Afar D E, Vivanco I, Hubert R S, Kuo J, Chen E, Saffran D C, Raitano A B, Jakobovits A
UroGenesys Inc., Santa Monica, California 90404, USA.
Cancer Res. 2001 Feb 15;61(4):1686-92.
We identified TMPRSS2 as a gene that is down-regulated in androgen-independent prostate cancer xenograft tissue derived from a bone metastasis. Using specific monoclonal antibodies, we show that the TMPRSS2-encoded serine protease is expressed as a Mr 70,000 full-length form and a cleaved Mr 32,000 protease domain. Mutation of Ser-441 in the catalytic triad shows that the proteolytic cleavage is dependent on catalytic activity, suggesting that it occurs as a result of autocleavage. Mutational analysis reveals the cleavage site to be at Arg-255. A consequence of autocatalytic cleavage is the secretion of the protease domain into the media by TMPRSS2-expressing prostate cancer cells and into the sera of prostate tumor-bearing mice. Immunohistochemical analysis of clinical specimens demonstrates the highest expression of TMPRSS2 at the apical side of prostate and prostate cancer secretory epithelia and within the lumen of the glands. Similar luminal staining was detected in colon cancer samples. Expression was also seen in colon and pancreas, with little to no expression detected in seven additional normal tissues. These data demonstrate that TMPRSS2 is a secreted protease that is highly expressed in prostate and prostate cancer, making it a potential target for cancer therapy and diagnosis.
我们确定跨膜丝氨酸蛋白酶2（TMPRSS2）是一种在源自骨转移的雄激素非依赖性前列腺癌异种移植组织中表达下调的基因。使用特异性单克隆抗体，我们发现TMPRSS2编码的丝氨酸蛋白酶以70000道尔顿的全长形式和32000道尔顿的裂解蛋白酶结构域形式表达。催化三联体中丝氨酸-441的突变表明蛋白水解切割依赖于催化活性，提示其是自切割的结果。突变分析揭示切割位点位于精氨酸-255处。自催化切割的一个结果是，表达TMPRSS2的前列腺癌细胞将蛋白酶结构域分泌到培养基中，以及分泌到荷前列腺肿瘤小鼠的血清中。临床标本的免疫组织化学分析表明，TMPRSS2在前列腺和前列腺癌分泌上皮的顶端以及腺腔内表达最高。在结肠癌样本中检测到类似的管腔染色。在结肠和胰腺中也有表达，而在另外七种正常组织中几乎未检测到表达。这些数据表明，TMPRSS2是一种分泌性蛋白酶，在前列腺和前列腺癌中高度表达，使其成为癌症治疗和诊断的潜在靶点。
