michelle L., additional, Herrlich, Peter, additional, Hewat, Elizabeth A., additional, Hille, Bertil, additional, Hilton, Douglas J., additional, Hinchliffe, K.A., additional, Ho, Steffan N., additional, Ho, Su-Chin, additional, Hochstrasser, Mark, additional, Hofmann, Franz, additional, Hogue, Christopher W., additional, Hol, Wim G.J., additional, Holash, Jocelyn, additional, Holmgren, Robert A., additional, Honig, Barry, additional, Hostager, Bruce S., additional, Hubbard, Stevan R., additional, Huber, Michael, additional, Hunter, Tony, additional, Huttenlocher, Anna, additional, Hymowitz, Sarah G., additional, Ihle, James N., additional, Imler, Jean-Luc, additional, Irvine, R.F., additional, Isacoff, Ehud Y., additional, Iturrioz, Xavier, additional, Iversen, Lars F., additional, Iyengar, Ravi, additional, Jackson, Stephen P., additional, Jan, Lily Yeh, additional, Janiak-Spens, Fabiola, additional, Janmey, Paul A., additional, Jansen, Peter Gildsig, additional, Jarriault, Sophie, additional, Javitch, Jonathan A., additional, Jensen, Elwood V., additional, Jepsen, Kristen, additional, Jones, E. Yvonne, additional, Jones, Katherine A., additional, Jordan, J. Dedrick, additional, Joseph, Jomon, additional, Justement, Louis B., additional, Kafri, Yariv, additional, Kahn, Richard A., additional, Kang, Shin W., additional, Karlin, Arthur, additional, Kast-Woelbern, Heidi R., additional, Kaufman, Randal J., additional, Kazlauskas, Andrius, additional, Keen, James H., additional, Kemler, Rolf, additional, Kemp, Bruce E., additional, Kennedy, Mary B., additional, Kennedy, Matthew A., additional, Kikkawa, Ushio, additional, Kim, Albert H., additional, Kim, Soo-A, additional, Kim, Sung-Hou, additional, Kim, Youngjoo, additional, King-Jones, Kirst, additional, Kintner, Chris, additional, Kivimäe, Saul, additional, Klee, Claude B., additional, Klein, Rüdiger, additional, Kleppisch, Thomas, additional, Kliewer, Steven A., additional, Klinghoffer, Richard A., additional, Knoblich, Juergen A., additional, Kobe, Bostjan, additional, Kochs, George, additional, Kong-Beltran, Monica, additional, König, Rolf, additional, Koong, Albert C., additional, Korc, Murray, additional, Kornitzer, Daniel, additional, Kossiakoff, Anthony A., additional, Kotera, Jun, additional, Kovalenko, M.V., additional, Kozasa, Tohru, additional, Kozlov, Sergei, additional, Kozminski, Keith G., additional, Krugmann, Sonja, additional, Kuriyan, John, additional, Kurokawa, Riki, additional, Kwong, Peter D., additional, Lai, Wi S., additional, Lamar, Elise, additional, Lambert, Millard H., additional, Lambright, David G., additional, Lancet, Doron, additional, Landry, Reiko, additional, Langdon, Wallace Y., additional, Langeberg, Lorene K., additional, Lasko, Paul, additional, Latham, Vaughn, additional, Lavin, Martin F., additional, Lease, Kevin A., additional, Leffler, Hakon, additional, Lemmon, Mark A., additional, Leonard, Ann E., additional, Levitzki, Alexander, additional, Liao, Hong-Jun, additional, Liaw, Lucy, additional, Liberi, Giordano, additional, Lickert, Heiko, additional, Liddington, Robert C., additional, Lincoln, Thomas M., additional, Linder, Jürgen U., additional, Linder, Maurine E., additional, Liu, Hui, additional, Liu, Zhengchang, additional, Lohela, Marja K., additional, Louie, Sarah H., additional, Luttrell, Deirdre K., additional, Luttrell, Louis M., additional, Lyons, Karen M., additional, Macaulay, S. Lance, additional, Maceyka, Michael, additional, Maciag, Thomas, additional, Macian, Fernando, additional, MacKintosh, Carol, additional, MacLennan, David H., additional, Mahmood, Nadir A., additional, Malbon, Craig C., additional, Malik, Sohail, additional, Man, Orna, additional, Manahan, Carol L., additional, Mandinova, Anna, additional, Manganiello, Vincent C., additional, Manley, James L., additional, Mann, Matthias, additional, Manning, Gerald, additional, Manser, Ed, additional, Margeta-Mitrovic, Marta, additional, Margolskee, Robert F., additional, Marinissen, Julia, additional, Mariuzza, Roy A., additional, Marmor, Mina