Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity
Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity
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DOI：
10.1128/mcb.20.16.6147-6158.2000
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发表时间：
2000-08-01
影响因子：
5.3
通讯作者：
Xiong, Y
中科院分区：
文献类型：
--
作者：
Franklin, DS;Godfrey, VI;Xiong, Y
两个不同的哺乳动物细胞周期蛋白依赖性激酶(CDK)抑制基因家族的存在被认为介导了将各种细胞过程与细胞周期控制途径联系起来的复杂性。CDK抑制基因在组织中表达的不同模式表明，它们可能具有不同的组织特异性，具有肿瘤抑制作用。为了验证这一假设，我们鉴定了两种缺失p18(INK4c)和p27(KIP1)或p18(INK4c)和p21(CIP1/WAF1)的双突变小鼠。P18和p27功能的丧失导致至少8种不同类型的增生性组织和/或肿瘤在3个月龄时自发发展，这些增生性组织和/或肿瘤发生在垂体、肾上腺、甲状腺、甲状旁腺、睾丸、胰腺、十二指肠和胃，其中6种这些增生性组织和肿瘤位于内分泌器官，并且几种类型的肿瘤通常在同一动物体内发展，这种表型使人联想到在人类多发性内分泌肿瘤综合征中看到的那种表型。另一方面，p18-p21双缺失小鼠在以后的生活中患上了垂体腺瘤、多灶性胃神经内分泌增生和肺细支气管肺泡瘤。G(1)在缺乏单独CDK抑制剂的小鼠正常组织和肿瘤组织中，CDK2和CDK4的活性均增加，并被两种CDK抑制剂同时丧失所协同刺激。这表明G(1)CDK活性的增加是肿瘤生长过程中的关键步骤，但不足以促进肿瘤的生长。我们的结果表明，不同的CDK抑制基因之间的功能协作是组织特有的，并在细胞生长控制和肿瘤抑制方面提供了另一种水平的调节。
The presence of two families of seven distinct mammalian cyclin-dependent kinase (CDK) inhibitor genes is thought to mediate the complexity of connecting a variety of cellular processes to the cell cycle control pathway. The distinct pattern of tissue expression of CDK inhibitor genes suggests that they may function as tumor suppressors with different tissue specificities. To test this hypothesis, we have characterized two strains of double mutant mice lacking either p18(INK4c) and p27(KIP1) or p18(INK4c) and p21(CIP1/WAF1). Loss of both p18 and p27 function resulted in the spontaneous development by 3 months of age of at least eight different types of hyperplastic tissues and/or tumors in the pituitary, adrenals, thyroid, parathyroid, testes, pancreas, duodenum, and stomach, Six of these hyperplastic tissues and tumors were in endocrine organs, and several types of tumors routinely developed within the same animal, a phenotype reminiscent of that seen in combined human multiple endocrine neoplasia syndromes. The p18-p21 double null mice, on the other hand, developed pituitary adenomas, multifocal gastric neuroendocrine hyperplasia, and lung bronchioalveolar tumors later in life. G(1) CDK2 and CDK4 kinase activities were increased in both normal and neoplastic tissues derived from mice lacking individual CDK inhibitors and were synergistically stimulated by the simultaneous loss of two CDK inhibitors. This indicates that an increase in G(1) CDK kinase activity is a critical step during but is not sufficient for tumor growth. Our results suggest that functional collaborations between distinct CDK inhibitor genes are tissue specific and confer yet another level of regulation in cell growth control and tumor suppression.