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首页> 外文期刊>Molecular and Cellular Biology >p18Ink4c, but Not p27Kip1, Collaborates with Men1 To Suppress Neuroendocrine Organ Tumors
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p18Ink4c, but Not p27Kip1, Collaborates with Men1 To Suppress Neuroendocrine Organ Tumors

机译：p18Ink4c，而非p27Kip1，与Men1合作抑制神经内分泌器官肿瘤

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Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18Ink4c and p27Kip1 develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice. Compared with their corresponding single mutant littermates, the p18?/?; Men1+/? mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and pancreatic islets, phosphorylation of the retinoblastoma (Rb) protein at both CDK2 and CDK4/6 sites was increased in p18?/? and Men1+/? cells and was further increased in p18?/?; Men1+/? cells. The remaining wild-type Men1 allele was lost in most tumors from Men1+/? mice but was retained in most tumors from p18?/?; Men1+/? mice. Combined mutations of p27?/? and Men1+/?, in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth. These results demonstrate that functional collaboration exists between p18 and Men1 and suggest that menin may regulate additional factor(s) that interact with p18 and p27 differently.
机译：缺少细胞周期蛋白依赖性激酶（CDK）抑制剂p18 Ink4c 和p27 Kip1 的突变小鼠会产生让人联想到的肿瘤谱多发性内分泌肿瘤（MEN）综合征的诊断。为了确定 p18 和 p27 如何与家族性MEN1中突变的抑癌基因 Men1 遗传相互作用，我们对 p18 - Men1 和 p27-Men1 双重突变小鼠。与相应的单个突变同窝仔相比， p18 ？ / ？; Men1 + / ？小鼠以加快的速度发展肿瘤，并在垂体，甲状腺，甲状旁腺和胰腺中发病率增加。在垂体和胰岛中， p18 ？ / 中的视网膜母细胞瘤（Rb）蛋白在CDK2和CDK4 / 6位点的磷酸化增加。 ？和 Men1 + / ？细胞，并且在 p18 ？ / ？; Men1 + / ？细胞。剩下的野生型 Men1 等位基因在大多数 Men1 + / ？小鼠的肿瘤中丢失，但保留在大多数来自 p18 ？ / ？的肿瘤; Men1 + / ？小鼠。 p27 ？ / ？和 Men1 + / <相反，/ sup> ？没有表现出对Rb激酶活性，细胞增殖和肿瘤生长的明显协同刺激。这些结果表明 p18 和 Men1 之间存在功能协作，并且表明Menin可能调节与 p18 和 p27 不同。

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