D., additional, Martin, G. Steven, additional, Martin, Karen H., additional, Martinez, Sergio E., additional, Mathews, Michael B., additional, Mayer, Bruce J., additional, Mayer, Mark L., additional, Mazzoni, Maria R., additional, McCormick, Frank, additional, McGowan, Clare H., additional, McKay, Melissa M., additional, McKeehan, Wallace L., additional, McLean, Alison J., additional, Means, Anthony R., additional, Meili, Ruedi, additional, Meng, Jingwei, additional, Merchant, Mark, additional, Mercurio, Frank, additional, Milligan, Graeme, additional, Ming, Guo-Li, additional, Minor, Daniel L., additional, Moghal, Nadeem, additional, Møller, Neils Peter H., additional, Mongillo, Marco, additional, Montminy, Marc, additional, Moon, Randall T., additional, Morimoto, Richard I., additional, Moss, Stephen E., additional, Mott, Helen R., additional, Mouta, Carla, additional, Muda, Marco, additional, Mumby, Marc C., additional, Murphy, Gretchen A., additional, Muzi-Falconi, Marco, additional, Nagaraj, Raghavendra, additional, Nahorski, Stefan R., additional, Nairn, Angus C., additional, Nash, Piers, additional, Neel, Benjamin G., additional, Newton, Alexandra C., additional, Nishizuka, Yasutomi, additional, Noel, Joseph P., additional, Nollen, Ellen A.A., additional, Nooren, Irene M.A., additional, O'Connor, Rodney, additional, Offermanns, Stefan, additional, Olender, Tsviya, additional, Ong, Shao-En, additional, Owen, Darerca, additional, Pagliari, Lisa J., additional, Pao, Lily, additional, Papaconstantinou, John, additional, Pardo, Leonardo, additional, Park, Hay-Oak, additional, Park, Young Chul, additional, Parker, Peter J., additional, Parsons, J. Thomas, additional, Passner, J.M., additional, Pawson, Tony, additional, Pelliccioli, Achille, additional, Perez-Polo, J. Regino, additional, Perrimon, Norbert, additional, Petite, Fabrice G., additional, Petroulakis, Emmanuel, additional, Pfaff, Samuel L., additional, Piehler, Jacob, additional, Pike, Linda J., additional, Pinkoski, Michael J., additional, Pixley, Fiona J., additional, Plevani, Paolo, additional, Poo, Mu-ming, additional, Pozzan, Tullioi, additional, Prescott, Stephen M., additional, Prudovsky, Igor, additional, Putney, James W., additional, Radimerski, Thomas, additional, Radzio-Andzelm, Elzbieta, additional, Ram, Prahlad T., additional, Rameh, Lucia, additional, Ramljak, Danica, additional, Ranscht, Barbara, additional, Rao, Anjana, additional, Raport, Carol J., additional, Reeves, Jacqueline D., additional, Rehman, Holger, additional, Reichman, Trevor W., additional, Reiter, Eric, additional, Resnick, Michael A., additional, Reth, Michael, additional, Rhee, Sue Goo, additional, Richter, Joel D., additional, Rietze, Rodney L., additional, Rini, James M., additional, Ripperger, Jürgen A., additional, Rizo, Josep, additional, Robishaw, Janet D., additional, Roderick, H. Llewelyn, additional, Roeder, Robert G., additional, Rohrschneider, Larry R., additional, Ron, David, additional, Rosenfeld, Michael G., additional, Rosenfeldt, Hans, additional, Rossman, Kent L., additional, Roth, Christopher B., additional, Rudolph, Markus G., additional, Ruppelt, Anja, additional, Saez, Lino, additional, Sakmar, Thomas P., additional, Salvesen, Guy S., additional, Sassone-Corsi, Paolo, additional, Saxe, Charles L., additional, Schäfer, Beat W., additional, Schibler, Ueli, additional, Schindler, Christian W., additional, Schmelzle, Tobias, additional, Schmid, Sandra L., additional, Schmidt, Anja, additional, Schmidt, Eric F., additional, Schreiber, Gideon, additional, Schultz, Joachim E., additional, Schwaller, Beat, additional, Schwamborn, Klaus, additional, Schwartz, Thue, additional, Schwindinger, William F., additional, Scita, Giorgio, additional, Scott, John D., additional, Scott, Shaun, additional, Seebeck, Thomas, additional, Serhan, Charles N., additional, Shabb, John B., additional, Shaw, Andrey S., additional, Shears, Stephen B., additional, Shenolikar, Shirish, additional, Shi, Lei, additional, Shin, Chanseok, additional, Shiozaki, Kazuhiro, additional, Shokat, Kevan