Unusual deregulation of cell cycle components in early and frank estrogen-induced renal neoplasias in the Syrian hamster.
Unusual deregulation of cell cycle components in early and frank estrogen-induced renal neoplasias in the Syrian hamster.
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DOI：
10.1093/carcin/21.12.2167
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发表时间：
2000-12
期刊：
影响因子：
4.7
通讯作者：
D. Liao;X. Hou;S. Bai;S. Li;J. Li
中科院分区：
文献类型：
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作者：
D. Liao;X. Hou;S. Bai;S. Li;J. Li
有强有力的证据表明，雌激素参与各种癌症的病因、促进和进展，包括乳腺癌和子宫内膜癌。叙利亚仓鼠雌激素诱导的雌激素依赖性肾肿瘤是一种成熟的动物模型，用于阐明仅雌激素诱导的致癌过程中涉及的细胞和分子机制。在雌激素诱导的早期肾肿瘤灶和去势雄性仓鼠的大肾肿瘤中研究了G（1）细胞周期进程。细胞周期蛋白D1，细胞周期蛋白E和视网膜母细胞瘤（pRb）蛋白的水平在这些肾肿瘤高于相邻的未涉及的肾组织和肾脏未经处理，年龄匹配的动物。特别令人感兴趣的是在原发性肾肿瘤中存在主要的35 kDa细胞周期蛋白E蛋白变体形式。此外，磷酸化形式的细胞周期蛋白依赖性激酶（cdk）2和4的数量减少，和RNA和蛋白质水平的p27（kip 1）（p27），细胞周期蛋白依赖性激酶抑制剂，在早期和坦率的肾肿瘤显着高于相邻的未涉及的肾组织和肾脏的未经处理，年龄匹配的动物。这些细胞周期成分的变化与肾肿瘤细胞增殖的增加相一致。然而，升高的p27蛋白与细胞周期蛋白E、cdk 2和cdk 4的结合没有受损，表明这种细胞周期抑制蛋白是功能性的。此外，细胞周期蛋白D1-，cdk 2-，cdk 4-和细胞周期蛋白E相关的激酶活性也低于这些雌激素诱导的肾肿瘤比未经治疗，年龄匹配的肾脏。有趣的是，当与未治疗的肾组织相比时，早期和坦率的肾肿瘤具有较少的62 kDa天然形式的E2 F1，并含有57 kDa的变体形式。因此，我们的特点是一个不寻常的失调的细胞周期在雌激素诱导的肾肿瘤发生在叙利亚仓鼠，仍然允许雌激素驱动的肾肿瘤细胞增殖，并可能有助于早期发现的基因组不稳定性。
There is strong evidence that estrogens are involved in the etiology, promotion and progression of a variety of cancers, including the cancers of the breast and endometrium. The Syrian hamster estrogen-induced, estrogen-dependent renal neoplasm is a well-established animal model used to elucidate the cellular and molecular mechanisms involved in solely estrogen-induced carcinogenic processes. G(1) cell cycle progression was studied in estrogen-induced early renal tumor foci and in large kidney tumors of castrated male hamsters. Levels of cyclin D1, cyclin E and retinoblastoma (pRb) proteins were higher in these renal neoplasias than in adjacent uninvolved renal tissue and kidneys from untreated, age-matched animals. Of particular interest is the presence of a predominant 35 kDa cyclin E protein variant form in primary renal tumors. In addition, amounts of the phosphorylated forms of cyclin-dependent kinases (cdk) 2 and 4 were decreased, and both RNA and protein levels of p27(kip1) (p27), a cyclin-dependent kinase inhibitor, were markedly higher in early and frank renal tumors than in adjacent uninvolved renal tissue and kidneys of untreated, age-matched animals. These changes in cell cycle components coincided with a rise in renal tumor cell proliferation. Binding of the elevated p27 protein to cyclin E, cdk2 and cdk4, however, was not impaired, suggesting that this cell cycle suppressor protein is functional. In addition, cyclin D1-, cdk2-, cdk4- and cyclin E-associated kinase activities were also lower in these estrogen-induced renal neoplasms than in untreated, age-matched kidneys. Interestingly, when compared with untreated kidney tissue, early and frank renal neoplasms had less of the 62 kDa native form of E2F1 and contained a 57 kDa variant form. Thus we have characterized an unusual deregulation of the cell cycle during estrogen-induced renal tumorigenesis in Syrian hamsters which still allows for estrogen-driven kidney tumor cell proliferation and may contribute to the early genomic instability found.