Compromised HOXA5 function can limit p53 expression in human breast tumours
Compromised HOXA5 function can limit p53 expression in human breast tumours
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DOI：
10.1038/35016125
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发表时间：
2000-06-22
期刊：
影响因子：
64.8
通讯作者：
Sukumar, S
中科院分区：
文献类型：
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作者：
Raman, V;Martensen, SA;Sukumar, S
p53基因的表达可保护细胞免于恶性转化（1，2）。尽管p53降解的控制一直是严格审查的主题，但对调节p53合成的因素知之甚少（1，2）。在这里，我们表明，p53信使RNA水平低，在很大一部分乳腺肿瘤。为了寻找p53转录的潜在调节因子，我们在p53启动子中发现了共有HOX结合位点（3，4）（5）。Hox/HOXA 5的瞬时转染激活了p53启动子。HOXA 5在表达野生型p53的上皮癌细胞中表达，但在缺乏p53基因的同基因变体中不表达（6），导致凋亡性细胞死亡。此外，乳腺癌细胞系和患者肿瘤显示出p53和HOXA 5 mRNA和蛋白表达的协调损失。HOXA 5启动子区甲基化的20例p53阴性乳腺肿瘤标本中有16例。我们的结论是，在人类乳腺癌中p53表达的损失可能主要是由于缺乏HOXA 5的表达。
Expression of the p53 gene protects cells against malignant transformation(1,2). Whereas control of p53 degradation has been a subject of intense scrutiny, little is known about the factors that regulate p53 synthesis(1,2). Here we show that p53 messenger RNA levels are low in a large proportion of breast tumours. Seeking potential regulators of p53 transcription, we found consensus HOX binding sites(3,4) in the p53 promoter(5). Transient transfection of Hox/HOXA5 activated the p53 promoter. Expression of HOXA5 in epithelial cancer cells expressing wild-type p53, but not in isogenic variants lacking the p53 gene(6), led to apoptotic cell death. Moreover, breast cancer cell lines and patient tumours display a coordinate loss of p53 and HOXA5 mRNA and protein expression. The HOXA5 promoter region was methylated in 16 out of 20 p53-negative breast tumour specimens. We conclude that loss of expression of p53 in human breast cancer may be primarily due to lack of expression of HOXA5.