M., additional, Shuttleworth, Trevor J., additional, Siderovski, David P., additional, Siegelbaum, Steven A., additional, Silverstein, Adam M., additional, Singer, Robert H., additional, Skinner, Michael K., additional, Slack-Davis, Jill K., additional, Smerdon, Stephen J., additional, Smith, Graeme C.M., additional, Smits, Guillaume, additional, Smolik, Sarah M., additional, Smotrys, Jessica E., additional, Smyth, Emer M., additional, Snyder, Jason T., additional, Sogame, Naoko, additional, Soldi, Raffaella, additional, Sondek, John, additional, Sonenberg, Nahum, additional, Sonneberg, Erica Dutil, additional, Sparrow, Lindsay G., additional, Spiegel, Sarah, additional, Sprang, Stephen R., additional, Srivastava, Deepak, additional, Stanfield, Robyn L., additional, Stanley, E. Richard, additional, Stauber, Deborah J., additional, Stefan, Christopher, additional, Stenson-Holst, Lena, additional, Stephens, Len, additional, Sternberg, Paul W., additional, Sternweis, Paul C., additional, Steward, Ruth, additional, Stickney, John T., additional, Stoker, Andrew W., additional, Strittmatter, Stephen M., additional, Stronach, Beth E., additional, Strong, Roland K., additional, Stroud, Robert M., additional, Südhof, Thomas C., additional, Sunahara, Roger K., additional, Sutton, Brian J., additional, Szabolcs, Sipeki, additional, Tang, Xiao-Bo, additional, Taskén, Kjetil, additional, Tatebe, Hisashi, additional, Tauszig-Delamasure, Servane, additional, Taylor, Colin W., additional, Taylor, Garry L., additional, Taylor, Laura J., additional, Taylor, Susan S., additional, Thomas, George, additional, Thomas, Robert P., additional, Thompson, E. Brad, additional, Thompson, Michael J., additional, Thornton, Janet M., additional, Thummel, Carl S., additional, Togashi, Hideaki, additional, Tong, Amy Hin Yan, additional, Tonks, Nicholas K., additional, Tontonoz, Peter, additional, Topham, M.K., additional, Torgersen, Knut Martin, additional, Tran, Hien, additional, Tremblay, Michel L., additional, Tsai, Ming-Jer, additional, Tsai, Sophia Y., additional, Tsunoda, Susan, additional, Turley, Stewart, additional, Tyson, Darren, additional, Van Etten, Robert L., additional, Vassart, Gilbert, additional, Verveer, Peter J., additional, Vlaeminck, Virginie, additional, de Vos, Abraham M., additional, Voss, Ty C., additional, Walczak, Robert, additional, Walker, Graham C., additional, Walker, John C., additional, Walter, Gernot, additional, Walter, Mark R., additional, Wang, Fen, additional, Wang, Jean Y.J., additional, Wang, Weiru, additional, Ward, Richard J., additional, Wedegaertner, Philip, additional, Wehrle, Christian, additional, Weiss, Arthur, additional, Weiss, Jamie L., additional, Wells, Alan, additional, Werner, Claudia, additional, West, Ann H., additional, Weston, Marie C., additional, Westwick, John K., additional, Wetterholm, Anders, additional, White, Morris F., additional, Whitman, Malcolm, additional, Whorton, Matt R., additional, Wiesmann, Christian, additional, Williams, Roger L., additional, Willis, William D., additional, Willson, Timothy M., additional, Wilson, Ian A., additional, Wiser, Ofer, additional, Wishart, Matthew J., additional, Wittinghofer, Alfred, additional, Woodgett, James R., additional, Worthylake, David K., additional, Wrana, Jeffrey L., additional, Wu, Hao, additional, Xiao, Yijin, additional, Xu, H. Eric, additional, Xu, Yan, additional, Xu, Zheng, additional, Yaffe, Michael B., additional, Yamada, Kenneth M., additional, Yang, Seun-Ah, additional, Yang, Wannian, additional, Yarden, Yosef, additional, Ye, Hong, additional, Ye, Weilan, additional, Yeates, Todd O., additional, Yin, Helen L., additional, York, John D., additional, Young, Edgar C., additional, Young, Kenneth W., additional, Young, Matthew A., additional, Young, Michael W., additional, Yu, Minmin, additional, Zaccai, Nathan R., additional, Zaccolo, Manuela, additional, Zamir, Eli, additional, von Zastrow, Mark, additional, Zhang, Chao, additional, Zhang, Xuewu, additional, Zhang, Zhong-Yin, additional, Zhou, Wenhong, additional, and Zoraghi, Roya, additional

