High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors
High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors
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DOI：
10.1210/jc.85.1.322
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发表时间：
2000-01-01
影响因子：
5.8
通讯作者：
Gicquel, C
中科院分区：
文献类型：
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作者：
Bourcigaux, N;Gaston, V;Gicquel, C
母体11p15区杂合性缺失（LOH）和胰岛素样生长因子(IGF)-II基因过表达与散发性肾上腺皮质肿瘤的恶性表型相关。在11p15印迹区，p57（KIP2）基因在母体中表达，并编码细胞周期蛋白依赖性激酶（CDK）抑制剂，参与细胞周期的G(1)/S期。我们假设恶性肾上腺皮质肿瘤的母体LOH可能导致p57（KIP2）基因表达的缺失，因此可能有利于细胞周期的进展。我们检测了3例正常肾上腺、31例肾上腺皮质肿瘤[11例IGF-II基因表达正常（主要为良性），20例IGF-II基因过表达（主要为恶性）]和人肾上腺皮质肿瘤细胞系NCI H295R的p57（KIP2）基因表达、G1细胞周期蛋白（cyclin D2和E）和G1 CDK（CDK2、CDK3和CDK4）蛋白含量及G1周期蛋白-CDK复合物激酶活性。良性肿瘤中p57（KIP2）、G1 cyclins和G1 CDKs的表达与正常肾上腺组织相似，G1 cyclins - cdk复合物的激酶活性与正常肾上腺组织相似。相比之下，在恶性肿瘤和H295R细胞系中，p57（KIP2）基因表达的缺失以及G1周期蛋白（cyclin E）和G1 CDKs （CDK2和CDK4）表达的增加与G1周期蛋白- cdk复合物的高活性相关。这些数据提示p57（KIP2）基因可能在肾上腺皮质肿瘤中起肿瘤抑制基因的作用。具有父本等位基因重复或11p15区域病理性功能印记的母本LOH是导致p57（KIP2）基因表达缺失和IGF-II基因表达增加的原因。因此，这两种情况都有利于恶性肾上腺皮质肿瘤的细胞增殖。
Maternal loss of heterozygosity (LOH) of the 11p15 region and overexpression of the insulin-like growth factor (IGF)-II gene are associated with the malignant phenotype in sporadic adrenocortical tumors. In the imprinted 11p15 region, the p57(KIP2) gene is maternally expressed and encodes a cyclin-dependent kinase (CDK) inhibitor involved in G(1)/S phase of the cell cycle.We hypothesized that maternal LOH in malignant adrenocortical tumors could be responsible for loss of p57(KIP2) gene expression and, thus, could favor progression through the cell, cycle.We investigated 3 normal adrenals, 31 adrenocortical tumors [11 tumors with normal expression of the IGF-II gene (mainly benign) and 20 with IGF-II gene overexpression (mainly malignant)], and the human adrenocortical tumor cell Line NCI H295R for expression of the p57(KIP2) gene, G1 cyclins (cyclin D2 and E) and G1 CDK(CDK2, CDK3 and CDK4) protein contents and for kinase activity of G1 cyclin-CDK complexes.The expression of p57(KIP2), G1 cyclins, and G1 CDKs in benign tumors was similar to that in normal adrenal tissues, as were kinase activities of G1 cyclin-CDK complexes. By contrast, abrogation of the p57(KIP2) gene expression and increased expression of G1 cyclins (cyclin E) and G1 CDKs (CDK2 and CDK4) were associated with high activity of G1 cyclin-CDK complexes in malignant tumors and in the H295R cell Line.These data suggest that the p57(KIP2) gene might act as a tumor suppressor gene in adrenocortical tumors. Maternal LOH with duplication of the paternal allele or pathological functional imprinting of the 11p15 region are responsible for loss of expression of the p57(KIP2) gene and increased expression of the IGF-II gene. Consequently, both events favor cell proliferation in malignant adrenocortical tumors.