Wiese


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501A Bock Labs
1525 Linden Drive

Madison, WI 53706-1596
USA

Office:
(608) 263-7608
Lab Rm 501

   

Christiane Wiese

           

Assistant Professor, Kimmel Scholar
B.A., B.S.: University of Kansas
Ph.D.: Johns Hopkins University School of Medicine

      

Molecular mechanisms of mitotic spindle assembly and microtubule nucleation; cell-cycle dependent regulation of spindle assembly proteins; centrosome structure and function

Many fundamental cellular processes take advantage of the intrinsic polarity of microtubules. Processes that use microtubules as molecular tracks include vesicular trafficking, cell motility, organelle translocation, and, most prominently, cell division. In animal cells, microtubules are organized by the centrosome, which aids in microtubule initiation (termed 'nucleation'), anchoring, and organization. Centrosome defects are thought to be involved in a variety of human diseases, including male infertility and cancer. Centrosomes nucleate radial arrays of microtubules during interphase and mark the poles of the elaborate macromolecular structure required for the proper segregation of chromosomes, the mitotic spindle, during mitosis. Because defects in cell division are central to the progression of cancer, a molecular understanding of spindle structure and function could lead to a better understanding of cancer and its potential therapies.

Our long-term goal is to elucidate the principles that underlie the assembly and function of the mitotic spindle and to identify and study the roles of individual proteins that are involved in this process. We focus our current efforts on proteins required for microtubule nucleation, stabilization, and organization. The small Ras-like GTPase, RanGTP, which is required for nuclear transport during interphase, has recently been identified as a regulator of spindle assembly in mitotic Xenopus laevis egg extracts. We discovered that Ran exerts its effects through importin β, a protein which functions as a nuclear import receptor during interphase. We showed that during mitosis, importin β functions as a potent inhibitor of spindle assembly. This inhibition by importin β is relieved in the presence of RanGTP, which is known to interact with importin-β and to cause it to release its `cargo'. We are currently trying to understand the molecular mechanism of the effect of importin β on spindle assembly factors. Some of our questions are: How does importin β inhibit spindle assembly? Does its binding to spindle assembly factors prevent these from performing their functions? Does its binding prevent phosphorylation (or other secondary modifications) of the spindle assembly factors? Does it prevent interaction with other proteins?

In another line of investigation, we are interested in understanding the molecular mechanism of a protein complex involved in the nucleation of microtubules from centrosomes. This protein complex, known as the γ-tubulin ring complex (γTuRC), can nucleate microtubules in vitro. In addition, it also caps the so-called minus ends of microtubules, preventing their growth and shrinkage. We want to understand the biophysical properties of the interaction between the γTuRC and the end of the microtubule. In a more cell biological approach, we want to identify cellular factors that regulate the interaction of the γTuRC with the microtubule, as well as those that regulate the interaction of the γTuRC with the centrosome.


figureTwo models for the interaction between the γTuRC (red, blue, green) and the end of the microtubule (yellow, light blue) have been proposed, differing mainly by the arrangement of γ-tubulin (green) and the other γTuRC subunits (red, blue) with respect to tubulin (yellow, light blue).



    

 

 

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