Mechanisms of cyclin E associated tumorigenesis

描述（由申请人提供）：Cyclin E及其伙伴激酶Cdk2控制细胞周期从G1期到S期的进展。大多数人类癌症在调节G1期到S期进展的主要途径中含有突变，这些突变解除了对细胞周期蛋白E-Cdk2活性的调节。尽管不受调控的周期蛋白E- cdk2活性被认为直接促进肿瘤转化，但将周期蛋白E与肿瘤发生联系起来的机制仍不清楚。我们研究了原代细胞中cyclin E失调的后果，出乎意料地发现，cyclin E过表达启动了一种抑制cyclin E- cdk2活性的稳态反应。当这种反应被灭活时，过度表达的细胞周期蛋白E诱导了深刻的细胞周期异常和遗传不稳定的证据。因此，这种需要p53肿瘤抑制蛋白和细胞周期蛋白依赖性激酶抑制剂p21的反应，可以保护细胞免受周期蛋白E失调的影响，并可能构成抵抗周期蛋白E相关癌症的生理屏障。

DESCRIPTION (provided by applicant): Cyclin E, with its partner kinase Cdk2, controls cell cycle progression from G1 to S phase. Most human cancers contain mutations in the major pathway that regulates G1 to S phase progression, and these mutations deregulate cyclin E-Cdk2 activity. Though deregulated cyclin E-Cdk2 activity is thought to contribute directly to neoplastic transformation, the mechanisms connecting cyclin E to tumorigenesis remain unclear. We studied the consequences of cyclin E deregulation in primary cells and unexpectedly found that cyclin E overexpression initiates a homeostatic response that restrains cyclin E-Cdk2 activity. When this response is inactivated, overexpressed cyclin E induces profound cell cycle abnormalities and evidence of genetic instability. Therefore, this response, which requires the p53 tumor suppressor protein and the cyclin dependent kinase inhibitor, p21, protects cells against cyclin E deregulation and may comprise a physiologic barrier against cyclin E associated cancer. The experiments proposed in this application seek to understand the cellular consequences of cyclin E deregulation and the contributions of cyclin E deregulation to tumorigenesis. The goal of Specific Aim 1 is to elucidate the mechanism by which cyclin E activates p53. Excess cyclin E-cdk2 activity induces defective S phase progression and accumulated cytogenetic abnormalities. The goal of Specific Aim 2 is to understand the mechanisms through which cyclin E activity causes genome damage and whether p53 inactivation is an obligatory step in this process. The combination of cyclin E deregulation and p53 loss may be synergistically oncogenic by promoting genetic damage while inactivating the major cellular protective response against this damage. The goal of Specific Aim 3 is thus to determine if cyclin E and p53 loss cooperate during tumorigenesis by developing mouse models of cyclin E associated cancers. The career development goal of this proposal is to enable the principal investigator to acquire the necessary skills to develop a successful and independent research career with interests bridging cell cycle regulation and tumor biology, This proposal is co-mentored by Drs. Bruce Clurman and James Roberts, who have extensive experience studying cell cycle regulation in normal and cancer cells. The Fred Hutchinson Cancer Research Center includes a thriving community of scientists and physicians with expertise in diverse areas of cancer biology and thus provides an ideal training environment for this research proposal.