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Research Projects

The Nuclear Periphery and the Oncogenic Protein Mlp/Tpr:
Functional Studies of its Yeast Homolog

The instructions encoded in the DNA present in each cell are at the heart of regulating cell growth and development in organisms as diverse as yeast and humans. Exciting recent discoveries point to how it is not just changes in the instructions themselves, but how they are organized and controlled, that cause cancers.

Diagram of the yeast nucleus.
Diagram of the yeast nucleus.
The facing upper quadrant of the nuclear envelope is cut away.
Mlp2p interact with the core of assembled SPBs.
Mlp2p interact with the
core of assembled SPBs.

Mlp2p interacts with assembled SPB cores. DynaBeads carrying Mlp1p-PrA (a) or Mlp2p-PrA (b, c and d) containing complexes were prepared from either haploid (a, b, and c) or diploid (d) cells and visualized by TEM. Small arrows, clearly discernable haploid SPBs. (c) Three representative examples of haploid SPBs bound to Mlp2p-PrA beads at higher magnification. (d) Three examples of diploid SPBs bound to Mlp2p-PrA beads. Bars, 500nm (c and d); 100nm (e and f).

DNA is packaged in a highly ordered fashion inside a central container termed the nucleus. This container is surrounded by a barrier called the nuclear envelope (NE), which also anchors the DNA around the edges of the nucleus. Scattered across the envelope are many small circular channels, called nuclear pores, which act as the gatekeepers of the nucleus. By regulating what can get in and out of the nucleus, and by allowing only some of the anchored DNA to be accessible, the NE can thus play a crucial role in controlling which of the instructions in the DNA are active. The importance of the NE to proper control of the cell's DNA is demonstrated by the finding of many cancers associated with mutations in NE and nuclear pore proteins, and of cancer-like changes in cells associated with changes in how a set of DNA instructions is attached to the NE.

The only protein known to bridge between the nuclear pores and the sites where DNA is found anchored to the NE is Mlp/Tpr. It is known to play crucial roles in the gatekeeping and DNA control functions of the NE. Despite its importance, we still know almost nothing about what Mlp/Tpr actually does.
Strambio-de-Castillia et al., 1999 (PDF)

Our project uses the simple model cell yeast to find the binding partners of Mlp/Tpr within the cell nucleus. We have developed biochemical and cell biological methods to dissect the processes Mlp/Tpr controls in the cell. These methods have allowed us to identify Mlp/Tpr's nuclear pore binding sites. In addition, we discovered that yeast Mlp/Tpr binds to the organelle responsible for the organization of microtubules, cellular division and growth called the spindle pole body (SPB). We have made considerable advances in the understanding of the significance of these interactions on the regulation of cell proliferation.
Niepel et al., 2005 (PDF)