BACKGROUND Breast cancer is the most common cancer to affect women and one of the leading causes of cancer-related deaths. Proper regulation of cell cycle checkpoints plays a critical role in preventing the accumulation of deleterious mutations. Perturbations in the expression or activity of mediators of cell cycle progression or checkpoint activation represent important events that may increase susceptibility to the onset of carcinogenesis. The atypical cyclin-like protein Spy1 was isolated in a screen for novel genes that could bypass the DNA damage response. Clinical data demonstrates that protein levels of Spy1 are significantly elevated in ductal and lobular carcinoma of the breast. We hypothesized that elevated Spy1 would override protective cell cycle checkpoints and support the onset of mammary tumourigenesis. METHODS We generated a transgenic mouse model driving expression of Spy1 in the mammary epithelium. Mammary development, growth characteristics and susceptibility to tumourigenesis were studied. In vitro studies were conducted to investigate the relationship between Spy1 and p53. RESULTS We found that in the presence of wild-type p53, Spy1 protein is held 'in check' via protein degradation, representing a novel endogenous mechanism to ensure protected checkpoint control. Regulation of Spy1 by p53 is at the protein level and is mediated in part by Nedd4. Mutation or abrogation of p53 is sufficient to allow for accumulation of Spy1 levels resulting in mammary hyperplasia. Sustained elevation of Spy1 results in elevated proliferation of the mammary gland and susceptibility to tumourigenesis. CONCLUSIONS This mouse model demonstrates for the first time that degradation of the cyclin-like protein Spy1 is an essential component of p53-mediated tumour suppression. Targeting cyclin-like protein activity may therefore represent a mechanism of re-sensitizing cells to important cell cycle checkpoints in a therapeutic setting.

中文翻译：

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非典型细胞周期蛋白样蛋白Spy1超越了p53介导的肿瘤抑制作用，并促进了对乳腺肿瘤发生的敏感性。

背景技术乳腺癌是影响女性的最常见癌症，并且是与癌症相关的死亡的主要原因之一。正确调节细胞周期检查点在防止有害突变的积累中起着至关重要的作用。细胞周期进程或检查点激活介质表达或活性的扰动代表重要事件，可能会增加对致癌作用的敏感性。在筛选可能绕过DNA损伤反应的新基因的筛选中，分离出非典型的细胞周期蛋白样蛋白Spy1。临床数据表明，乳腺导管和小叶癌中Spy1的蛋白质水平显着升高。我们假设升高的Spy1将超越保护性细胞周期检查点，并支持乳腺肿瘤发生的发生。方法我们生成了驱动Spy1在乳腺上皮中表达的转基因小鼠模型。研究了乳腺发育，生长特性和对肿瘤发生的敏感性。进行了体外研究以研究Spy1和p53之间的关系。结果我们发现，在存在野生型p53的情况下，Spy1蛋白通过蛋白降解被“抑制”，这代表了一种确保保护性检查点控制的新型内源性机制。p53对Spy1的调节处于蛋白质水平，部分由Nedd4介导。p53的突变或消除足以使Spy1水平积聚，从而导致乳腺增生。Spy1的持续升高会导致乳腺增生和对肿瘤发生的敏感性。结论该小鼠模型首次证明细胞周期蛋白样蛋白Spy1的降解是p53介导的肿瘤抑制的重要组成部分。因此，靶向细胞周期蛋白样蛋白活性可以代表在治疗环境中使细胞对重要的细胞周期检查点重新敏感的机制。