Antiproliferative B cell translocation gene 2 protein is downregulated post-transcriptionally as an early event in prostate carcinogenesis
Antiproliferative B cell translocation gene 2 protein is downregulated post-transcriptionally as an early event in prostate carcinogenesis
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DOI：
10.1093/carcin/22.8.1271
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发表时间：
2001-08-01
期刊：
影响因子：
4.7
通讯作者：
Walden, PD
中科院分区：
文献类型：
--
作者：
Ficazzola, MA;Fraiman, M;Walden, PD
B细胞易位基因2（BTG 2）是一个p53靶点，可响应DNA损伤和其他应激而负调节细胞周期进程。本研究的目的是研究BTG 2在前列腺细胞中的表达、调节和肿瘤抑制特性。通过免疫组织化学，在来自人前列腺外周区的良性腺体中的基底细胞中检测到类似于50%的BTG 2蛋白。BTG 2在检查的所有过度增殖性萎缩性外周区病变（单纯萎缩、萎缩后增生和增殖性炎性萎缩）中表达，但在HGPIN和前列腺癌的过度增殖性上皮细胞中检测不到或检测到非常低的水平。在非恶性前列腺上皮（PE）细胞和LNCaP细胞中检测到BTG 2 mRNA，但在PC-3细胞中未检测到，这与p53依赖性调节一致。在PE细胞中，通过免疫组织化学在细胞融合区域检测到BTG 2蛋白。LNCaP细胞中的BTG 2蛋白通过免疫组织化学检测不到，但通过免疫印迹检测到的水平比PE细胞低8- 9倍。BTG 2蛋白水平被证明是由泛素-蛋白酶体系统调节。BTG 2在PC-3细胞中的强制表达伴随着细胞增殖速率的降低和这些细胞在体内的致瘤性的降低。总之，这些发现表明BTG 2在前列腺细胞中作为肿瘤抑制因子发挥作用，其通过细胞静止、作为正反馈机制的一部分的细胞生长刺激以及响应于DNA损伤或其他细胞应激而被激活。低稳态水平的BTG 2蛋白在HGPIN和前列腺癌，增加蛋白体降解的潜在后果，可能有重要意义的恶性前列腺病变的开始和进展。此外，这些发现表明，即使在没有p53基因突变的情况下，前列腺癌中p53 G（1）阻滞通路的重要组成部分也可能失活。
B cell translocation gene 2 (BTG2) is a p53 target that negatively regulates cell cycle progression in response to DNA damage and other stress. The objective of this study was to examine the expression, regulation and tumor suppressor properties of BTG2 in prostate cells. By immunohistochemistry BTG2 protein was detected in similar to 50 % of basal cells in benign glands from the peripheral zone of the human prostate. BTG2 was expressed in all hyperproliferative atrophic peripheral zone lesions examined (simple atrophy, post-atrophic hyperplasia and proliferative inflammatory atrophy), but was undetectable or detectable at very low levels in the hyperproliferative epithelial cells of HGPIN and prostate cancer. BTG2 mRNA was detected in non-malignant prostate epithelial (PE) cells and in LNCaP cells, but not in PC-3 cells, consistent with p53-dependent regulation. In PE cells BTG2 protein was detected in areas of cell confluence by immunohistochemistry. BTG2 protein in LNCaP cells was undetectable by immunohistochemistry but was detected by immunoblotting at 8- to 9-fold lower levels than in PE cells. BTG2 protein levels were shown to be regulated by the ubiquitin-proteosome system. Forced expression of BTG2 in PC-3 cells was accompanied by a decreased rate of cell proliferation and decreased tumorigenicity of these cells in vivo. Taken together, these findings suggest that BTG2 functions as a tumor suppressor in prostate cells that is activated by cell quiescence, cell growth stimuli as part of a positive feedback mechanism and in response to DNA damage or other cell stress. The low steady-state levels of BTG2 protein in HGPIN and prostate cancer, a potential consequence of increased protcosomal degradation, may have important implications in the initiation and progression of malignant prostate lesions. Furthermore, these findings suggest that a significant component of the p53 G(1) arrest pathway might be inactivated in prostate cancer even in the absence of genetic mutations in p53.