Bioprobe Application Research Unit (Closed)

Nobumoto Watanabe
Unit Leader
N. Watanabe

We are studying the regulation of cell cycle regulatory proteins, especially proteins that regulate mitosis. A complex of mitotic cyclin and cyclin dependent kinase (CDK) is the main regulator of mitosis and there are several proteins that regulate the activity of the complex. One such protein we have focused on is Wee1, a protein kinase that inactivates cyclin/CDK until cells become ready for mitosis. Upon the onset of mitosis, Wee1 is inactivated both by protein phosphorylation and degradation. As shown in the figure, we have recently identified a protein kinase cascade that induces the degradation of human somatic type Wee1 (Wee1A) through protein ubiquitination and proteasome dependent manner.
We also study an HIV-1 encoded protein, Vpr, that also inhibits the entry of mitosis. Vpr is important in AIDS pathogenesis, therefore we would like to know its mode of action. Using the knowledge about the action of these cell cycle regulatory proteins, we are currently focusing on the isolation of small molecule inhibitors of them. We recently established a screening system for the inhibitors of phosphorylation dependent protein-protein interaction such as polo box domain (PBD) dependent binding that is important for the Wee1 degradation upon the onset of mitosis. We also made a screening system for Vpr inhibitors using budding yeast, Saccharomyces cerevisiae, and isolated inhibitors of Vpr.

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