Published
2003
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37. Transgenic complementation of MARCKS deficiency with a nonmyristoylatable, pseudo-phosphorylated form of MARCKS: evidence for simultaneous positive and dominant-negative effects on central nervous system development

Author

Kim, Hae Sook, Swierczynski, Sharon L., Tuttle, Jane S., Lai, Wi S., and Blackshear, Perry J.

Subjects
Protein kinases -- Research, Central nervous system -- Research, Mice -- Research, Biological sciences
Abstract

MARCKS is a widely expressed protein kinase C substrate that is essential for normal prenatal development of the central nervous system in mice. MARCKS-deficient mice exhibit universal perinatal mortality and numerous developmental abnormalities of the brain and retina. To determine which domains of the protein were important in complementing these neurodevelopmental anomalies, we have interbred MARCKS knockout mice with transgenic mice expressing an epitope-tagged human MARCKS transgene that can completely correct the MARCKS-deficient phenotype. Previous structure-function studies showed that a nonmyristoylatable form of MARCKS could correct all of the neuroanatomical abnormalities, and resulted in approximately 25% viable pups that grew to adulthood and were fertile. The present experiment attempted a similar complementation strategy in which a nonmyristoylatable, 'pseudo-phosphorylated' form of the protein was used, which has been shown to be almost completely cytosolic in cell expression studies. Surprisingly, this transgene was able to complement almost all of the cerebral anatomical abnormalities characteristic of the knockout mice. However, these mice also exhibited a universal, novel phenotype: profound retinal ectopia, in which retinal tissue was often found in the vitreous humor as well as extraocularly. Retrospective evaluation of the original MARCKS knockout phenotype revealed that this anomaly was present in about 43% of the knockout mice, and was clearly detectable as early as embryonic day 12.5, before retinal cell differentiation begins. These data suggest that a nonmyristoylatable, pseudo-phosphorylated form of MARCKS can complement most if not all cerebral aspects of the MARCKS-deficient phenotype, but that it appears to worsen a retinal phenotype, perhaps by exerting a dominant-negative effect on a coexpressed MARCKS homologue.

Published
1998

38. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin

Author

Carballo, Ester and Lai, Wi S.

Subjects
Tumor necrosis factor -- Research, Cellular signal transduction -- Research, Science and technology, Research
Abstract

Tumor necrosis factor-[Alpha] (TNF-[Alpha]) is a major mediator of both acute and chronic inflammatory responses in many diseases. Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-[Alpha] production from macrophages by destabilizing its messenger RNA. This effect appeared to result from direct TTP binding to the AU-rich element of the TNF-[Alpha] messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-[Alpha] production, including TNF-[Alpha] itself. These findings identify TTP as a component of a negative feedback loop that interferes with TNF-[Alpha] production by destabilizing its messenger RNA. This pathway represents a potential target for anti-TNF-[Alpha] therapies., TNF-[Alpha] is one of the principal mediators of the inflammatory response in mammals (1). In addition to its well-known role in acute septic shock, it has been implicated in the [...]

