STRUCTURE/FUNCTION OF PITSLRE KINASES

一组与p34(Cdc2)相关的蛋白激酶，与细胞周期相关 激酶的存在，显然起着控制细胞各个方面的作用 周期调节。这个家族的一个成员是PITSLRE蛋白激酶， P38-PITSLREbeta1.这种蛋白激酶是至少十种异构体之一。 PITSLRE家族，所有这些基因都表达于三个紧密相连的基因 染色体1p36上约90kb的基因。最小异位 PITSLREbeta1在CHO细胞中的表达导致晚期端粒延迟， 染色体异常分离，并诱导细胞凋亡。基于 其他研究表明PITSLRE的诱导和激活 在Fas受体介导的T细胞死亡过程中，我们已经确定 至少有三种PITSLRE激酶亚型可能发挥作用 细胞凋亡信号转导。此外，我们对PITSLRE的研究 神经母细胞瘤细胞系中的基因座显示缺失和/或 这些基因的易位发生在大多数N-myc扩增的细胞系中 基因。此外，PITSLRE亚型Gamma1的表达发生了变化 在几个这样的细胞系中也观察到了。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失活所致 通路(S)，可能是由于一个或一个完全失活的部分 更多的是PITSLRE蛋白激酶(S)。我们的假设是 PITSLRE激酶亚型(S)在细胞凋亡信号中的作用 转导，这些异构体的激活与 检查站控制。为了证明这一假设，我们计划确定 PITSLRE激酶是否是细胞凋亡发生所必需的。至 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 PITSLRE细胞凋亡信号转导途径的研究 确定这些激酶的潜在底物和/或调节子。 最后，我们将确定PITSLRE激酶是如何在 凋亡，以及它们是否与细胞周期检查点有关。这个 上述研究将确定一个或多个PITSLRE 激酶(S)是细胞凋亡信号转导通路的效应者。

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.