Cell proliferation is regulated by several control points, termed checkpoints, and deregulation of these checkpoints may lead to cancer. Protein phosphorylation by the mitotic kinase Cdc2, mainly on Ser/Thr-Pro motifs, plays an essential role in triggering a programmed set of mitotic events. We have recently cloned two novel genes, Pini and Pin2, involved in mitotic regulation. Pini is a novel and conserved peptidyl-prolyl isomerase that specifically catalyzes prolyl isomerization of the phosphorylated Ser/Thr-Pro bond and is the only PPIase documented to be essential for cell survival. Pini uses its N-terminal WW domain, a novel phosphoserine-binding module, to interact with a defined subset of mitosis-specific phosphoproteins, including Cdc2 regulators and substrates. Furthermore, Pini regulates the activity of phosphoproteins and controls the timing of mitotic entry, presumably by phosphorylation-dependent prolyl isomerization. Thus, Pini is a novel post-phosphorylation regulator. Pin2 is a major expressed product of the Pin2/TRF1 gene, which regulates maintenance of telomeres. Telomeres are genetic elements that are essential for preserving chromosome integrity and are implicated in mitotic checkpoint control. Interestingly, Pin2 is also involved in regulation of mitosis. Pin2 interacts with and is also phosphorylated by the ATM protein kinase, encoded by the gene responsible for the human genetic disorder ataxia telangiectasia. This autosomal recessive disorder displays a wide range of abnormalities, including genomic instability, cell cycle checkpoint defects and predisposition to cancer and aging, which are believed to be related to telomere dysfunction. Based on the above findings, we hypothesize that Pini and Pin2 play critical roles in coordinating telomere maintenance and cell division, whose aberrations contribute to oncogenesis. To test this hypothesis, we will :

1. elucidate the molecular mechanism of Pin 1-dependent mitotic regulation,
2. determine the role of the Pin2 and ATM interaction in regulating the cell cycle and telomere maintenance, and
3. evaluate the role of Pin 1 and Pin2 in cancer. These studies should help us understand the molecular mechanisms underlying control of the cell cycle and oncogenesis, and may eventually lead to the development of new therapeutic reagents