STRUCTURE/FUNCTION OF PITSLRE KINASES

一组与p34（cdc 2）相关的蛋白激酶，细胞周期相关 激酶存在并显然起着控制细胞各个方面作用 周期调节该家族的一个成员是PITSLRE蛋白激酶， p38-PITSLRE β 1。这种蛋白激酶是一种至少十种亚型， PITSLRE家族，所有这些家族都由三个串联连接的 染色体1 p36上约90 kb的基因。 极轻微异位 PITSLRE β 1在CHO细胞中的表达导致晚期末期延迟， 异常染色体分离和诱导细胞凋亡。基于 证明PITSLRE诱导和激活的其他研究 在Fas受体介导的T细胞死亡过程中，我们已经确定， 至少三种PITSLRE激酶同种型可以作为 凋亡信号转导此外，我们对PITSLRE的研究 在神经母细胞瘤细胞系中的基因座已经显示，缺失和/或 这些基因的易位发生在具有扩增的N-myc的大多数细胞系中 基因.此外，PITSLRE的一种亚型γ 1的表达改变， 在这些细胞系中也观察到。基于这些结果，我们 已经提出N-myc提供的增殖优势 过度表达可能是由于细胞凋亡信号的失能 途径，可能是由于一个或多个细胞的部分或完全失活， 更多的PITSLRE蛋白激酶。我们的假设是 PITSLRE激酶亚型作为凋亡信号的效应子 转导，并且这些同种型的激活与 检查点控制为了证明这一假设，我们计划确定 PITSLRE激酶是否是凋亡发生所必需的。到 证明这一点，我们将确定是否抑制，或消融， PITSLRE激酶活性抑制细胞凋亡。此外，我们计划 通过以下方式表征PITSLRE凋亡信号转导途径： 鉴定这些激酶的潜在底物和/或调节剂。 最后，我们将确定PITSLRE激酶是如何调节的， 凋亡，以及它们是否与细胞周期检查点有关。的 上述研究将确定一个或多个PITSLRE 激酶是凋亡信号转导途径的效应物。

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.