Published
1998

40. Interaction of retroviral tax oncoproteins with tristetraprolin and regulation of tumor necrosis factor-[alpha] expression

Author

Twizere, Jean-Claude, Kruys, Veronique, Lefebvre, Laurent, Vanderplasschen, Alain, Collete, Delphine, Debacq, Christophe, Lai, Wi S., Jauniaux, Jean-Claude, Bernstein, Lori R., Semmes, O. John, Burny, Arsene, Blackshear, Perry J., Kettmann, Richard, and Willems, Luc

Subjects
Leukemia -- Development and progression, Cancer -- Diagnosis, Cancer -- Genetic aspects, Cancer -- Research, Health
Abstract

Background: The Tax oncoproteins are transcriptional regulators of viral expression involved in pathogenesis induced by complex leukemogenic retroviruses (or delta-retroviruses, i.e., primate T-cell leukemia viruses and bovine leukemia virus). To better understand the molecular pathways leading to cell transformation, we aimed to identify cellular proteins interacting with Tax. Methods: We used a yeast two-hybrid system to identify interacting cellular proteins. Interactions between Tax and candidate interacting cellular proteins were confirmed by glutathione S-transferase (GST) pulldown assays, co-immunoprecipitation, and confocal microscopy. Functional interactions between Tax and one interacting protein, tristetraprolin (TTP), were assessed by analyzing the expression of tumor necrosis factor-[alpha] (TNF-[alpha]), which is regulated by TTP, in mammalian cells (HeLa, D17, HEK 293, and RAW 264.7) transiently transfected with combinations of intact and mutant Tax and TTP. Results: We obtained seven interacting cellular proteins, of which one, TTP, was further characterized. Tax and TTP were found to interact specifically through their respective carboxyl-terminal domains. The proteins colocalized in the cytoplasm in a region surrounding the nucleus of HeLa cells. Furthermore, coexpression of Tax was associated with nuclear accumulation of TTP. TTP is an immediate-early protein that inhibits expression of TNF-[alpha] at the post-transcriptional level. Expression of Tax reverted this inhibition, both in transient transfection experiments and in stably transfected macrophage cell lines. Conclusion: Tax, through its interactions with the TTP repressor, indirectly increases TNF-[alpha] expression. This observation is of importance for the cell transformation process induced by leukemogenic retroviruses, because TNF-[alpha] overexpression plays a central role in pathogenesis.

Published
2003

41. Tunable emission properties of Eu ions in KBPO4(B = Ca, Sr, and Ba) via variation in their valence states

Author

Lee, D. J., Kwark, M. C., Kim, D. Y., Wi, S. W., Chung, J.-S., Kim, Il Won, Kwark, Young-Je, and Lee, Y. S.

Abstract

We investigated the luminescent behavior of KBPO4(KBPO4:Eu) nanocrystals (NC) doped with europium (Eu) ions, where B = Ca, Sr, and Ba. The NC samples were fabricated via the chemical method and annealed in different ambient environments for regulating the number of oxygen vacancies in the NCs. We observed that the as-synthesized KBPO4:Eu exhibited red emissions, which is a characteristic of Eu3+. In the H2-annealed samples, where the number of oxygen vacancies increased via the reduction process, the orange–red luminescence from Eu3+was considerably suppressed and blue emission from Eu2+was significant. After subsequent O2-annealing to decrease oxygen vacancies via oxidation, the red emissions of the KBPO4:Eu were recovered. This reversible conversion between Eu2+and Eu3+occurred commonly in the NCs irrespective of B ions. The results suggest that H2/O2-annealing in the local environment around the Eu ions can control the valence states of Eu ions and the related emission color of KBPO4:Eu.

Published
2022
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42. Enhanced stability of tristetraprolin mRNA protects mice against immune-mediated inflammatory pathologies

Author

Alan D. Curtis, Perry J. Blackshear, Mark D. Mannie, Gordon P. Flake, Georgette D. Hill, Sonika Patial, Deborah J. Stumpo, and Wi S. Lai

Subjects
0301 basic medicine, Encephalomyelitis, Autoimmune, Experimental, medicine.medical_treatment, Tristetraprolin, Arthritis, Dermatitis, Mice, Transgenic, Inflammation, Biology, medicine.disease_cause, Proinflammatory cytokine, Autoimmunity, Mice, 03 medical and health sciences, medicine, Animals, RNA, Messenger, Cells, Cultured, Imiquimod, Multidisciplinary, Experimental autoimmune encephalomyelitis, Biological Sciences, medicine.disease, Arthritis, Experimental, 030104 developmental biology, Cytokine, Mutation, Immunology, Aminoquinolines, Tumor necrosis factor alpha, Collagen, medicine.symptom
Abstract

