FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor
FAPα, a surface peptidase expressed during wound healing, is a tumor suppressor
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DOI：
10.1038/sj.onc.1207730
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发表时间：
2004-07-15
期刊：
影响因子：
8
通讯作者：
Houghton, AN
中科院分区：
文献类型：
--
作者：
Ramirez-Montagut, T;Blachere, NE;Houghton, AN
成纤维细胞活化蛋白-α（FAP）是一种细胞表面丝氨酸蛋白酶，在胚胎发育中的组织重塑位点表达。FAP在成熟的体细胞组织中不表达，但在伤口愈合或肿瘤间质中的活化的黑素细胞和成纤维细胞中表达。FAP表达在恶性转化过程中增殖的黑素细胞中特异性沉默。为了研究FAP作为肿瘤抑制因子的作用，克隆了小鼠fap基因，并在催化结构域进行突变（FAP丝氨酸突变体，FSM）。我们发现，在小鼠黑色素瘤细胞中，FAP或FSM在生理水平的表达废除了致瘤性。值得注意的是，缺乏特异性丝氨酸蛋白酶活性的突变形式FSM是更有效的肿瘤抑制剂。肿瘤排斥不是由于适应性免疫应答，因为用表达FAP或FSM的黑素瘤细胞攻击的RAG 1-/-小鼠不是致瘤性的。在体外实验中，FAP或FSM表达恢复接触抑制，导致细胞周期停滞在G 0/G1期，并增加对应激诱导的凋亡的敏感性。FAP +或FSM +黑色素瘤细胞中的细胞死亡很容易通过培养基中存活因子的耗尽而触发，导致随后通过内源性途径激活半胱天冬酶。这些结果表明，FAP的表达是一种肿瘤抑制因子，通过调节细胞生长和存活来消除致瘤性。
Fibroblast activation protein-alpha (FAP) is a cell surface serine protease expressed at sites of tissue remodeling in embryonic development. FAP is not expressed by mature somatic tissues except activated melanocytes and fibroblasts in wound healing or tumor stroma. FAP expression is specifically silenced in proliferating melanocytic cells during malignant transformation. To study the role of FAP as a tumor suppressor, the gene for mouse fap was cloned and mutated at the catalytic domain (FAP serine mutant, FSM). We found that expression of FAP or FSM at physiologic levels in mouse melanoma cells abrogated tumorigenicity. Remarkably, the mutant form FSM lacking specific serine protease activity was a more potent tumor suppressor. Tumor rejection was not due to adaptive immune responses because RAG1-/- mice challenged with melanoma cells expressing either FAP or FSM were not tumorigenic. In in vitro assays, FAP or FSM expression restored contact inhibition, led to cell cycle arrest at G0/G1 phase, and increased susceptibility to stress-induced apoptosis. Cell death in FAP + or FSM + melanoma cells was readily triggered by depletion of survival factors from the media, leading to subsequent activation of caspases via the intrinsic pathway. These results show that expression of FAP is a tumor suppressor that abrogates tumorigenicity through regulation of cell growth and survival.