Cleavage of growth differentiation factor 15 (GDF15) by membrane type 1-matrix metalloproteinase abrogates GDF15-mediated suppression of tumor cell growth
Cleavage of growth differentiation factor 15 (GDF15) by membrane type 1-matrix metalloproteinase abrogates GDF15-mediated suppression of tumor cell growth
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DOI：
10.1111/j.1349-7006.2007.00547.x
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发表时间：
2007-09-01
期刊：
影响因子：
5.7
通讯作者：
Sato, Hiroshi
中科院分区：
文献类型：
--
作者：
El-Aziz, Shaban H. Abd;Endo, Yoshio;Sato, Hiroshi
生长分化因子15(GDF15)是一个转化生长因子-β超家族成员，是从胎盘c DNA文库中克隆出来的一种促进膜型基质金属蛋白酶(MT)1-MMP2活化的基因产物。MT1-MMP在HEK293T细胞中的表达导致GDF15成熟型在N-252-M-253位发生裂解，产生一个6 kDa的C-末端片段。GDF15可诱导MCF7细胞P53的激活和p21的表达增强，但这一作用被MT1-MMPs的表达所抑制。GDF15处理细胞后，GDF15的mRNA合成也被诱导。GDF15处理MCF7细胞后，细胞增殖受到抑制。然而，GDF15对MCF7细胞的增殖没有影响，但在存在基质金属蛋白酶抑制剂BB94的情况下，GDF15抑制了MCF7细胞的增殖。转GDF15基因的HT1080细胞内源性表达MT1-MMP，可合成高水平的GDF15前体形式和低水平的成熟形式，BB94处理细胞可促进GDF15成熟形式的产生。与GDF15的产生一致，转GDF15基因的HT1080细胞的增殖几乎与对照细胞相同，BB94的加入有效地抑制了转GDF15基因的HT1080细胞的生长，并伴随着GDF15成熟形式的积累，但不影响对照细胞的生长。这些结果表明，MT1-MMP通过切割GDF15而促进肿瘤细胞的增殖，GDF15通过诱导p53和p21合成的激活而下调细胞的增殖。
Growth differentiation factor 15 (GDF15), a transforming growth factor (TGF)-beta superfamily member, has been cloned from a placenta cDNA library as a gene product that has promoted activation of pro-matrix metalloproteinase (MMP)2 mediated by membrane type (MT)1-MMP. Expression of MT1-MMP in HEK293T cells caused cleavage of the GDF15 mature form at N-252-M-253 to produce a 6-kDa C-terminal fragment. Treatment of MCF7 cells with GDF15 induced activation of p53 and enhanced expression of p21, which was abrogated by MT1-MMP expression. GDF15 mRNA synthesis was also shown to be induced by treatment of cells with GDF15. Treatment of MCF7 cells with GDF15 caused suppression of cell proliferation. However, proliferation of MCF7 cells transfected with the MT1-MMP gene was not affected by GDF15 treatment, but was suppressed in the presence of the MMP inhibitor BB94. HT1080 cells transfected with the GDF15 gene, which endogenously express MT1-MMP, synthesize a high-level GDF15 precursor form and a low-level mature form, and treatment of cells with BB94 enhanced production of the GDF15 mature form. Consistent with GDF15 production, HT1080 cells transfected with the GDF15 gene proliferated almost equally with control cells, and addition of BB94 effectively suppressed growth of HT1080 cells transfected with the GDF15 gene concomitant with the accumulation of the GDF15 mature form, but not control cells. These results suggest that MT1-MMP contributes to tumor cell proliferation through the cleavage of GDF15, which down-regulates cell proliferation by inducing activation of p53 and p21 synthesis.