STRUCTURE/FUNCTION OF PITSLRE KINASES

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A group of protein kinases related to p34(cdc2), cell cycle-related kinases, exist and apparently function to control various aspects of cell cycle regulation. One member of this family is the PITSLRE protein kinase, p38-PITSLREbeta1. This protein kinase is one of at least ten isoforms in the PITSLRE family, all of which are expressed from three tandemly linked genes spanning approximately 90 kb on chromosome 1p36. Minimal ectopic expression of PITSLREbeta1 in CHO cells results in a late telophase delay, abnormal chromosome segregation, and induction of apoptosis. Based on additional studies demonstrating the induction and activation of PITSLRE kinases during Fas receptor-mediated T cell death, we have determined that at least three of the PITSLRE kinase isoforms may function as effectors of apoptotic signal transduction. In addition, our studies of the PITSLRE gene locus in neuroblastoma cell lines have shown that deletion and/or translocation of these genes occur in most cell lines with amplified N-myc genes. Furthermore, altered expression of one PITSLRE isoform, gamma1, was also observed in several of these cell lines. Based on these results, we have proposed that the proliferative advantage offered by N-myc overexpression may result from the disabling of apoptotic signaling pathway(s), possibly due to the partial of complete inactivation of one or more of the PITSLRE protein kinase(s). Our hypothesis is that a subset of PITSLRE kinase isoform(s) function as effectors in apoptotic signal transduction, and that activation of these isoforms is linked to checkpoint control. In order to prove this hypothesis we plan to determine whether PITSLRE kinases are essential for apoptosis to occur. To demonstrate this, we will ascertain whether inhibition, or ablation, of PITSLRE kinase activity suppresses apoptosis. Furthermore, we plan to characterize the PITSLRE apoptotic signal transduction pathway by identifying potential substrates and/or regulators of these kinases. Finally, we will determine how the PITSLRE kinases are regulated during apoptosis, and whether they are linked to cell cycle checkpoints. The studies described above will establish whether one or more of the PITSLRE kinase(s) are effectors of an apoptotic signal transduction pathway.