Cleavage of growth differentiation factor 15 (GDF15) by membrane type 1-matrix metalloproteinase abrogates GDF15-mediated suppression of tumor cell growth.
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.
Abd El-Aziz
Shaban H
SH
Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan.
Endo
Yoshio
Y
Miyamaori
Hisashi
H
Takino
Takahisa
T
Sato
Hiroshi
H
D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D055436:Growth Differentiation Factor 15; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D006131:Growth Inhibitors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D053511:Matrix Metalloproteinase 14