Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts.
Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts.
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前列腺特异性抗原在 PTH 样结构域中裂解甲状旁腺激素相关蛋白：小鼠成骨细胞中 PTHrP 刺激的 cAMP 积累失活。
DOI：
10.1097/00005392-199608000-00076
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Peehl,DM
中科院分区：
文献类型：
--
作者：
Cramer,SD;Chen,Z;Peehl,DM
目的探讨甲状旁腺相关蛋白（PTHrP）是否为前列腺特异性抗原（PSA）的底物，以及PSA对PTHrP的切割作用对PTHrP生物学活性的影响。对印迹PSA切割的PTHrP肽片段进行五轮自动氨基末端氨基酸序列分析以确定PSA切割位点。小鼠成骨细胞系MC 3 T3-E1被用来测试是否PSA裂解PTHrP 1-141改变其刺激cAMP production. ResultsProstate特异性抗原的能力被发现特异性裂解PTHrP 1-141在时间和剂量依赖性的方式。通过PSA切割PTHrP 1-141在考马斯染色的丙烯酰胺凝胶上产生片段，其迁移率对应于19.5、17、15和小于7 kd。PTHrP 1-141的优选PSA切割位点被确定为在苯丙氨酸23的羧基末端，与PSA的胰凝乳蛋白酶样酶活性一致。裂解的PTHrP PSA完全废除的PTHrP刺激cAMP production.ConclusionsCleavage的PTHrP 1-141由PSA羧基末端苯丙氨酸23代表一个独特的模式PTHrP加工，可能是特定的前列腺的能力。前列腺特异性抗原对PTHrP 1-141的cAMP诱导活性的失活证明PSA切割调节PTHrP的生物活性。这些结果对PTHrP在前列腺癌骨转移中的作用及其随后对骨重建的调节具有意义。本研究中鉴定的PSA产生的PTHrP肽的生物活性的研究值得进一步研究。
PurposeTo determine whether parathyroid hormone-related protein (PTHrP) is a substrate of prostate-specific antigen (PSA) and how the biological activity of PTHrP may be altered by cleavage with PSA.Materials and MethodsProstate-specific antigen cleavage of recombinant human PTHrP 1-141 was conducted in vitro at 37C and analyzed by SDS-PAGE. Five rounds of automated amino-terminal amino acid sequence analysis were performed on blotted PSA-cleaved PTHrP peptide fragments to determine the PSA cleavage sites. The mouse osteoblast cell line MC3T3-E1 was used to test whether PSA cleavage of PTHrP 1-141 altered its ability to stimulate cAMP production.ResultsProstate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner. Cleavage of PTHrP 1-141 by PSA generated fragments on Coomassiestained acrylamide gels that migrated with mobilities that corresponded to 19.5, 17, 15 and less than 7 kd. The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production.ConclusionsCleavage of PTHrP 1-141 by PSA carboxyl-terminal to phenylalanine 23 represents a unique pattern of PTHrP processing that may be specific to the prostate. Prostate-specific antigen inactivation of the cAMP-inducing activity of PTHrP 1-141 demonstrates that PSA cleavage regulates the biological activity of PTHrP. These results have implications for the role of PTHrP in prostate cancer metastasis to bone and its subsequent regulation of bone remodeling Study of the biological activities of the PSA-generated PTHrP peptides identified in this study merits further investigation.
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DOI：
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期刊：
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