Pharmacology
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Edith Wang, Ph.D.,
Associate Professor

Lab Website
Publications
Course Websites
  phcol401  phcol510
  phcol513  phcol535
  phcol550  phcol572
Email: ehwang@uw.edu
Box 357280
HSC E417

Office: 206.616.5376
Lab: 206.616.5917
Fax: 206.685.3822
 

 

 

 

 

 

 

Control of gene expression in Cell Proliferation, Muscle Differentiation and Human Disease

The expression of protein encoding genes is essential for the execution of all cellular processes. My lab focuses on understanding the contribution of gene transcription to the regulation of cell proliferation, muscle differentiation, and the development of human disease. We use a variety of molecular, biochemical and cellular techniques to investigate the process of gene transcription and the protein components involved under normal and pathologic conditions.

Acetyltransferase Activity of TAF1 in Cell Cycle Gene Transcription

Figure We are interested in the molecular mechanisms governing the expression of cell cycle control genes. Mutations that disrupt the histone acetyltransferase activity (HAT) of TAF1, the largest subunit of the transcription factor TFIID factor complex, lead to defects in cyclin gene transcription and induce cells to undergo a G1 cell cycle arrest. Some questions that we are addressing include: "What regulates the acetyltransferase activity of TAF1?" and "What defines the acetyltransferase domain of TAF1 and does is represent a distinct family of enzymes with unique regulatory properties?" The binding of TAF1 to TAF7, another TFIID subunit, inhibits the acetyltransferase activity of TAF1. Phosphorylation of TAF1 by the autocatalytic kinase activity of TAF1 disrupts the interaction of TAF7 with TAF1 and therefore represents a potential mechanism for controlling TAF1 acetyltransferase activity and ultimately cell cycle progression. A long-term objective of this work is to determine if TAF1 represents a potential therapeutic target for inhibiting the uncontrolled proliferation characteristic of tumor cells.

MBNL3: An Inhibitor of Muscle Differentiation and its Role in Myotonic Dystrophy,

Figure Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disorder that is genetically linked to CUG and CCUG repeat expansions in the noncoding region of the DMPK and Znf9 genes, respectively. Since the DMPK and ZNF9 genes display no apparent functional similarities, it has been proposed that the expanded mutant RNA transcripts, which accumulate in the nuclei of diseased cells, gain a dominant negative function and are essential for DM pathogenesis. Our interest in myotonic dystrophy was initiated by the cloning of the MBNL3 gene. MBNL3 encodes a 342 amino acid zinc finger protein that displays 43% amino acid identity to drosophila muscleblind (Mbl), a nuclear protein essential for muscle development in flies. Three mammalian muscleblind-like (MBNL) proteins have been identified and all three proteins have shown the potential to colocalize with CUG and CCUG repeat expansions in myotonic dystrophy cells.

MBNL1 is thought to function as a positive regulator of muscle differentiation. We have complementary gain- and loss-of function results suggesting that MBNL3 is an inhibitor of muscle formation and down-regulates muscle gene expression. These findings suggest that a delicate balance between positive and negative regulators is critical for the proper execution of the myogenic program. Current research projects include the identification and characterization of MNBL3 binding proteins, investigation of mechanism of MBNL3 action in expression and pre-mRNA splicing of muscle genes, and mapping the domains of MBNL3 essential for its inhibitory function. Our long-term goal is to gain a better understanding of the molecular mechanisms of MBNL3 action during muscle differentiation and its contribution to the pathogenesis of myotonic dystrophy.



 

Recent Publications 

Pneumocystis pneumonia in solid organ transplant recipients: not yet an infection of the past. - ABSTRACT

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