Dr. Ann-Bin Shyu, Professor and Jesse H. Jones Chair
in Molecular Biology

Department of Biochemistry and Molecular Biology
Program in Biochemistry and Molecular Biology

University of Texas-Houston Medical School
P.O. Box 20708 - Houston, Texas 77225
(713) 500-6068 fax:(713)500-0575
email: Ann-Bin.Shyu@uth.tmc.edu

Ph.D, Indiana Univeristy, Bloomington
American Cancer Society Postdoctoral Fellow, Harvard Medical School
Juinior Faculty Research Award, American Cancer Society
Established Investigator Award, American Heart Association

Senior Investigator Award, Sandler Foundation for Asthma Research

mechanisms controlling mammalian mrna turnover and their roles in human disease

My laboratory is investigating the mechanisms responsible for mRNA turnover in mammalian cells, including elucidation of the relationship between translation and mRNA degradation, and their roles in regulating gene expression.  Both the translation and the stability of mRNAs are affected by deadenylation (i.e., shortening of the mRNA 3’ poly(A) tail), which begins when mRNAs arrive in the cytoplasm .  Deadenylation is often a rate-limiting step for mRNA decay and translational silencing and is thus a critical control point in both processes. Two recent developments in eukaryotic mRNA turnover underscore the importance of deadenylation in regulation of gene expression.  First, microRNAs (miRNAs) promote rapid decay of their mRNA targets by accelerating deadenylation as a major means of achieving gene silencing. Second, non-translatable mRNA-protein complexes (mRNPs) are found in RNA processing bodies (P-bodies), newly discovered cytoplasmic domains implicated in mRNA turnover, storage of non-translatable mRNPs, and translation repression. One major consequence of deadenylation is the formation of non-translatable mRNPs.  We hypothesized and subsequently demonstrated a close link between deadenylation and P-bodies in mammalian cells.  Our research focuses on addressing the following fundamental questions: 1) What are the mechanisms by which deadenylation is regulated and how does regulation of deadenylation affect the fate of mRNA?  2) What trans-acting factors are involved in miRNA-mediated deadenylation and decay? 3) How is miRNA-mediated mRNA decay regulated?  4) What changes does deadenylation trigger in mRNA-protein or mRNP complexes and how do these changes influence the fate of an mRNA?  5) What is the functional link between deadenylation and P-bodeis?  This line of research will reveal fundamental principles that govern mammalian mRNA turnover and provide crucial new insights into several key issues related to the dynamic relationship between mRNA decay, translational control, mRNP remodeling and P-bodies.

Another research area focuses on the post-transcriptional mechanisms controlling the inflammatory response of human bronchial epithelial cells—in health and in airway disease —particularly in the context of RNA biology.  Currently, our work along this line has focused on miRNA, the predominant small regulatory RNA subtype in humans (and in all animals).  The study of small regulatory RNAs is a relatively new and unexplored research field with much potential. miRNAs serve fundamental biological functions in all animals studied.  Our research aim is to analyze and manipulate these small molecules in order to learn how miRNA biology is altered in inflammatory airway diseases and how miRNAs help control decay and translation of mRNAs coding for inflammatory mediators and tissue remodeling factors.  We seek both to understand how miRNAs contribute to disease pathogenesis, and as a long-term goal to explore how specially designed RNAs may be applied for therapeutic strategies.

Chen, C-Y A, Zheng, D, Xia, Z, and Shyu, A-B. Ago-TNRC6 triggers microRNA-mediated decay by promoting two deadenylation steps. Nature Struct Mol Biol, 16:1160-1166, 2009. [Epub ahead of print].

Mauxion, F, Chen, C-Y A, Seraphin, B, and Shyu, A-B. BTG/Tob factors impact deadenylases. Trends Biochem Sci, Oct 12, 2009. [Epub ahead of print].

Fabian, MR, Mathonnet, G, Sundermeier, T, Mathys, H, Zipprich, JT, Svitkin, YV, Rivas, F, Jenik, M, Wohlschlegel, J, Doudna, JA, Chen, C-Y A, Shyu, A-B, Yates III, JR, Hannon, GJ, Filipowicz, W, Duchaine, TF, Sonenberg, N. Mammalian miRNA RISC recruits CAF1 and PABP to affect PABP-dependent deadenylation. Mol Cell, 35:868-80, 2009.

Chen C-Y A, Ezzeddine N, Shyu A-B. Messenger RNA half-life measurements in mammalian cells. Methods Enzymol. 448:335-357, 2008.

Martineau Y, Derry MC, Wang X, Yanagiya A, Berlanga JJ, Shyu A-B, Imataka H, Gehring K, Sonenberg N. Poly(A)-binding protein-interacting protein 1 binds to eukaryotic translation initiation factor 3 to stimulate translation. Mol Cell Biol. 28:6658-6667, 2008.

Zhai, Y, Zhong, Z, Chen, C-Y A, Xia, Z, Song, L, Blackburn, MR, Shyu, A-B. Coordinated changes in mRNA turnover, translation, and RNA processing bodies in bronchial epithelial cells following inflammatory stimulation. Mol Cell Biol. 28:7414-7426, 2008.

