Xiaomin Chen, Ph.D.

1995, University of California, Berkeley

The University of Texas M. D. Anderson Cancer Center
Department of Genetics

Contact Information

Research Interests:

One of the most direct pathways of polypeptide-stimuled gene activity is the JAK-STAT pathway. STATs are so named because they serve both as signal transducers in the cytoplasm and activators of transcription in the nucleus. The goal of our research is to define the structural and biochemical bases of STAT-mediated transcriptional synergism and the negative regulation of the JAK-STAT pathway.

Different transcriptional activators and DNA-binding proteins have been found to form macromolecular complexes on clustered DNA-recognition elements in enhancer and promoter regions. The resulting composite structures are called enhanceosomes, and they play an important role in synergistic transcriptional activation. However, the molecular details of their protein-protein and protein-DNA interactions remain to be elucidated. Recently, several STAT-involved enhanceosomes have been identified, and they are the targets of our studies.

Inappropriate activation of the STAT proteins has been found in human pathogenesis and malignancy. An understanding of the way in which the activated STATs and their upstream proteins are downregulated will aid in the design of anticancer drugs that target these molecules. Two classes of protein inhibitors have been found to negatively regulate the JAK-STAT pathway. SOCS (suppressors of cytokine signaling) and related proteins are SH2-containing molecules that bind to phosphotyrosine residues on receptors or JAK kinases, preventing downstream signaling. A second class of inhibitors, called PIAS (protein inhibitors of the activated STATs), are STAT-specific inhibitors. The PIAS proteins appear to suppress the DNA-binding activity of STATs, although the exact mechanism is still unclear. Structures of these protein inhibitors in complex with appropriate ligands should allow us to elucidate how this specific inhibition is achieved. Homeostasis of animals is regulated not only by cell growth and differentiation but also by programmed cell death (apoptosis). DNA fragmentation factor (DFF) has recently been found to play an essential role in regulating DNA fragmentation and chromatin condensation during apoptosis. DFF is a heterodimeric protein complex: DFF40 possesses a nuclease activity, whereas DFF45 functions as a molecular chaperone and a specific inhibitor of DFF40. In the event of an apoptotic signal, DFF45 is cleaved and dissociates from DFF40, allowing DFF40 to form an oligomeric complex to cleave DNA. Many of the biochemical details of the DFF pathway remain to be ascertained. Efforts will be made to crystallize and determine the structures of the pathway's proteins and protein complexes.

Depending on the student's interests, a tutorial in my laboratory would provide experience with biochemistry, biophysics, molecular biology, structural biology, as well as molecular biology.


Selected Publications:

Bromberg J, Chen X (2001) STAT proteins: Signal transducers and activators of transcription. Methods Enzymol 333, 138-151

Chen X, Vinkemeir U, Zhao Y, Jeruzalmo D, Darnell JE, Jr, Kuriyan J (1998) Crystal structure of a tyrosine phosphorylates STAT-1 dimer on DNA. Cell 93:827-839

Chen X, Koshland DE Jr (1997) Probing the structure of the cytoplasmic domain of the aspartate receptor by targeted disulfide cross-linking. Biochemistry 36, 11858-11864

Sano T, Pandori MW, Chen X, Smith CL, Cantor CR (1995) Recombinant core streptavidins. A minimum-sized core streptavidin has enhanced structural stability and higher accessibility to biotinylated macromolecules. J Biol Chem 270, 28204-28209

Ito M, Guerriero V Jr, Chen XM, Hartshorne DJ (1991) Definition of the inhibitory domain of smooth muscle myosin light chain kinase by site-directed mutagenesis. Biochemistry 30, 3498-3503

Additional Publications

 

Program Affiliation:

Program in Genes and Development