Function and dysfunction of the human oncoprotein MDM2.
Function and dysfunction of the human oncoprotein MDM2.
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DOI：
10.2741/a723
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
S. Deb
中科院分区：
文献类型：
--
作者：
S. Deb
由小鼠双微体2（mdm2）基因的人类同源物编码的MDM2蛋白在人类恶性乳腺肿瘤和其他肿瘤中频繁过表达。从转化的鼠细胞系中人工扩增mdm2基因增强鼠细胞的致瘤性。这些证据表明人或小鼠MDM2的致癌特性。MDM2的致瘤特性并不出乎意料，因为MDM2可以抑制肿瘤抑制因子p53的几种功能。该蛋白还与几种细胞周期调节蛋白相互作用，这可能有助于其致瘤能力。已经在过表达MDM2的细胞中检测到MDM2的几种剪接形式。由这些剪接形式编码的蛋白质的功能还不清楚。从其cDNA过表达全长MDM2阻止正常人或小鼠细胞的G1到S期转变。癌蛋白的生长抑制结构域的消除诱导肿瘤发生。一些癌症衍生的细胞系对MDM2介导的生长停滞部分不敏感。正常细胞可以诱导MDM2响应致癌的挑战，如紫外线照射或雌激素治疗。正常细胞可以诱导全长MDM2响应致癌的挑战，以防止过早的细胞周期进展。如果癌蛋白在生长停滞中有缺陷，或者如果细胞对MDM2介导的生长停滞不敏感，则细胞周期的过早进展可能导致肿瘤发生。阐明MDM2的生长调节功能可能有助于开发用于癌症治疗的新药。
The protein MDM2 coded by the human homologue of mouse double minute-2 (mdm2) gene frequently overexpresses in malignant human breast and other tumors. Artificial amplification of mouse mdm2 gene derived from a transformed murine cell line enhances tumorigenic potential of murine cells. These evidences suggest oncogenic properties of human or mouse MDM2. The tumorigenic property of MDM2 is not unexpected as MDM2 can inactivate several functions of the tumor suppressor p53. The protein also interacts with several cell cycle regulatory proteins that may contribute to its tumorigenic ability. Several spliced forms of MDM2 have been detected in cells that overexpress MDM2. The function of the proteins coded by these spliced forms is not well understood. Overexpression of full-length MDM2 from its cDNA arrests G1 to S phase transition of normal human or murine cells. Elimination of the growth inhibitory domains of the oncoprotein induces tumorigenesis. Some cancer-derived cell lines are partially insensitive to MDM2-mediated growth arrest. Normal cells can induce MDM2 in response to oncogenic challenges such as UV irradiation or estrogen treatment. Normal cells may induce full-length MDM2 in response to oncogenic challenges to protect against premature cell cycle progression. If the oncoprotein is defective in growth arrest or if the cells are insensitive to MDM2 mediated growth arrest, premature progression of cell cycle may lead to tumorigenesis. Elucidation of the growth regulatory functions of MDM2 may help develop new drug design for cancer treatment.