CDC2-RELATED KINASES AND THE CONTROL OF CELL CYCLE

细胞分裂的决定最终取决于它的反应能力 对环境线索的正确反应。细胞外信号被解释为 细胞通过一个由正负信号组成的复杂系统 连接到控制细胞分裂的机器的通路。什么时候 这些调节通路运行正常，正常控制细胞分裂 是有可能的。然而，当这些系统像它们在人类癌症中所做的那样失效时， 不受控制的分裂可能会导致灾难性的后果。 细胞分裂是由精心策划的一系列事件控制的。 也许细胞周期研究中最耐人寻味的发现是 真核细胞似乎使用类似的机制来调节进程。 通过细胞周期的重要控制点。这是最明显的 当比较细胞从G2期到有丝分裂的转变时。 细胞通过激活一种由以下组成的激酶复合体来调节这种转变 催化亚基cdc2和调节亚单位细胞周期蛋白B。 这种酶复合体的性质现在形成了细胞周期的范例 监管。所有已研究过的真核细胞都含有同源物。 对于cdc2和Cyclin B，它们在类似的有丝分裂中调节进入有丝分裂 方式。现在清楚的是，细胞周期中的其他关键调节点 进程由这种模式的有趣变化控制。为 例如，在酵母中，从G1期到S期的转变是由 相同的催化亚基，但与其他已知的周期蛋白 在哺乳动物细胞中，这种模式甚至更复杂，为8 现在已经发现了不同的气旋。一般来说，人们对此知之甚少。 关于他们正确的催化伙伴或关于他们的调节。 最近，我们已经确定了八种新的人类激酶，其中六种显示了 与cdc2的氨基酸同源性超过50%。虽然分析了 这些激酶还处于早期阶段，已经很明显，其中一些 蛋白激酶具有细胞周期调节蛋白激酶的特征；它们与 与细胞周期蛋白结合，并显示时间调节的激酶活性。 这项拨款建议研究这些新的激酶在 哺乳动物细胞周期进程的控制。我们的第一个目标将是 完成这些激酶的初始特征。这项工作是 目前正在进行中，包括物理和免疫化学 激活型多肽的性质，它们的激活期 激活，以及它们的表达模式。初步研究表明， 其中一些激酶与cdc2激酶密切相关，而这些 蛋白质将成为更详细的细胞周期研究的焦点。我们 将决定这些激酶是否对细胞周期是必需的 进展，它们的激酶活性是如何调节的，是什么底物 它们被磷酸化，以及区别它们的结构特征 与cdc2的功能差异。距离更远的激活酶 与cdc2相关的是我们最后一个目标的重点。在这里，我们将研究 这些不同属性的意义，特别注意 非CDC2或其近亲家族所特有的特征 会员。

A cell's decision to divide ultimately rests on its ability to respond correctly to environmental cues. Extracellular signals are interpreted by the cell through a complex system of positive and negative signalling pathways that connect to the machinery that controls cell division. When these regulatory pathways behave correctly, normal controlled cell division is possible. However, when these systems fail as they do in human cancer, uncontrolled division can lead to disastrous results. Cell division is controlled by a carefully orchestrated cycle of events. Perhaps the most intriguing finding of cell cycle research is that all eukaryotic cells appear to use a similar mechanism to regulate progression through important control points of the cell cycle. This is most evident when comparing the transition of cells from the G2 phase into mitosis. Cells regulate this transition by activating a kinase complex, composed of a catalytic subunit, cdc2, and regulatory subunit, cyclin B. The properties of this enzyme complex now form the paradigm of cell cycle regulation. All eukaryotic cells that have been studied contain homologs for cdc2 and cyclin B, and they regulate entry into mitosis in similar ways. It is now clear that other key regulatory points in cell cycle progression are controlled by interesting variations of this pattern. For example, in yeast the transition from G1 into S phase is controlled by the same catalytic subunit but in association with other cyclins known as CLN's. In mammalian cells this pattern is even more complicated, as eight different cyclins have now been discovered. In general, little is known about their correct catalytic partners or about their regulation. Recently, we have identified eight novel human kinases, six of which show greater than 50% amino acid identity with cdc2. Although the analysis of these kinases is at an early stage, it is already clear that some of these kinases have the hallmarks of cell-cycle-regulating kinases; they associate with cyclins and display temporally regulated kinase activity. This grant proposes to investigate the function of these new kinases in the control of mammalian cell cycle progression. Our first goal will be to complete the initial characterization of these kinases. This work is currently underway and encompasses the physical and immunochemical properties of the kinase polypeptides, the timing of their kinase activation, and their patterns of expression. Initial studies show that some of these kinases are closely related to the cdc2 kinase, and these proteins will be come the focus of more detailed cell cycle studies. We will determine whether these kinases are essential for cell cycle progression, how their kinase activities are regulated, what substrates they phosphorylate, and the structural features that distinguish their functional differences from cdc2. The kinases that are more distantly related to cdc2 are the focus of our last goal. Here we will examine the significance of these different properties, paying particular attention to features that are not characteristic of cdc2 or its closely related family members.