Tissue inhibitor of metalloproteinase-1 promotes hematopoietic differentiation via caspase-3 upstream the MEKK1/MEK6/p38alpha pathway.
Besides its matrix metalloproteinases inhibitory activity, TIMP-1 exhibits other biological activities such as cell survival and proliferation. The intracellular signalling pathway elicited by TIMP-1 begins to be elucidated. We have shown previously that the caspase-3 and the p38alpha MAP kinase were activated during TIMP-1-induced UT-7 cells erythroid differentiation. In this study, we demonstrated that TIMP-1 differentiating effect can be extended to the IL-3-dependent myeloid murine 32D cell line and human erythroid progenitors derived from cord blood CD34(+) cells. By performing small interfering RNA transfection and using chemical inhibitors, we evidenced that caspase-3 was involved in TIMP-1 differentiating effect. We then identified the MEKK1 kinase as a caspase-3 substrate and demonstrated that the MEKK1/MEK6/p38alpha pathway was activated downstream the caspase-3 in TIMP-1-induced hematopoietic differentiation.
Dassé
E
E
Laboratoire de Biochimie, CNRS 6198, IFR 53 Biomolécules, UFR Sciences Exactes et Naturelles, BP 1039, Université de Reims Champagne Ardenne, Reims, France.
Bridoux
L
L
Baranek
T
T
Lambert
E
E
Salesse
S
S
Sowa
M L
ML
Martiny
L
L
Trentesaux
C
C
Petitfrère
E
E
D015703:Antigens, CD / Q000502:physiology; D018952:Antigens, CD34 / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*
D015703:Antigens, CD; D018952:Antigens, CD34; D034741:RNA, Small Interfering; D019715:Tissue Inhibitor of Metalloproteinase-1; D048308:Mitogen-Activated Protein Kinase 14; D048728:MAP Kinase Kinase Kinase 1; D048669:MAP Kinase Kinase 6; D053148:Caspase 3