Dirks P B, Rutka J T
Brain Tumor Research Laboratory, Hospital for Sick Children, University of Toronto, Ontario, Canada.
Neurosurgery. 1997 May;40(5):1000-13; discussion 1013-5. doi: 10.1097/00006123-199705000-00025.
Uncontrolled cellular proliferation is the hallmark of human malignant brain tumors. Their growth proceeds inexorably, in part because their cellular constituents have an altered genetic code that enables them to evade the checks and balances of the normal cell cycle. Recently, a number of major advances in molecular biology have led to the identification of several critical genetic and enzymatic pathways that are disturbed in cancer cells resulting in uncontrolled cell cycling. We now know that the progression of a cell through the cell cycle is controlled in part by a series of protein kinases, the activity of which is regulated by a group of proteins called cyclins. Cyclins act in concert with the cyclin-dependent kinases (CDKs) to phosphorylate key substrates that facilitate the passage of the cell through each phase of the cell cycle. A critical target of cyclin-CDK enzymes is the retinoblastoma tumor suppressor protein, and phosphorylation of this protein inhibits its ability to restrain activity of a family of transcription factors (E2F family), which induce expression of genes important for cell proliferation. In addition to the cyclins and CDKS, there is an emerging family of CDK inhibitors, which modulate the activity of cyclins and CDKs. CDK inhibitors inhibit cyclin-CDK complexes and transduce internal or external growth-suppressive signals, which act on the cell cycle machinery. Accordingly, all CDK inhibitors are candidate tumor suppressor genes. It is becoming clear that a common feature of cancer cells is the abrogation of cell cycle checkpoints, either by aberrant expression of positive regulators (for example, cyclins and CDKs) or the loss of negative regulators, including p21Cip1 through loss of function of its transcriptional activator p53, or deletion or mutation of p16ink4A (multiple tumor suppressor 1/CDKN2) and the retinoblastoma tumor suppressor protein. In this review, we describe in detail our current knowledge of the normal cell cycle and how it is disturbed in cancer cells. Because there have now been a number of recent studies showing alterations in cell cycle gene expression in human brain tumors, we will review the derangements in both the positive and negative cell cycle regulators that have been reported for these neoplasms. A thorough understanding of the molecular events of the cell cycle may lead to new opportunities by which astrocytoma cell proliferation can be controlled either pharmacologically or by gene transfer techniques.
不受控制的细胞增殖是人类恶性脑肿瘤的标志。它们的生长无情地进行着，部分原因是其细胞成分的遗传密码发生了改变，使其能够逃避正常细胞周期的制衡。最近，分子生物学的一些重大进展已导致鉴定出几种关键的遗传和酶促途径，这些途径在癌细胞中受到干扰，导致细胞周期不受控制。我们现在知道，细胞通过细胞周期的进程部分受一系列蛋白激酶的控制，这些蛋白激酶的活性由一组称为细胞周期蛋白的蛋白质调节。细胞周期蛋白与细胞周期蛋白依赖性激酶（CDK）协同作用，使关键底物磷酸化，从而促进细胞通过细胞周期的每个阶段。细胞周期蛋白-CDK酶的一个关键靶点是视网膜母细胞瘤肿瘤抑制蛋白，该蛋白的磷酸化会抑制其抑制一类转录因子（E2F家族）活性的能力，这些转录因子可诱导对细胞增殖重要的基因的表达。除了细胞周期蛋白和CDK外，一个新兴的CDK抑制剂家族正在出现，它们可调节细胞周期蛋白和CDK的活性。CDK抑制剂抑制细胞周期蛋白-CDK复合物，并转导作用于细胞周期机制的内部或外部生长抑制信号。因此，所有CDK抑制剂都是候选肿瘤抑制基因。越来越明显的是，癌细胞的一个共同特征是细胞周期检查点的废除，这要么是通过正调节因子（例如细胞周期蛋白和CDK）的异常表达，要么是通过负调节因子的丧失，包括通过其转录激活因子p53功能丧失导致的p21Cip1，或p16ink4A（多种肿瘤抑制因子1/CDKN2）和视网膜母细胞瘤肿瘤抑制蛋白的缺失或突变。在本综述中，我们详细描述了我们目前对正常细胞周期的了解以及它在癌细胞中是如何受到干扰的。由于最近有多项研究表明人类脑肿瘤中细胞周期基因表达发生了改变，我们将综述这些肿瘤中已报道的细胞周期正调节因子和负调节因子的紊乱情况。对细胞周期分子事件的透彻理解可能会带来新的机会，通过药理学或基因转移技术来控制星形细胞瘤细胞的增殖。