Tristetraprolin (TTP) is an inducible, tandem zinc-finger mRNA binding protein that binds to adenylate-uridylate-rich elements (AREs) in the 3'-untranslated regions (3'UTRs) of specific mRNAs, such as that encoding TNF, and increases their rates of deadenylation and turnover. Stabilization of Tnf mRNA and other cytokine transcripts in TTP-deficient mice results in the development of a profound, chronic inflammatory syndrome characterized by polyarticular arthritis, dermatitis, myeloid hyperplasia, and autoimmunity. To address the hypothesis that increasing endogenous levels of TTP in an intact animal might be beneficial in the treatment of inflammatory diseases, we generated a mouse model (TTPΔARE) in which a 136-base instability motif in the 3'UTR of TTP mRNA was deleted in the endogenous genetic locus. These mice appeared normal, but cultured fibroblasts and macrophages derived from them exhibited increased stability of the otherwise highly labile TTP mRNA. This resulted in increased TTP protein expression in LPS-stimulated macrophages and increased levels of TTP protein in mouse tissues. TTPΔARE mice were protected from collagen antibody-induced arthritis, exhibited significantly reduced inflammation in imiquimod-induced dermatitis, and were resistant to induction of experimental autoimmune encephalomyelitis, presumably by dampening the excessive production of proinflammatory mediators in all cases. These data suggest that increased systemic levels of TTP, secondary to increased stability of its mRNA throughout the body, can be protective against inflammatory disease in certain models and might be viewed as an attractive therapeutic target for the treatment of human inflammatory diseases.

Published
2016

43. Emergence and evolution of Zfp36l3

Author

Timothy J. Gingerich, Scott J. Steppan, Thomas A. Randall, Deborah J. Stumpo, Perry J. Blackshear, and Wi S. Lai

Subjects
0301 basic medicine, Peromyscus, Retroelements, Placenta, Rodentia, Article, Evolution, Molecular, 03 medical and health sciences, Tristetraprolin, Start codon, Pregnancy, Phylogenetics, Gene expression, Genetics, Animals, Humans, Gene family, RNA, Messenger, Muroidea, Molecular Biology, Gene, Phylogeny, Ecology, Evolution, Behavior and Systematics, Repetitive Sequences, Nucleic Acid, Cell Nucleus, biology, Intron, Proteins, biology.organism_classification, Introns, Muridae, 030104 developmental biology, Female
Abstract

In most mammals, the Zfp36 gene family consists of three conserved members, with a fourth member, Zfp36l3, present only in rodents. The ZFP36 proteins regulate post-transcriptional gene expression at the level of mRNA stability in organisms from humans to yeasts, and appear to be expressed in all major groups of eukaryotes. In Mus musculus, Zfp36l3 expression is limited to the placenta and yolk sac, and is important for overall fecundity. We sequenced the Zfp36l3 gene from more than 20 representative species, from members of the Muridae, Cricetidae and Nesomyidae families. Zfp36l3 was not present in Dipodidae, or any families that branched earlier, indicating that this gene is exclusive to the Muroidea superfamily. We provide evidence that Zfp36l3 arose by retrotransposition of an mRNA encoded by a related gene, Zfp36l2 into an ancestral rodent X chromosome. Zfp36l3 has evolved rapidly since its origin, and numerous modifications have developed, including variations in start codon utilization, de novo intron formation by mechanisms including a nested retrotransposition, and the insertion of distinct repetitive regions. One of these repeat regions, a long alanine rich-sequence, is responsible for the full-time cytoplasmic localization of Mus musculus ZFP36L3. In contrast, this repeat sequence is lacking in Peromyscus maniculatus ZFP36L3, and this protein contains a novel nuclear export sequence that controls shuttling between the nucleus and cytosol. Zfp36l3 is an example of a recently acquired, rapidly evolving gene, and its various orthologues illustrate several different mechanisms by which new genes emerge and evolve.

