PITSLRE KINASE GENE ALTERATIONS IN NEUROBLASTOMA

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DESCRIPTION: A group of protein kinases related to p34cdc2, 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, p58-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 -90 kb on chromosome 1p36. At least three of the PITSLRE kinase isoforms appear to function as effectors of apoptotic signal transduction. The p36 region of chromosome 1 is frequently deleted during the late stages of tumorigenesis in neuroblastoma, as well as other tumors. Several groups have proposed that at least two tumor suppressor genes reside within this chromosome region. The 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, they have proposed that the proliferative advantage offered by N-myc overexpression occurs after apoptotic signaling pathway(s) have been disabled, most likely due to the partial of complete inactivation of one or more of the PITSLRE protein kinase(s). Mutating or extinguishing the expression of proteins involved in apoptotic pathways may be a critical step in tumor cell development. To test this hypothesis in human neuroblastoma they will perform the studies outlined in this proposal. First, they will identify any genetic lesions in the PITSLRE isoforms expressed in neuroblastoma cell lines and in neuroblastoma patient material. The functional properties of PITSLRE mutants identified in this screen will be assayed in vitro and in vivo. Secondly, wild-type PITSLRE kinase activity will be restored in neuroblastoma cells containing altered PITSLRE isoforms and amplified N-myc genes. The ability of neuroblastoma cells with normal PITSLRE kinase levels and normal N-myc levels to tolerate experimentally induced amplification and overexpression of N-myc will also be tested. Finally, defects in receptor-mediated apoptotic signaling pathways involving PITSLRE kinase(s) have been observed in several of these neuroblastoma cell lines. They will examine these pathways in an attempt to determine the nature of their defect. The studies described above will establish whether haploinsufficiency and/or total inactivation of the PITSLRE kinase(s), as well as the ability of N-myc genes to amplify and enhance tumor growth, are synergistic.