Zheng, D, Ezzeddine, N, Chen, C-Y A , Zhu, W, He, X, and Shyu, A-B. Deadenylation is prerequisite for P-body formation and mRNA decay in mammalian cells. J Cell Biol 182:89-101, 2008.

Shyu, A-B, Wilkinson, M, and van Hoof, A. Messenger RNA regulation: To translate or to degrade. EMBO J, 27: 471-481, 2008.

Ezzeddine, N, Chang, T-C, Yamshita, A, Chen, C-Y A, Zhu, W, Zhong, Z, Yamashita, Y, Zheng, D. and Shyu, A-B. Human TOB, an anti-proliferative transcription factor, is a PABP-dependent positive regulator of cytoplasmic mRNA deadenylation. Mol Cell Biol, 27: 7791-7801, 2007.

Chen, C-Y A, Yamashita, Y, Chang, T-C, Yamshita, A, Zhu, W, Zhong, Z, and Shyu, A-B. Versatile applications of transcriptional pulsing to study of mRNA turnover in mammalian cells. RNA, 13: 1775-86, 2007.

Siddiqui, N, Mangus, D A, Chang, T-C, Palermino, J-M, Shyu, A-B, and Gehring, K. Poly(A)-nuclease interacts with the PABC domain from poly(A)-binding protein. J Biol Chem. 282: 25067-75, 2007.

Lim NS, Kozlov G, Chang TC, Groover O, Siddiqui N, Volpon L, De Crescenzo G, Shyu A-B, Gehring K. Comparative peptide-binding studies of PABC domains from the E3 ubiquitin ligase HYD and poly(A)-binding protein: Implications for HYD function. J Biol Chem. 281: 14376-14382, 2006.

Shyu, A-B. UNRaveling the regulation of dosage compensation. Nature Struct & Mol Biol, 13: 189-190, 2006.

Yamashita, A., Chang, T-C, Yamashita, Y, Zhong, Z, Zhu, W, Chen, C-Y A, and Shyu, A-B. Concerted action of poly(A) nucleases and decapping enzyme in mammalian mRNA turnover. Nature Struct & Mol Biol, 12: 1054-1063, 2005. (*Featured in News & Views by the Journal, see pp. 1024-25)

Chen, C-Y A, Xu, N, Zhu, W, and Shyu, A-B. Functional Dissection of hnRNP D Suggests that Nuclear Import Is Necessary Before hnRNP D Can Modulate mRNA Turnover in the Cytoplasm. RNA, 10:669-680, 2004.

Chang, T-C, Yamashita, A., Chen, C-Y A., Yamashita, Y, Zhu, W, Durdan, S, Kahvejian, A, Sonenberg, S, and Shyu, A-B. UNR, a new partner of poly(A)-binding protein, plays a key role in translationally coupled mRNA turnover mediated by the c-fos major coding-region determinant. Genes & Dev., 18: 2010-2023, 2004. (*Selected for Journal Research Highlights in Nature Structural and Molecular Biology, 11:811, 2004.

Chen, C-Y A, and Shyu, A-B. Rapid Deadenylation Triggered by Nonsense Codon Precedes Decay of the RNA Body in a Mammalian Cytoplasmic Nonsense-Mediated-Decay Pathway. Mol. Cell. Biol. 23: 4805-4813, 2003.

Atasoy, U, Curry, S L, de Silanes, I L, Shyu, A-B, Casolaro, V, Gorospe, M, and Stellato, C. Regulation of eotaxin gene expression by TNFα and IL-4 through messenger RNA stabilization. J Immunology. 171:4369-4378, 2003.

Wilkinson, M.F. and Shyu, A-B. "RNA surveillance by nuclear scanning?" Nature Cell Biol, 4: E144-E147, 2002.

Chen, C-Y A, Xu, N, and Shyu, A-B. Highly Selective Actions of HuR in Antagonizing AU-Rich Element-Mediated mRNA Destabilization. Mol. Cell. Biol. 22: 7268-7278, 2002.

Xu, N, Chen, C-Y A, Shyu, A-B. A versatile role for hnRNP D isoforms in the differential regulation of cytoplasmic mRNA turnover. Mol. Cell. Biol. 21: 6960-6971, 2001.

Wilkinson, M F and Shyu, A-B. Bifunctional regulatory proteins that control gene expression in both the nucleus and the cytoplasm. BioEssays 23:775-787, 2001.

Grosset, C, Chen, C.-Y. A., Xu, N., Jacquemin-Sablon, H., Sonenberg, N. and Shyu, A.-B. A mechanism for translationally-coupled mRNA turnover: interaction between the poly(A) tail and an RNA stability determinant in the c-fos coding region via a novel protein complex. Cell, 103: 29-40, 2000.

Shyu, A-B and Wilkinson, M. The double lives of shuttling RNA-binding proteins. Cell 102: 135-138, 2000.

Search PubMed for a complete list of Dr. Shyu's publications.