Published
2016

44. A Knock-In Tristetraprolin (TTP) Zinc Finger Point Mutation in Mice: Comparison with Complete TTP Deficiency

Author

Deborah J. Stumpo, Roberta Faccio, Perry J. Blackshear, Lian-Qun Qiu, and Wi S. Lai

Subjects
0301 basic medicine, RNA Stability, Mutant, Tristetraprolin, RNA-binding protein, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, hemic and lymphatic diseases, Animals, Humans, Point Mutation, Amino Acid Sequence, Gene Knock-In Techniques, RNA, Messenger, Molecular Biology, AU-rich element, Zinc finger, AU Rich Elements, Mice, Knockout, Messenger RNA, RNA, Zinc Fingers, Cell Biology, respiratory system, Molecular biology, Mice, Inbred C57BL, 030104 developmental biology, 030220 oncology & carcinogenesis, Knockout mouse, Mutation, Research Article
Abstract

Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that can bind to AU-rich element-containing mRNAs and promote their decay. TTP knockout mice develop a severe inflammatory syndrome, largely due to excess tumor necrosis factor (TNF), whose mRNA is a direct target of TTP binding and destabilization. TTP's RNA binding activity and its ability to promote mRNA decay are lost when one of the zinc-coordinating residues of either zinc finger is mutated. To address several long-standing questions about TTP activity in intact animals, we developed a knock-in mouse with a cysteine-to-arginine mutation within the first zinc finger. Homozygous knock-in mice developed a severe inflammatory syndrome that was essentially identical to that of complete TTP deficiency, suggesting that TTP's critical anti-inflammatory role in mammalian physiology is secondary to its ability to bind RNA. In addition, there was no evidence for a "dominant-negative" effect of the mutant allele in heterozygotes, as suggested by previous experiments. Finally, mRNA decay experiments in mutant macrophages demonstrated that TTP can regulate the stability of its own mRNA, albeit to a minor extent. These studies suggest that RNA binding is an essential first step in the physiological activities of members of this protein family.

Published
2018

50. Tristetraprolin (TTP) coordinately regulates primary and secondary cellular responses to proinflammatory stimuli

Author

Wi S. Lai, Lian-Qun Qiu, Darryl C. Zeldin, Perry J. Blackshear, and Alyce Bradbury

Subjects
Lipopolysaccharides, Transcription, Genetic, Chemokine CXCL1, RNA Stability, Recombinant Fusion Proteins, IER3, Chemokine CXCL2, Immunology, Tristetraprolin, Biology, Leukemia Inhibitory Factor, Immediate early protein, Immediate-Early Proteins, Proinflammatory cytokine, Mice, hemic and lymphatic diseases, Animals, Humans, Immunology and Allergy, heterocyclic compounds, RNA, Messenger, 3' Untranslated Regions, neoplasms, Cells, Cultured, AU Rich Elements, Inflammation, Mice, Knockout, AU-rich element, Regulation of gene expression, Messenger RNA, Binding Sites, Tumor Necrosis Factor-alpha, Macrophages, Inflammation, Extracellular Mediators, & Effector Molecules, Toll-Like Receptors, Cell Biology, Fibroblasts, respiratory system, Molecular biology, Mice, Inbred C57BL, Chemotaxis, Leukocyte, Gene Expression Regulation, Cyclooxygenase 2, Tumor necrosis factor alpha, therapeutics
Abstract

TTP is an anti-inflammatory protein that acts by binding to AREs in its target mRNAs, such as Tnf mRNA, and promoting their deadenylation and decay. TNF released from inflammatory cells can then stimulate gene expression in tissue cells, such as fibroblasts. To determine whether TTP could affect the decay of TNF-induced transcripts in fibroblasts, we exposed primary embryonic fibroblasts and stable fibroblast cell lines, derived from WT and TTP KO mice, to TNF. The decay rates of transcripts encoded by several early-response genes, including Cxcl1, Cxcl2, Ier3, Ptgs2, and Lif, were significantly slowed in TTP-deficient fibroblasts after TNF stimulation. These changes were associated with TTP-dependent increases in CXCL1, CXCL2, and IER3 protein levels. The TTP-susceptible transcripts contained multiple, conserved, closely spaced, potential TTP binding sites in their 3′-UTRs. WT TTP, but not a nonbinding TTP zinc finger mutant, bound to RNA probes that were based on the mRNA sequences of Cxcl1, Cxcl2, Ptgs2, and Lif. TTP-promoted decay of transcripts encoding chemokines and other proinflammatory mediators is thus a critical post-transcriptional regulatory mechanism in the response of secondary cells, such as fibroblasts, to TNF released from primary immune cells.

Published
2015

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